Effect of Penetration Enhancers as Cosurfactants on Transdermal Delivery of Caffeine and Using Microemulsions

Abstract

Transdermal drug delivery offers several advantages over conventional routes. However, its use is limited by the low permeability of the stratum corneum. This limitation is especially significant in the case of hydrophilic drugs such as caffeine. This study explored microemulsion systems to enhance the transdermal delivery of caffeine (CF) using chemical penetration enhancers as cosurfactants. Kolliphor^® PS80 (PS80), Kolliphor^® RH40 (RH40), Kolliphor^® PS20 (PS20), and Kollicream^® OD (OD) were evaluated as cosurfactants for the first time in microemulsion formulations consisting of water, oil, and a fixed surfactant-to-cosurfactant ratio of 4:1 (w/w), with 14% of each cosurfactant incorporated. CF skin permeation from microemulsions was assessed via in vitro permeation studies using Franz diffusion cells and human cadaver skin.

The results showed that OD-based microemulsions achieved approximately 3-fold higher CF skin permeation compared with the control formulation and 1.4–1.6-fold higher permeation compared with formulations containing PS80, RH40, and PS20. Furthermore, CF solubility in the four cosurfactants followed the order: PS20 > RH40 > PS80 > OD. These findings indicate that PS20 provides the highest solubility for CF among the tested cosurfactants. The results also included visual evaluations. No significant changes in appearance or physical properties were observed during the 10-month study. All samples remained clear and stable throughout the testing period. This study uniquely highlights the critical role of cosurfactant selection in optimizing microemulsion-based transdermal delivery systems. This work addresses a previously unexplored aspect, namely, the effect of cosurfactants with different physicochemical properties on the skin permeation of caffeine. The findings provide valuable insight into developing more effective transdermal and topical drug delivery systems.

Introduction

Transdermal drug delivery has gained considerable interest as an alternative to conventional administration routes due to its ability to improve patient compliance, bypass first-pass metabolism, and provide sustained drug release [1]. However, a significant challenge in transdermal delivery is the low permeability of the stratum corneum, the outermost skin layer and a natural barrier to drug penetration [2,3]. To overcome this limitation, researchers have investigated chemical penetration enhancers and advanced delivery systems such as microemulsions [4].

Microemulsions are thermodynamically stable isotropic systems composed of oil, water, and surfactants, offering significant potential for enhancing transdermal drug delivery [5]. Their ability to solubilize both hydrophilic and lipophilic drugs, along with their small droplet size (typically less than 100 nm), facilitates efficient skin permeation. Surfactants and cosurfactants influence skin permeability, drug partitioning, and mobility within the formulation, thereby affecting drug bioavailability [6]. Several studies have demonstrated the effectiveness of microemulsions combined with permeation enhancers for transdermal delivery, including oxcarbazepine, disulfiram and olanzapine [4,7,8]. Additional investigations have reported the role of formulation components and surfactant systems in improving caffeine emulsion stability and skin penetration [9].

Microemulsions are particularly useful for delivering compounds with diverse physicochemical properties, such as caffeine, oil, and surfactant mixtures [7,10]. Surfactant–cosurfactant combinations enhance formulation stability and drug permeation, while hydrophilic lipophilic balance (HLB) plays a critical role in microemulsion formation [11,12]. Cosurfactants improve interfacial film flexibility and reduce repulsive forces, facilitating microemulsion formation and increasing permeability [12].

Caffeine (CF) is widely consumed and could benefit from transdermal delivery due to improved bioavailability and reduced gastrointestinal side effects [13]. However, its hydrophilic nature and low log p value (0.07) hinder skin permeation [14], making it an appropriate model drug for evaluating permeation enhancers [15].

