Impact of the State of Water on the Dispersion Stability of a Skin Cream Formulation Elucidated by Magnetic Resonance Techniques

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: )mentioning

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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“…Both MR parameters are known to be sensitive to the state of water. 2,[12][13][14] Here, the basic states of water are known as free and bound water. They differ in terms of molecular mobility.…”

Section: Resultsmentioning

confidence: 99%

“…[2][3][4] MRI is one of the most popular molecular imaging methods; it permits the nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, MRI can visualize the state of water in a sample by using magnetic resonance (MR) parameters.…”

mentioning

confidence: 99%

“…Water in pharmaceutical emulsions can exist in various states depending on its particular location and microenvironment. 2) Once creaming has occurred in emulsions, the layer of close-packed droplets (creaming layer) shows a different state of water from the aqueous phase. This is because the molecular mobility of water in the creaming layer is tightly restricted by surfactants on the oil droplets.…”

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confidence: 99%

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Self-organizing Map Analysis for Understanding Comprehensive Relationships between Formulation Variables, State of Water, and the Physical Stability of Pharmaceutical Emulsions

Hasegawa

Horita³

et al. 2015

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The physical stability of pharmaceutical emulsions is an important quality attribute to be considered. To obtain a better understanding of this issue, this study investigated the contribution of the state of water to the physical stability of pharmaceutical emulsions. The key technology to evaluate the state of water was magnetic resonance imaging (MRI). For sample preparation, model emulsions with different formulation variables (surfactant content, water content, and hydrophilic-lipophilic balance) were prepared. The T 1 relaxation time, diffusion coefficient, and viscosity were measured as physical properties. The physical stability of the samples was evaluated using apparent diffusion coefficient maps acquired by MRI. Data analysis of the observed data was performed using the nonlinear response surface method and Kohonen's self-organizing map (SOM). It was determined that, depending on the formulation variables, the state of water was substantially changed and it played a significant role in the physical stability. SOM analysis successfully classified the conditions of formulation variables into four distinct clusters in terms of the similarity of the physical properties of the resultant emulsions, and then clarified the characteristics of the stable emulsions. This study provided us with a comprehensive understanding of the formulation variables, physical properties, and stability concerning the preparation of the model emulsion.Key words pharmaceutical emulsion; magnetic resonance imaging; physical stability; T 1 relaxation time; diffusion coefficient Oil-in-water type emulsions are widely used for various semisolid topical dosage forms. Pharmaceutical emulsions are less greasy than ointments, they are easier to apply and can be easily washed off from the skin surface; thus, they are highly acceptable to patients. 1) For the development of pharmaceutical emulsions, physical stability is a very important quality attribute to be considered. This is because emulsions are thermodynamically unstable by nature. In general, the destabilization processes of emulsions are classified into four distinct processes: creaming, flocculation, coalescence, and Ostwald ripening.1) Coalescence and Ostwald ripening are the most serious types of destabilization, whereas creaming and flocculation are subtle destabilization processes.We have been investigating the physical stability of pharmaceutical emulsions using magnetic resonance imaging (MRI).2-4) MRI is one of the most popular molecular imaging methods; it permits the nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, MRI can visualize the state of water in a sample by using magnetic resonance (MR) parameters. In a previous study, we established a new method to monitor destabilization processes of pharmaceutical emulsions.4) The key technology is the visualization of the state of water. Water in pharmaceutical emulsions can exist in various states depending on its particular location and microenvironment.2) Once cre...

“…Recently, we have applied magnetic resonance imaging (MRI) to evaluate the physical stability of pharmaceutical emulsions. 7,8) MRI is one of the most popular molecular imaging methods, and enables nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, it can visualize the molecular mobility of a sample using magnetic resonance (MR) parameters.…”

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confidence: 99%

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

Funatani

Yokawa³

et al. 2015

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A mixed preparation consisting of a water-in-oil emulsion-type moisturizing cream and a steroid ointment is frequently prescribed for the treatment of atopic dermatitis. We have investigated the compatibility of moisturizing creams and ointments because there are concerns regarding the physical stability of these mixed preparations. The key technology used in this study was magnetic resonance imaging (MRI). A commercial moisturizing cream and white petrolatum or clobetasone butyrate (CLB) ointment samples were mixed in a weight ratio of 1 : 1. A centrifugation test protocol (20000 g for 3 min) was implemented to accelerate the destabilization processes in the samples. After centrifugation, the mixed preparations separated into three distinct layers (upper, middle, and lower), while no phase separation was observed using moisturizing cream alone. The phase separation was monitored using chemical shift selective images of water and oil and quantitative T 2 maps. In addition, MR and near-infrared spectroscopy were employed for component analysis of each phase-separated layer. Collectively, it was confirmed that the lower layer contained water, oils, and organic solvent, while the upper and middle layers were composed solely of oils. Furthermore, this study investigated the distribution of CLB in the phase-separated samples and showed that a heterogeneous distribution existed. From our results, it was confirmed that the mixed preparation became unstable because of the incompatibility of the moisturizing cream and ointment.Key words mixed external preparation; magnetic resonance (MR) spectroscopy; MR imaging (MRI); chemical shift selective image; quantitative T 2 map; clobetasone butyrate ointment In the treatment of atopic dermatitis, moisture retention of the skin is regarded as being important, in addition to steroid therapy. From this perspective, a combination therapy containing a steroid ointment and a moisturizing cream is widely prescribed to patients. To make the application of these preparations easier, pharmacists frequently mix moisturizing cream with a steroid ointment when preparing the prescription.Nowadays, numerous moisturizing creams are available from several manufacturers. Water-in-oil (w/o) emulsion-type creams are regarded as being the most suitable for preparing mixed preparations because the oily continuous phase is assumed to be miscible with the ointment. However, it is doubtful whether these pharmaceutical emulsions remain stable after being mixed with other preparations. Their formulations were not designed under the assumption that they would be mixed with other preparations, and by mixing these formulations with other preparations the optimal hydrophile-lipophile balance (HLB) and surfactant content necessary to maintain a stable dispersion state may be changed. Four distinct destabilization processes of emulsions are known: creaming, flocculation, coalescence, and Ostwald ripening.