Permeation Enhancer in Microemulsions and Microemulsion-Based Gels: A Comparison of Diethylene Glycol Monoethyl Ether and Oleyl Alcohol

Abstract

Microemulsions have been commonly used with various permeation enhancers to improve permeability through the skin. The purpose of this study was to compare the release and permeation ability of two commonly used permeation enhancers—diethylene glycol monoethyl ether (DGME) and oleyl alcohol—by the changes in oil composition, the addition of a gelling agent, and water content using ibuprofen as a model drug. Four microemulsions were formulated, selection was based on ternary phase diagrams, and physicochemical properties were evaluated. The release and permeation of the microemulsion formulations were performed in vitro by Franz cell studies on a regenerated cellulose membrane and a Strat-M^® membrane, respectively, and the amount of ibuprofen permeated and released was analyzed by high-performance liquid chromatography (HPLC). All four microemulsions were compatible with the skin pH, and the average pH ranged from 4.9 to 5.6. The average droplet size of the microemulsions ranged from 119.8 to 153.3 nm. Drug release was significantly the highest from the gel-based microemulsions (59% and 64%, p < 0.05). However, there was a fourfold difference in drug permeation from these gels—a significantly higher permeation from the microemulsion-gel containing oleic acid and oleyl alcohol compared to the DGME formulation. These results indicated that the microemulsion-gel with oleyl alcohol as the permeation enhancer could be a preferable formulation approach for the topical administration of ibuprofen. These results highlight the need for optimization of the microemulsion formulation to confirm the permeation-enhancing effects of chosen permeation enhancers despite being a well-known permeation enhancer.

Introduction

The skin is a selectively permeable membrane in which the stratum corneum (SC) layer provides the barrier function [1]. The entry of molecules through the skin is controlled by the stratum corneum (SC) allowing selective passage of the molecules with the molecular weight usually below 500 Daltons and lipophilicity with a log Poctanol/water partition coefficient ranging from 1 to 3 through the skin [2]. Other parameters influencing permeability of the skin are solubility, hydrogen bonding, and melting point [3,4,5]. Various approaches, including the utilization of physical and chemical techniques, have been performed to reduce the limitations in permeation provided by the SC and enhance dermal drug delivery. Examples of physical approaches include iontophoresis [6], microneedles [7], and sonophoresis [8,9].
A commonly used chemical approach is the use of microemulsion formulations with various permeation enhancers. Microemulsions are single-phase, transparent dispersion systems of water, oil, and surfactant, mostly in combination with fixed ratios of co-surfactant(s). Microemulsions are thermodynamically stable liquid systems compared to other emulsion systems [10]. The formation of microemulsions largely depends on the properties of the constituents used and the ratios of the oil–surfactant–water constituents. Thus, the microemulsion formation usually falls in limited concentration ranges, and the region of microemulsion formation is generally represented in pseudo-ternary phase diagrams. The pseudo-ternary phase diagrams show the regions of microemulsion formation as ratios of water, oil, and a predetermined combination of surfactant and co-surfactant ratios. The internal structure of a microemulsion affects the diffusivity of the oil and water phases [11] and thus the diffusion of a drug from the phases. An increase in the permeation capacity of oil components, surfactants, and penetration enhancers can be achieved by the following mechanisms: (1) disruptions of the lipid components of the SC layer, or (2) increasing the partition coefficient of the drug in the skin compared to the vehicle, i.e., increased solubility in the skin. [12].

Various approaches for dermal delivery of ibuprofen include microemulsions [13], microemulsions-based gels [14], hydrogel-based microemulsions systems [15], and emulgels [16]. The increment in drug loading capacity due to the amphiphilic interface and an area for enhancement of drug solubility offers advantage to microemulsions [12,17,18,19]. The reduction in droplet size and hence the increased surface area–volume ratio can lead to increased drug permeation from microemulsions. Additionally, optimization of the surfactant–co-surfactant ratio (S/Co-S) [17,20,21] is a key factor to be considered in microemulsion development.

The composition of the oil phase influences parameters including drug release, drug solubility in the microemulsion, and skin permeation [22]. The type of gelling agent has shown significant differences in the permeation, where xanthan gum was a suitable gelling agent compared to carbomer 940 in the preparation of ibuprofen microemulsion, showing higher stability [23]. However, carbomer gel showed higher permeation compared to xanthan gel in a tretinoin microemulsion [24]. The permeation effect of oleic acid was significantly improved with a decreased amount of oleic acid, a well-known permeation enhancer [25].

In this study, we compared the release and permeation effects of two commonly used permeation enhancers, DGME and oleyl alcohol, with and without the presence of a gelling agent (carbomer 940). While carbomer 940 has been studied in combination with different permeation enhancers in ibuprofen formulations, the specific comparison of DGME + carbomer 940 with oleyl alcohol + carbomer 940 has not been previously reported. This is an important distinction, as both DGME and oleyl alcohol are widely used permeation enhancers in commercial formulations. Although the properties of these enhancers have been individually reported, the data were obtained under varying conditions and therefore the comparisons may not accurately reflect the overall understanding of the permeation ability. The investigation into the effects of gelling agents on the release and permeation of microemulsions containing oleyl alcohol and DGME is valuable because their effect can vary depending on the permeation enhancers, and the specific composition of the formulation. By systematically evaluating the interplay between these formulation components, we provide novel insights that could guide the rational design of ibuprofen delivery systems. Although the focus was on comparing microemulsions and microemulsion-based gels using ibuprofen, our findings could be beneficial for other topical drugs, including topical NSAIDs, in formulation optimization to facilitate drug permeation through the skin barrier.

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Materials

Ibuprofen 25 received from BASF (Ludwigshafen, Germany) was used. Triethanolamine and Carbomer 940 were purchased from Making Cosmetics (Snoqualmie, WA, USA). Oleyl alcohol and oleic acid were provided by Croda (Newark, NJ, USA), Tween® 80 (Polysorbate 80) was purchased from Fisher Scientific (Hampton, NJ, USA) and Transcutol® (diethylene glycol monoethyl ether) was received from Gattefosse (Lyon, France). Other chemicals used were of analytical grade, which were used without additional purification. The deionized water used was from the Health Science Campus of the University of Toledo.

Pandey, S.; Baki, G. Permeation Enhancer in Microemulsions and Microemulsion-Based Gels: A Comparison of Diethylene Glycol Monoethyl Ether and Oleyl Alcohol. Gels 2025, 11, 41. https://doi.org/10.3390/gels11010041

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