Development of sarpogrelate external preparation for intractable pain control. I. Pre-formulation study on application of modified beta-cyclodextrins.

To optimize the formulation of in-hospital sarpogrelate (SPG) preparation for external use, various cyclodextrins (CDs) were investigated for their ability to improve the aqueous solubility and chemical stability of SPG. Although hydrolysis of SPG was markedly accelerated at above pH 7.0 in aqueous solution, the addition of modified beta-CD resulted in suppressed SPG hydrolysis. Addition of sulfobutylether-beta-CD (SBE-beta-CD, Captisol had the most significant stabilization effect. Phase solubility diagram and (1)H-NMR analyses indicated that dimethyl-beta-CD and SBE-beta-CD formed significantly stable inclusion complexes with SPG in aqueous solution, thereby contributing to both the increased solubility and chemical stabilization of SPG. In terms of the clinical safety of CD derivatives, SBE-beta-CD was determined to be the most suitable solubilizing agent for external SPG preparation.

Formulation study of intravesical oxybutynin instillation solution with enhanced retention in bladder.

A formulation study of intravesical oxybutynin (OB) preparations was carried out in order to improve the effectiveness in intravesical instillation therapy for spastic neurogenetic bladder. Sodium hyaluronate (HYA) was introduced to enhance the muco-adhesiveness of the instillation preparation, and the physicochemical properties of the OB formulation were evaluated in comparison with a conventional formulation containing hydroxypropylcellulose (HPC). The viscous properties and in vitro adhesiveness increased with the amount of the polymeric additives, and retention properties of OB in rabbit bladder were comparable after addition of 0.4% HYA and 1.0% HPC. HYA was able to enhance the intravesical retention properties of OB instillation solution to a lesser degree than HPC, it seemed to be a useful additive in the OB instillation due to its safety and mucosal-protective effect.

[Evidence-based quality management of clinical formulations: determination of expiration date of powdered medicine prepared by grinding tablets].

Beraprost sodium (BPS) is often used for pediatric patients with pulmonary hypertension. The purpose of this study was to determine the expiration date of the powdered medicine prepared by grinding tablets. In the present study, the hygroscopicity and stability of the beraprost tablet (DORNER tablet), ground Dorner tablet and powder formulation (Dorner powder) consisting of the ground DORNER tablet and lactose (EFC lactose) were investigated after storage at various relative humidities (RHs) and light exposures. While the DORNER tablets and ground DORNER tablets were found to adsorb significant amounts of water vapor at an RHs of greater than 51.0%, Dorner powder scarcely adsorbed water. The stability of BPS in the Dorner powder decreased after storage under 3000 lux for 90 days. From these results, the expiration date and storage conditions of Dorner powder were determined to "90 days without exposure to light." We also investigated the stability of BPS in solutions of various pH values on the assumption that Dorner powder may be given to pediatric patients after dissolving in soft drinks. Because BPS degraded significantly below pH 2, pharmacists should alert patients not to take Dorner powder with acidic soft drinks.

Dual effect of saikogenin D: in vitro inhibition of prostaglandin E2 production and elevation of intracellular free Ca2+ concentration in C6 rat glioma cells.

To clarify the pharmacological profile of saikogenin D, we examined the effect of saikogenin D on prostaglandin E2 (PGE2) production and intracellular free Ca2+ concentration ([Ca2+]i) in C6 rat glioma cells. Saikogenin D (1-20 microM) inhibited PGE2 production induced by the Ca2+ ionophore A23187 in a concentration-dependent manner with the IC50 of about 3 microM. Saikogenin D did not affect the conversion of arachidonic acid into PGE2 in microsomal preparations. On the other hand, saikogenin D elevated [Ca2+]i in a concentration-dependent manner (10-100 microM) with the EC50 value of about 35 microM in the presence or absence of extracellular Ca2+. These results suggest that saikogenin D possesses a dual effect: an inhibition of A23187-induced PGE2 production without a direct inhibition of cyclooxygenase activity; and an elevation of [Ca2+]i that is attributed to Ca2+ release from intracellular stores.

Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells.

Baicalein is a flavonoid derived from the Scutellaria root. In investigations of the inhibitors of prostaglandin synthesis in C6 rat glioma cells, we found that baicalein had a potent inhibitory activity on prostaglandin synthesis induced by either histamine or A23187, a Ca(2+) ionophore. Baicalein inhibited histamine- or A23187-induced phosphorylation of p42/p44 extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), which causes the phosphorylation of cytosolic phospholipase A(2) (PLA(2)). Baicalein also inhibited the phosphorylation of MAPK kinase-1 (MEK-1) induced by histamine or A23187 in the cells. To examine the site of action of baicalein, MEK-1 and Raf-1 were prepared by immunoprecipitation with anti-MEK-1 and anti-Raf-1 antibodies, respectively. Baicalein inhibited the phosphorylation of exogenous MEK-1 by Raf-1 under cell-free conditions, while it did not change the phosphorylation of exogenous p42 MAPK by MEK-1. These results imply that baicalein inhibits the ERK/MAPK cascade, acting on the phosphorylation of MEK-1 by Raf-1.