Purpose: Cold flow (CF) occurs in plasters and patches because a plastic adhesive migrates beyond the edge of the preparation or through the slit in the release liner. Excessive CF can adversely affect the quality of the product, for example, reduced dose and adhesion failure. Although the “Cold Flow Test” has been listed as one of the specific tests for transdermal delivery systems in the general requirements of USP 41 Chapter <3>, no compendial testing method has been established. In the present study, we applied a method to forcibly induce CF phenomenon by loading a weight on a sample. The applicability of the method and effects of excipients on the CF were investigated using transdermal patches of tulobuterol approved in Japan.
Methods: One brand-name and 15 generic tulobuterol patches with various combinations of excipients used in the adhesive were studied. The patches were punched out into circular samples using a belt punch (⌀12 mm). The sample was sandwiched between a two-fold fluoropolymer-coated polyethylene film (3M Scotchpak® 9755; inner side coated, 55×75 mm) after peeling off the release liner, taking care to ensure no wrinkles. Each sample was then stored at 40°C/75% RH while applying to it a 2 kg force provided by a stainless-steel block (50×50×101 mm). After storage for 5 days, the samples were removed from the chamber and photographed from above in macro mode to quantify the area of the adhesive oozing out beyond the edge using image analysis software (Lumina Vision, MITANI Corp.). The degree of CF was expressed as the percentage of the CF area to the total area (sum of the initial backing film and the oozing adhesive area).
Results: The degree of CF varied widely among the products, ranging from 3.2±1.2 to 51.0±1.7%, while the variation in the same product was rather small with the standard deviation less than 4.5 (n=4–6). The 16 products studied were grouped into eight patterns based on the combination of excipients used in the adhesive, and patches having the same combination exhibited almost the same degree of CF even for different brands. The results indicated that the CF properties are strongly related to the composition of the adhesive. In this study, we applied the method originally reported by Krishnaiah et al. [J. Pharm. Sci., 103:1433-1442 (2014)] with small modifications. The applicability of the method to both the preparations whose adhesive highly and moderately migrates was confirmed. Furthermore, prior storage at 50°C/60% RH, whereby the adhesive was intentionally deteriorated, decreased the degree of CF in some preparations. It suggests that the influence of high temperature and humidity on the adhesive varies according to the combination of excipients.
Conclusion: The testing method evaluated in this study was able to characterize the CF properties of each preparation, as well as detect the change in quality of the adhesive. It is thus applicable for quality control testing of transdermal patches.
Hitomi Kanno– National Institute of Health Sciences
Yukio Aso– National Institute of Health Sciences, Kanagawa
Ken-ichi Izutsu– National Institute of Health Sciences, Kanagawa
Yukihiro Goda– National Institute of Health Sciences, Kanagawa