Reverse Micelles: The Gateway for Oral (Poly)Peptide Delivery

Abstract

Reverse micelles (RM) have played a central role in biotechnology, yet their pharmaceutical use has been constrained by instability, high water content and non-biocompatible surfactants. Classical wet RM (wRM) contain a discrete aqueous core whose size and solubilization behavior are governed by surfactant packing, hydration level and physicochemical properties of the hydrophobic phase. Although these systems provided insights into nanoconfined environments, their sensitivity to dilution and environment has limited translation into drug delivery. Recent developments renew interest in dry RM (dRM), which reduce internal water to below 1% and rely mainly on interfacial rather than bulk-like water domains, with electrostatic and non-covalent interactions contributing to stabilization of highly hydrophilic (poly)peptides (pP).

dRMs expand the application space for pP therapeutics, supporting delivery routes requiring low hydration and robust microenvironments. This review integrates RM architecture and outlines performance criteria for oral pP delivery, including high loading capacity, increased pP lipophilicity, protection from enzymatic degradation, enhanced epithelial permeation and favorable safety. In vivo studies demonstrate that dRM achieve comparable or improved oral bioavailability relative to hydrophobic ion pairs or wRM in selected systems, underscoring why RM remain relevant and why maintaining minimal hydration and formulation flexibility are central to unlocking their therapeutic potential.

Introduction

The concept of reverse micelles (RM) has its origins in mid-20th-century studies on water-in-oil emulsions. Early work by Schulman and co-workers in the 1950s first demonstrated that surfactants in nonpolar media can organize into nanoscale structures capable of hosting confined water pools [1]. Subsequent physicochemical investigations by Scriven, Davis, Nagarajan and Ruckenstein (1960s–1970s) established RM as discrete supramolecular assemblies governed by interfacial packing and limited hydration [2-4]. A major conceptual consolidation occurred in the 1970s–1980s through the work of Paolo L. Luisi, who introduced RM as controllable nanoconfined aqueous environments and demonstrated their utility as model systems for enzymatic catalysis, solubilization phenomena and interfacial organization [5].

Building on these early conceptual foundations, modern RM are understood as nanoscale assemblies of amphiphilic surfactants in nonpolar media that create a confined polar interior capable of solubilizing water and hydrophilic molecules. Their internal organization is governed by hydration level, typically expressed as the molar water-to-surfactant ratio (w0), which dictates the balance between interfacial and bulk-like water states and thereby controls solute mobility, reaction kinetics and biomolecular stability [6-9]. RM differ from water-in-oil (w/o) microemulsions not in an absolute structural sense, but through an operational definition governed primarily by the molar water-to-surfactant ratio (w0 = [H2O] /[Surfactant]) and the resulting physicochemical state of the encapsulated water. Building on the classical descriptions by Luisi and Straub as well as Maitra, RM represent molecularly discrete, curvature-dominated assemblies constrained by low hydration (w0 ≲ 10−15). In this regime, water molecules are strictly nanoconfined and predominantly bound to the surfactant headgroups, lacking true bulk-like properties [10, 11].

In contrast, w/o microemulsions represent thermodynamically stable swollen phases—strictly distinct from kinetically stable nanoemulsions—occurring at higher w0 values, accommodating larger aqueous cores characterized by a distinct central region of free, bulk-like water [10, 12, 13]. The high interfacial curvature and minimal hydration of RM thus position them as the limiting case at the high-curvature end of the w/o structural spectrum—a concept explicitly framed by Ruckenstein and Nagarajan [14]. By defining the boundary operationally via w0 and the emergence of core bulk water, the structural continuity between wet RM and conventional w/o microemulsions is reconciled with their distinct local physicochemical environments.

Classical wet reverse micelles (wRM) contain a discrete aqueous core and exhibit rapid fusion–fission dynamics that facilitate equilibration but also render them structurally fragile. Their strong dependence on water content, temperature and dilution, together with the frequent use of non-biocompatible surfactants, has historically limited their translation into pharmaceutical delivery systems [8, 15]. Under gastrointestinal conditions, wRM are prone to dilution-induced disassembly or uncontrolled restructuring, compromising their ability to retain polar payloads.

Dry reverse micelles (dRM) represent a functional evolution of RM architecture. By reducing internal water to below an operational threshold of 1%, dRM—as observed in systems like Span-based formulations—eliminate bulk-like aqueous domains while retaining a polar interfacial microenvironment capable of stabilizing hydrophilic or charged species [16-19]. Suppressed internal mobility and reduced fusion–fission dynamics confer markedly improved robustness under pharmaceutically relevant conditions, including resistance to dilution and compatibility with lipid-based formulations. These features make dRM particularly attractive for the delivery of highly hydrophilic compounds—especially (poly)peptides (pP)—that remain challenging to incorporate into conventional lipid carriers. Acting as nanoscopic interfacial mediators, dRM enable the assembly of polar molecules with lipophilic matrices without chemical modification [17-19].

Despite growing interest in dRM, the field remains fragmented: fundamental studies on RM structure and dynamics often remain disconnected from applied formulation research and the transition from wRM to dRM has not been systematically conceptualized in terms of thermodynamics, interfacial organization or behavior under dynamic physiological conditions. A unified physicochemical framework is therefore needed to connect classical RM principles with emerging formulation strategies and translational requirements.

This review aims to provide such a framework by integrating fundamental concepts of RM and dRM organization with preparation as well as characterization strategies and by evaluating their performance within lipid-based delivery platforms under biorelevant conditions. In doing so, it highlights the potential of dRM as next-generation tools for the oral delivery of pP and other hydrophilic therapeutics.

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Excipients mentioned in the study: Labrafac MC60, Maisine CC, Labrafac Lipophile WL 1349, Brij 93, Kolliphor RH40

M. Ramona Schmidt, M. Lena Ebert, and A. Bernkop-Schnürch, “ Reverse Micelles: The Gateway for Oral (Poly)Peptide Delivery.” Small (2026): e76409. https://doi.org/10.1002/smll.76409