Magnetic Resonance Imaging of the Phase Separation in Mixed Preparations of Moisturizing Cream and Steroid Ointment after Centrifugation

Machida

Yokawa³

et al. 2015

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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.

Section: Resultsmentioning

confidence: 99%

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

Machida

Yokawa³

et al. 2015

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“…[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.…”

Section: )mentioning

confidence: 99%

“…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.…”

Section: Effects Of Surfactants On the Emulsion Stability Of The Creammentioning

confidence: 99%

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

Yokokawa

Utsumi

et al. 2016

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A menthol-diphenhydramine cream is prepared in hospital pharmacies and then prescribed to patients for the treatment of pruritus associated with chronic kidney disease. The purpose of this study is to design a stable formulation without any concern about phase separation during its clinical use on patients. As a preventive measure against phase separation, various surfactants and thickeners were incorporated into the creams. The test creams were stored at 40°C, and then their phase separation behaviors were monitored. The key technology was magnetic resonance imaging T 2 mapping. From the T 2 maps, some surfactants showed a certain stabilizing effect. In addition, the data analysis using Kohonen's self-organizing map revealed that hydrophilic-lipophilic balance of the surfactant is an important factor for the stabilizing effects of the surfactants. However, as a whole, the effect of surfactant was not sufficient to improve completely the low stability. By contrast, the creams were significantly stabilized by addition of thickeners. In particular, the stabilizing effect of carbomer Hiviswako105 ® (H105) was very high; no phase separation was observed from the cream containing H105 even after 30 d storage at 40°C. This study also verified the combination effect of surfactants and thickeners on the improvement of the emulsion stability. In conclusion, we successfully established a stable formulation of menthol-diphenhydramine cream.

“…10) These observations suggest that the stability of a preparation is diminished by mixing creams and ointments. It is therefore necessary to determine objectively and scientifically the types of blending variations that are induced by mixing different * To whom correspondence should be addressed.…”

mentioning

confidence: 99%

Analysis of the Stability of External-Application Dermatologic Preparations: Consideration from Rheological Measurements

Yamamoto

Kumetani

et al. 2016

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The present study examined the stability of mixtures of various combinations of moisturizers, water in oil (w/o)-type or oil in water (o/w)-type cream preparations containing heparinoids, and steroidal ointments or creams (o/w-type) frequently used in children. Centrifugation at room temperature led to separation of mixtures of w/o-type moisturizers and steroidal ointments into three layers. Polarized microscopic observations, near-infrared (NIR) spectroscopy, and dye-based analyses revealed the presence of oily components in the upper and middle layers and water-soluble components in the lower layer. Separation into three layers upon centrifugation was also observed for mixtures of o/w-type moisturizers and steroidal ointments. In contrast, neither the o/w-type moisturizer and steroidal cream nor the w/o-type moisturizer and steroidal cream mixtures separated into layers upon centrifugation. Consideration of the characteristics of each preparation is necessary when mixing external-application dermatologic preparations. Centrifugation at 4°C did not result in layer separation of the w/o-type moisturizer and steroidal ointment mixture, suggesting that cold storage of such mixtures provides superior stability compared with room temperature storage. However, despite no obvious layer separation, the NIR spectra indicated that water movement was induced within the mixture. These results clearly indicate that methods such as NIR spectroscopy are useful for early determinations of the stability of mixed external-application dermatologic preparations.