Previous studies have examined formulation variables, skin models, and permeation behavior of caffeine and approached the topic from different angles. For instance, Zhang et al. investigated the effect of varying water and oil ratios on the skin permeation of caffeine, a hydrophilic compound, and compared it to lidocaine, a hydrophobic molecule [15]. Sintov et al. evaluated caffeine’s ability to penetrate the skin of various animals, including rats, rabbits, and pigs, and assessed whether using fresh versus frozen/thawed skin altered permeation results [13]. Limpongsa et al. [16] developed grapefruit oil-based microemulsions for transdermal caffeine delivery, examining the impact of formulation parameters such as grapefruit oil concentration, Tween 20, cosurfactant type and quantity, and caffeine content on both microemulsion properties and skin permeation, using pig ear skin as the model.

In addition, Abd et al. reported that the type of vesicular or colloidal carrier system, including microemulsion-like structures, significantly influences caffeine penetration and deposition in human skin, underscoring the critical role of formulation microstructure in delivery efficiency [17]. Similarly, Todo et al. demonstrated that modifying the microenvironment of caffeine through formulation strategies can markedly enhance its skin permeation, particularly for hydrophilic compounds. Furthermore, Mekarun et al. investigated caffeine-containing emulsified systems and highlighted the importance of surfactant composition, hydrophilic–lipophilic balance (HLB), and oil phase characteristics in determining formulation stability and drug release behavior [18].

More recently, Salimi et al. reported enhanced transfollicular delivery of caffeine using optimized oil-in-water microemulsions, emphasizing the role of formulation design in targeting alternative skin penetration pathways [19]. In agreement with these findings, Bolzinger et al. demonstrated that oil-in-water microemulsions can achieve faster permeation and improved skin retention of caffeine compared to conventional emulsions and gel systems, further highlighting the advantages of microemulsion-based delivery systems [20].

However, this work uniquely focuses on the role of cosurfactant physicochemical characteristics in modulating caffeine permeation. This study evaluates selected solubilizing agents and penetration enhancers through in vitro permeation testing using human cadaver skin, aiming to provide insights into the design of effective topical and transdermal delivery systems for hydrophilic drugs. The present study aims to systematically investigate the role of selected chemical penetration enhancers (PS80, RH40, PS20, and OD) when used as cosurfactants in microemulsion systems for transdermal delivery of caffeine. Beyond formulation development, this work is designed to deepen our understanding of the physicochemical behavior of these excipients, particularly in terms of their solubilization capacity, hydrophilic–lipophilic balance, and interactions within the microemulsion system.

By maintaining constant oil, water, and surfactant composition, this study isolates the contribution of each cosurfactant, enabling a mechanistic evaluation of how their intrinsic properties influence drug solubility, thermodynamic activity, and skin permeation. The primary objective is to compare each formulation to a control system to quantify the extent to which these excipients enhance transdermal delivery, thereby providing insight into their functional role in topical and transdermal applications.

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2. Materials and Methods

Caffeine (CF) was purchased from Sigma Aldrich, St. Louis, MO, USA, and is used as a drug molecule. PS80, PS20, OD, and RH40 were investigated as penetration enhancers and were kindly gifted by BASF Corporation, 500 White Plains Road, Tarrytown, NY, USA. Labrasol^® Caprylocaproyl Polyoxyl-8 glycerides (LS) was gifted by Gattefosse Corporation, Paramus, NJ, USA. HPLC grade methanol, water and Kollicream Isopropyl Myristate (IPM) were gifts from BASF Corporation, 500 White Plains Road, Tarrytown, NY, USA. Phosphate-buffered saline (PBS) was prepared by dissolving one PBS tablet in 100 mL of water. PBS tablets (100 mM) were purchased from MP Biomedicals, Solon, OH, USA. Dermatomed human cadaver 500 µm skin from the posterior torso region of a 63-year-old male was used for the ex vivo permeation study. It was supplied by Science Care Skin Bank, Phoenix, AZ, USA.

Moh’d, H.; Albayati, N.; Virani, A.; Ho, G.; Michniak-Kohn, B. Effect of Penetration Enhancers as Cosurfactants on Transdermal Delivery of Caffeine and Using Microemulsions. J. Pharm. BioTech Ind. 2026, 3, 17. https://doi.org/10.3390/jpbi3030017

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