Impact of Drug Hydrophilicity on Transdermal Delivery by Nanoemulsions

Abstract

Background/Objectives: Nanoemulsions (NEs) are a promising platform for transdermal drug delivery (TDD); however, how the polarity of the active pharmaceutical ingredient (API) influences NE structure–performance relationships remains insufficiently understood. This study aimed to systematically compare the transdermal delivery behavior of a hydrophilic API, salbutamol hemisulphate (log P ≈ 0.1), and a lipophilic API, ibuprofen (log P ≈ 3.3), incorporated into compositionally matched nanoemulsion systems.

Methods: Kolliphor EL–based NEs were prepared using identical excipients, with systematic variation of oil, surfactant, and water ratios. Thirty-six formulations were produced for each API. Physical stability, droplet size, and viscosity were characterized, and in vitro skin permeation studies were conducted using excised mouse skin. Flux and cumulative permeation were quantified, and statistical analyses were performed to identify key compositional drivers of permeation.

Results: Ibuprofen-containing NEs exhibited superior physical stability compared to salbutamol formulations, likely due to interfacial interactions that imparted surfactant-like behavior. Both APIs formed nanoscale droplets, with salbutamol formulations ranging from 16 to 507 nm and ibuprofen formulations spanning 12–563 nm, more frequently yielding sub-100 nm droplets. Viscosity values covered broad ranges (3–9532 mPa·s for salbutamol; 13.4–9759 mPa·s for ibuprofen), with salbutamol generating an extended high-viscosity domain at 50% (w/w) surfactant and ibuprofen showing a narrower viscosity maximum at 30–40% surfactant. Salbutamol NEs achieved high fluxes (up to 374 µg/cm²·h) and cumulative permeation of approximately 80% of the applied dose, whereas ibuprofen formulations showed markedly lower fluxes (maximum 32 µg/cm²·h) and cumulative permeation below 6%. High surfactant levels suppressed permeation for both APIs, but the dominant positive drivers differed: balanced oil–water ratios for salbutamol and hydration-dependent diffusional resistance for ibuprofen.

Conclusions: These findings demonstrate that API polarity and interfacial portioning behavior decisively govern NE performance, providing a framework for rational tailoring of oil–surfactant–water ratios to maximize transdermal delivery efficiency.

Introduction

Dermal drug delivery systems (DDDs) have gained significant attention in recent years as a non-invasive alternative to oral and parenteral routes. They encompass both local (dermal) and systemic (transdermal) approaches, aiming to deliver therapeutic agents into or across the skin barrier. They offer numerous advantages, including ease of administration, improved patient compliance, bypassing first-pass metabolism, maintaining steady plasma drug levels, and reducing dosing errors, particularly in vulnerable groups such as pediatric and geriatric patients [1,2,3]. Reflecting this interest, there has been a notable increase in the number of DDD and TDD products introduced into the global pharmaceutical market [4,5].

Despite these benefits, the development of efficient TDDs remains challenging due to the barrier properties of the skin. The stratum corneum (SC), the outermost layer, acts as the main protective shield, consisting of keratinized corneocytes embedded in a dense lipid bilayer (“brick and mortar” structure). While this architecture is critical for defense against environmental insults, it also restricts the penetration of both hydrophilic and lipophilic molecules, thereby limiting drug permeation through or into the skin [5,6,7]. Overcoming the SC barrier is therefore essential for achieving effective systemic delivery through the skin.

Various approaches have been investigated to enhance transdermal permeation, including chemical penetration enhancers, vesicular systems like liposomes, microneedles, and energy-based methods like sonophoresis and electroporation [5,8]. Over the last decade, nano-formulations have emerged as particularly promising strategies. Their nanometric droplet size provides a large surface area for interaction with skin lipids, promotes close contact with the SC, and can enhance local occlusion, indirectly improving skin hydration, temporarily disrupting the barrier, and improving permeability [9,10].

Among nano-formulations, NEs are especially attractive due to their kinetic stability, high-drug-loading capacity, and ease of preparation by both high- and low-energy methods. Unlike microemulsions, NEs typically require lower surfactant concentrations to maintain droplet stability, thereby minimizing potential irritation or toxicity [11,12,13]. Importantly, NEs have demonstrated the capacity to enhance the delivery of both hydrophilic and lipophilic drugs, underlining their broad applicability [14,15].

