Takayama Kozo

Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

Abstract The effect of temperature on the enhancement action of d -limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d -limonene in the hydrogel. The steady-state permeability coefficients ( P ) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d -limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d -limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d -limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d -limonene, may effectively change the dense barrier structure of the stratum corneum.

Influence of novel percutaneous absorption enhancers, cyclohexanone and piperidone derivatives, on histopathology of rat skin

Abstract The influences of 2- n -octylcyclohexanone, 2- tert -butylcyclohexanone, 1- n -dodecylpiperidone, 1- n -cetylpiperidone and Azone ® on the histopathology of rat skins which were treated with gel ointments containing 1–10% of these enhancers were investigated in order to gain insight into the skin damage caused by the enhancer and its irritation activity. All of the enhancers at each concentration caused epidermal liquefaction and collagen fiber swelling to some extent. The skin damage by the enhancer increased with increasing concentration of enhancer. At 3% concentration of these enhancers, certain recoverabilities of damaged skin were observed within 5 days after removing the test ointments. At low concentration (1%), recoverabilities were significantly observed, especially in the cases of 1- n -dodecylpiperidone and Azone®. No direct correlation was found between the permeation enhancement and the skin irritation of the enhancer.

The inactivation process of fibroblast interferon-β in the preparation stage and in rabbit nasal absorption of mixed and freeze-dried powder dosage forms

Abstract The present paper is concerned with a new finding with regard to the inactivation and the nasal bioavailability of IFN-β in two different powder dosage forms, i.e. mixed powder (MP) and freeze-dried powder (FP) dosage forms. The two types of preparations which contained bile salts were prepared. The IFN-β titer was determined by bioassay and enzyme immunoassay (EIA). Employing EIA, it was confirmed that the titers of sample MP and sample FP after preparation were different, while their bioavailabilities in the nasal absorption study were not significantly different. In an attempt to clarify the above result, studies of stability and rabbit nasal absorption of IFN-β were performed, additionally investigating the effects of cryoprotectants for sample FP. As a result, in the case of sample MP, rapid inactivation seemed to take place mainly on the nasal mucosal membrane during the absorption stage, while for sample FP it appears mostly during the preparation stage on freeze-drying. Additionally, the pharmacokinetic behavior of IFN-β was found to differ between both samples.