Sachihiko Numajiri

The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid

The preparation of mefenamic acid (MH)-alkanolamine [monoethanolamine, diethanolamine, triethanolamine and propanolamine] complexes was attempted to increase the transdermal flux of MH. A lipophilic enhancer system consisting of isopropyl myristate (IPM) and ethanol (9:1; EI system) produced a marked enhancement of MH flux from the alkanolamine complexes through hairless rat skin membrane. Among the alkanolamines examined, the propanolamine complex had the greatest enhancing effect on the permeation of MH. The observed permeation enhancement of MH-alkanolamine complexes by the EI system was explained by an analysis based on a two-layer diffusion model. The stratum corneum immersed in IPM forms a continuous phase of vehicle and stratum corneum and, from the phase, ethanol transport the MH-alkanolamine complexes to the epidermis and dermis, and the complexes, which are more water soluble than MH, exhibit increased partition into the epidermis and dermis, as the flux increases.

Analysis of skin permeation-enhancing mechanism of iontophoresis using hydrodynamic pore theory

The effects of constant DC iontophoresis (0-1.5 mA/0.966 cm(2)) on the permeation of three hydrophilic compounds, antipyrine (ANP, M.W. 188.23), sucrose (SR, M.W. 342.30) and 1-kestose (KT, M.W. 506.73), through excised hairless rat skin were evaluated using hydrodynamic pore theory. The electro-osmotic flow caused by iontophoresis was measured using deuterium oxide (D(2)O). The penetration-enhancing mechanism of iontophoresis was found to increase solvent flow through electro-osmosis and pore enlargement and/or new pore production in the skin barrier, together with enhancement of electrochemical potential difference across the skin. These effects were closely related to the strength of the current applied. The electro-osmotic flow of D(2)O (J(D(2)O)) greatly enhanced the skin permeation clearance of all hydrophilic penetrants (CL(drug)). Pore production was classified into reversible and irreversible processes, which resulted from lower (0-0.5 mA/0.966 cm(2)) and higher (0.5-1. 5 mA/0.966 cm(2)) currents, respectively. Thus, the enhancing effects of iontophoresis on skin permeation of nonionic hydrophilic compounds can be explained by increase in pore size and higher solvent flow.

Non-invasive sampling of lactic acid ions by iontophoresis using chloride ion in the body as an internal standard

Non-invasive sampling of lactic acid, as a model endogenous compound, through hairless rat skin by iontophoresis was investigated using a two-chamber iontophoretic diffusion cell equipped with platinum electrodes and a pulse depolarization iontophoretic system. Chloride ion in the body was used as an internal standard. First, an in vitro experiment on the permeation of lactate and chloride ions through hairless rat skin was carried out to determine the flux ratio of these ions. The cathode side of the cell (dermis side) was filled with physiological saline containing lactic acid (0.5556, 1.111, 1.667 or 2.222 mmol cm-3) and the anode side (epidermis side) with phosphate buffer (pH 7.4). The amount of lactate and chloride ion permeated from the dermis side to the epidermis side through the skin at a constant current of 3.0 mA was determined using an automatic lactic acid analyser and high-performance ion chromatography, respectively. For construction of a calibration curve of lactic acid in the dermis side, the ionic mobility ratio of lactic acid/chloride ion (UCl/Ulac) was determined using a computer simulation program from the flux ratio of lactic acid and chloride ion and the applied concentration of lactic acid in the dermis side. Second, an in vitro non-invasive sampling experiment of lactic acid through rat skin was carried out at a constant current of 2.0 or 3.0 mA and 2.222 or 1.111 mmol cm-3 of lactic acid in the dermis side, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of depolarizing and direct current systems on iontophoretic enhancement of transport of sodium benzoate through human and hairless rat skin

Abstract— A direct current (DC) system and a pulsed depolarization (PD) system were evaluated for their iontophoretic permeation of sodium benzoate, as a model drug, through hairless rat and human skin. Approximately the same initial permeation of sodium benzoate through the hairless rat skin was obtained at 0·1 mA for the DC device and at 3·0 mA for the PD device. Study of the drugs permeation was performed using a two‐chamber iontophoretic diffusion cell, over two cycles of three successive on‐off experimental conditions [stage I (off) 0–4 h, II (on) 4–6 h, III (off) 6–10 h, saline washing 10–24 h, IV (off) 24–28 h, V (on) 28–30 h and VI (off) 30–34 h]. Skin permeation rate during stage IV of the iontophoresis as compared with the control group through hairless rat or human skin for the DC system was 2–4 times that in stage I, whereas in the same stage using the PD system it was almost the same as in stage I. Impedance of skin decreased during the application of either system (stage II); however, the value significantly recovered during stage III only in the case of the PD system use on human skin. Histological observation revealed no tissue alteration in the hairless rat skin after using either system. When the DC or PD system was applied to volunteers, the minimum current density producing pain was 0·016 or 2·7 mA cm−2, respectively. These results suggested that the PD system was more appropriate for iontophoresis application than the DC system from the point of view of skin permeability of the drug and effect on the skin.