The physicochemical properties of the API, particularly its hydrophilicity or lipophilicity (log P), have a strong influence on the localization of the drug within the NE and subsequent permeation behavior. Hydrophilic APIs typically reside in the aqueous domains or at the oil–water interface, while lipophilic APIs preferentially partition into the oil phase. These differences shape drug release dynamics, formulation stability, and interactions with the SC [7,16].

For hydrophilic APIs, adequate water mobility within the nanoemulsion and high thermodynamic activity are critical drivers of diffusion. Low-viscosity formulations can further promote rapid transport by facilitating molecular mobility within the vehicle and across the skin barrier [7,17]. The follicular pathway plays a substantial role in their permeation, as demonstrated by studies showing that occlusion of hair follicles markedly reduces the delivery of hydrophilic compounds such as caffeine, with a significant fraction of uptake occurring via this route [18,19].

In contrast, lipophilic APIs primarily rely on direct interactions with SC lipids for their transport. Surfactants and co-surfactants within the nanoemulsion can disrupt the tightly packed lipid bilayers, increase membrane fluidity, and facilitate the drug partitioning into the skin [20,21]. Lipophilic APIs thus predominantly exploit intercellular or transcellular lipid pathways, with nano-sized oil droplets further enhancing permeation by increasing surface contact and prolonging interaction with the SC. While follicular transport has also been suggested as a possible route for lipophilic compounds, its overall contribution to systemic delivery remains uncertain and context-dependent [7,22].

Together, these mechanistic differences underscore that while surfactant-induced barrier disruption supports permeation for both hydrophilic and lipophilic APIs, the dominant pathways differ; hydrophilic APIs benefit from aqueous domains and follicular penetration, whereas lipophilic APIs take advantage of lipid bilayer disruption and oil droplet partitioning.

Ultimately, the enhancement of transdermal delivery by NEs results from a multifactorial interplay rather than a single mechanism. Droplet size, viscosity, partition coefficient, and interactions with skin lipids all contribute to permeation behavior, and the outcome depends on both the physicochemical nature of the API and the composition of the NE [7]. The wide variability of these factors, combined with differences in skin models, makes it unlikely that a universal mechanistic framework can be established. Instead, tailored formulation design, adapted to the specific properties of the drug, remains essential to optimize performance.

In this context, salbutamol hemisulphate and ibuprofen were selected as representative hydrophilic and lipophilic APIs, respectively, to investigate how polarity influences NE behavior and transdermal performance. Salbutamol, a selective β2-adrenergic receptor agonist, has a low log P (0.11), low molecular weight (288 Da), and poor oral bioavailability, making it a suitable candidate for TDD [23,24]. Ibuprofen, in contrast, is a widely used non-steroidal anti-inflammatory drug (NSAID) with a higher log P (≈3.3), already marketed in various dermal formulations, making it a benchmark lipophilic compound for evaluating NE-mediated skin permeation [25,26].

Despite the growing interest in NE-based drug delivery, direct comparative studies using a consistent formulation platform to evaluate the role of API polarity remain scarce. By formulating both APIs into Kolliphor EL-based NEs with identical excipients and systematically varied compositions, this study enables a direct comparison of how drug polarity influences nanoemulsion behavior and skin permeation efficiency.

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Materials

Salbutamol hemisulfate (>98.0% purity) was purchased from TCI Chemicals (Tokyo, Japan). Ibuprofen (pharmaceutical grade) was obtained from BASF (Ludwigshafen, Germany). The oil phase used in all formulations was medium-chain triglycerides (MCT; Miglyol® 812, Ph. Eur. grade, supplied by Caelo, Hilden, Germany). Kolliphor® EL (Ph. Eur. Macrogolglycerol Ricinoleate/USP–NF Polyoxyl 35 Castor Oil) was generously provided by BASF (Ludwigshafen, Germany). Soybean-derived lecithin (≥97% purity) was obtained from Carl Roth (Karlsruhe, Germany). All other chemicals were of analytical grade.

Esen Yigit, Ö.; Lamprecht, A. Impact of Drug Hydrophilicity on Transdermal Delivery by Nanoemulsions. Pharmaceutics 2026, 18, 220. https://doi.org/10.3390/pharmaceutics18020220