Prediction of Plasma Concentration of GTS-21 in Hairless Rats Following Monolithic Transdermal Delivery.

Abstract

One of the most characteristic features of transdermal therapeutic systems (TTS) is a constant long-term delivery bypassing the first pass metabolism.1) This reduces the risk of side effects and prolongs the interval of administration. However, recent study has revealed that the constant therapeutic plasma concentration is not always effective for drugs such as nitroglycerin.2) It is also necessary to utilize the drug more effectively so that the dose is minimized. Under these circumstances, the rate of penetration of the skin may decrease with time because of the decreased partitioning on the skin surface.In this study, we have proposed a simple approach to predict the plasma concentration following monolithic transdermal delivery with low loading dose. The in vivo/in vitro correlation of penetration profiles of the model drug, GTS-21, [3][4][5] have also been investigated on the basis of bi-layer skin pharmacokinetic model. MATERIALS AND METHODSMaterials GTS-21 [(E)-3-(2,4-dimethoxybenzylidine)-3,4,5,6-tetrahydro-2,3Ј-bipyridine dihydrochloride] was supplied by Kobe Natural Products and Chemicals (Kobe, Japan). Polyethylene glycol 400, isopropyl myristate and sodium azide were purchased from Wako Pure Chemical Industries (Osaka, Japan). Other reagents and solvents were commercially available and of reagent grade or better.Preparation of GTS-21 Free-Base TTS GTS-21 freebase was prepared from GTS-21 by extraction with ethyl acetate at alkaline pH. The prepared compound was identified as free-base by NMR analysis. GTS-21 free-base was mixed with isopropyl myristate, toluene and silicone elastomer BIO-PSA Q7-4501 (Dow Corning Asia, Tokyo, Japan). This mixture was spread on a polyester release liner by a Baker type applicator (Tester Sangyo, Tokyo, Japan) and dried in an oven at 115°C for 1 min. Subsequently, the adhesive layer on the release liner was laminated with a polyethylene backing. The thickness of the adhesive layer was adjusted to between 50 and 60 mm. The content of GTS-21 free-base was controlled at 0.172 mg/cm 2 . The monolithic TTS devices used for GTS-21 free-base were cut to for each study.In Vitro Skin Permeation Experiment Excised abdominal skin from male WBN hairless rats (200-220 g, Ishikawa laboratory animal, Saitama, Japan) was used. The abdominal skin was shaven with a BS 5 585 shaver (Brown, Kanagawa, Japan) before the experiment. Either intact skin or stripped skin was mounted on a vertical diffusion cell (Ishii Shoten, Tokyo, Japan). The stripped skin was prepared by stripping the stratum corneum with cellophane tape (Nichiban, Tokyo, Japan) 20 times before excision. The receptor fluid, a 40% (v/v) aqueous solution of polyethylene glycol 400, was maintained at 38.0°C. GTS-21 free-base TTS (2.83 cm 2 ) was placed on the skin and the system was fixed with a cell cap and clamp. The receptor fluid (200 ml) was sampled periodically and the drug concentration was analyzed immediately by HPLC. The assay conditions were as follows: sample size, 20 ml; column, Develosil ODS-HG-5 (Nomura Chemical, ...

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

“…Sato et al 31) and Kawamata and Tojo. 32) tried to predict the plasma concentration of nicorandil or GTS-21 after topical application of nicorandil (gel) or GTS-21 (TTS) in hairless rats from the in vitro intact hairless rat skin permeation paramateres. However, they reported that some differences were observed between the observed (in vivo) and the calculated plasma concentration of drugs.…”

“…However, they reported that some differences were observed between the observed (in vivo) and the calculated plasma concentration of drugs. 31,32) Thus, the blood concentration of drugs after topical application in rat cannot be completely predicted by the in vitro skin permeation studies using the intact rat skins. Therefore, split skin, which is thicker than the epidermis, was selected for our in vitro permeation studies.…”

Impact of Humidity on In Vitro Human Skin Permeation Experiments for Predicting In Vivo Permeability

“…Franz‐type diffusion cells have been widely used for in vitro permeation experiments . A vertical Franz‐type diffusion cell has also been used for evaluating TTSs, and the diffusion cell is maintained at a constant temperature using a recirculation device or incubator.…”

Evaluation of the Predicted Time–Concentration Profile of Serum Tulobuterol in Human after Transdermal Application

“…6,7) Further, the predicted concentration-time profiles were evaluated by being compared with the experimental data. [8][9][10] Such predicted profiles were usually obtained from the simplified mathematical models where the skin penetration rate is regarded as a constant because the general governing formula for skin penetration is complex and difficult to use and the pharmacokinetic profiles of commercially-available TTSs are often predictable by such simplified models. When the flux is constant during TTS application, the terms for skin penetration rate of the mass-balance equations can be considered as a constant, and the term for drug release is omitted.…”

“…The other example is the prediction of the pharmacokinetic profile for a matrix-type TTS, where the tendency of attenuation of blood concentrations was expressed in the ratio of flux obtained from the in vitro skin penetration experiment. 8) The ratio defines arbitrary flux/ steady-state flux. However, this method is not precise because the in vivo absorption rate usually does not correspond to the in vitro flux exactly.…”