Magnetic Resonance Imaging Study on the Physical Stability of Menthol and Diphenhydramine Cream for the Treatment of Chronic Kidney Disease-Associated Pruritus

Abstract

A cream that contains menthol and diphenhydramine is widely prepared in hospital pharmacies and prescribed to patients for the treatment of pruritus associated with chronic kidney disease. However, there is a serious concern regarding its physical stability; therefore, we investigated this issue using magnetic resonance imaging (MRI). For a sample preparation, a menthol-containing ethanol solution was mixed with a commercial diphenhydramine cream. After storage for 7 d at 40°C, substantial phase separation into two distinct layers (upper and lower layers) was observed in the sample. This study further examined the components of the phase-separated layers using magnetic resonance (MR) spectroscopy and chemical shift selective images, and it was verified that the upper layer consisted of packed oil droplet layers, whereas the lower was an aqueous phase. Subsequently, the time-dependent phase separation of the sample at different temperatures was investigated. From the MR images, including a T 2 relaxation time map and apparent diffusion coefficient maps, it was obvious that the phase separation developed further with increasing temperature; the most substantial phase separation was observed from the sample stored at 40°C, while no phase separation was detected at 25°C. In the final phase of this study, we conducted a formulation study and succeeded in improving the cream's physical stability by adding a hydrophilic surfactant to the preparation.

Effect of Surfactants and Thickeners on the Stability of Menthol–Diphenhydramine Cream Identified by Magnetic Resonance Imaging

“…Although the sample stored at 25°C remained stable until the end of the experimental period of two weeks, the samples stored at 30 and 40°C showed obvious phase separation into two distinct layers. In the previous study, 10) we also conducted a component analysis of each phase-separated layer using MR spectroscopy and chemical shift selective images, and it was verified that the upper layer consisted of packed oil droplets (creaming layer), whereas the lower layer was an aqueous phase. The development of phase separation became more obvious with increasing temperature.…”

“…[10][11][12][13] MRI is a popular molecular imaging method using the principle of NMR. 14) As well as nondestructive monitoring of a sample, it enables visualization of the molecular mobility of a sample using magnetic resonance (MR) parameters.…”

“…Based on the MR techniques, we previously investigated the stability of menthol-diphenhydramine creams in detail. 10) They were stored at different temperatures (25, 30, 40°C), and then time-course monitoring with MRI was performed. According to a T 2 mapping, we successfully characterized the phase-separation behaviors of the samples.…”

“…Further details of the sample preparation were described in full previously. 10) For improvement of the formulation, surfactants and thickeners were added to the standard cream. Additional surfactants were added by dissolving them in the menthol-containing ethanol solution, and the final concentration in the creams was adjusted to 2.0 wt%.…”

“…From our previous studies, it has been confirmed that T 2 maps are a powerful tool to detect phase separation in pharmaceutical emulsions. 10,11,15) As far as oil-in-water (o/w)-type emulsion is concerned, the state of water is substantially changed depending on its surroundings.…”