Synergistic Effects of Iontophoresis and Jet Injector Pretreatment on the In-vitro Skin Permeation of Diclofenac and Angiotensin II

A non‐needle syringe (jet injector) was utilized to increase skin permeation of drugs by iontophoresis. Briefly, physiological saline was initially flushed by the injector to make a pore in the stratum corneum of excised hairless rat skin, and the iontophoretic skin permeation of two model compounds, sodium diclofenac and angiotensin II, was followed using a 2‐chamber diffusion cell. Constant voltage and constant current iontophoresis treatments were evaluated.

Identification and Characteristics of Time-Related Shifts in Suicide-Related Event Frequency During Smoking Cessation Treatment with Varenicline

Objectives: To survey time-related shifts in number of suicide-related events (SRE) during smoking cessation treatment with varenicline (VAR) in cases from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), as well as the characteristics of these shifts. Methods: We isolated cases from the FAERS database involving VAR usage where SRE was reported as an adverse event (SRE+/VAR+ case) and established a histogram of SRE+/VAR+ case numbers per week. Furthermore, we focused on “cases reporting specific adverse events prior to drug usage start” using X-bar and R chart concepts. We also attempted to exclude the influence of smoking history from the created histogram. Moreover, we constructed a histogram on central nervous system adverse events, which were frequently seen during VAR usage. Results: By removing the effects of smoking history, SRE onset signals were detected over a long period from the start of VAR use. However, expression signals for nausea and abnormal dreams were detected only in the early VAR administration period. Discussion: These results suggest that VAR use-induced SRE is expressed over a long timeframe from the start of treatment. Additionally, the period of SRE expression signal detection was longer than that of the other central nervous system adverse events (nausea and abnormal dreams). Therefore, SRE onset must be carefully monitored during smoking cessation treatment with VAR over the entire treatment period.

Comparison of the Benefit Feeling Rate Based on the Sho of OTC Kakkonto, Cold Remedy and Cold Remedy with Kakkonto Combination Product

Kakkonto (KK), a traditional Japanese Kampo formulation for cold and flu, is generally sold as an OTC pharmaceuticals used for self-medication. Kampo formulations should be used according to the Sho-symptoms of Kampo medicine. These symptoms refer to the subjective symptoms themselves. Although with OTC pharmaceuticals, this is often not the case. We surveyed the relationship of agreement of Sho with the benefit feeling rate (BFR) of patients who took KK (n=555), cold remedies with KK (CK, n=315), and general cold remedies (GC, n=539) using internet research. BFR of a faster recovery was greater in participants who took the medication early and who had confidence in their physical strength in all treatment groups. BFR was significantly higher in the GC group than in the KK group for patients with headache, runny nose, blocked nose, sneezing, and cough. BFR was also significantly higher in the GC group than in the CK group for headache (males) and cough (females). BFR was the highest in the KK group for stiff shoulders. All cold remedies were more effective when taken early, and the larger the number of Sho that a patient had, the greater the BFR increased. Therefore, a cold remedy is expected to be most effective when there are many cold symptoms and when it is taken at an early stage of the common cold.

Comparison of Drug Release Characteristics between Brand Name and Generic Cataplasms Using Artificial Sweat as Testing Medium

The drug release and swelling characteristics of cataplasms may be evaluated using artificial sweat. In our study, these characteristics were compared among brand name and generic cataplasms containing nonsteroidal anti-inflammatory drugs (NSAIDs ; indomethacin (IM) (8 products), ketoprofen (KP) (7 products) and flurbiprofen (FP) (4 products)) using artificial sweat and the apparatus described in JP 14 Dissolution Test Method 2. For cataplasms containing IM and FP, the degree of swelling of generic products was less than that of brand name products but there was no significant difference in release rate. On the other hand, for KP-containing cataplasms, disintegration of the base material was observed for three of the four generic products tested, and all four had higher release rates than the brand name products. Thus, the drug release testing method used in the present study showed that the release and swelling characteristics differed between brand name and generic cataplasms and we felt that it was a useful way of evaluating their quality.