Influence of Lipid Matrix Composition on the Intestinal Permeation of Curcumin-Loaded Lipid Nanoparticles

Abstract

Background: Lipid nanoparticles are widely investigated as oral drug delivery systems, but their intestinal performance remains difficult to predict based only on physicochemical properties. This study aimed to elucidate how the lipid matrix composition influences the intestinal permeation of curcumin from lipid nanoparticles.

Methods: Curcumin-loaded nanoemulsions, nanostructured lipid carriers with defined solid-to-liquid lipid ratios, and solid lipid nanoparticles were prepared by high-pressure homogenization. All formulations were characterized with respect to particle size, polydispersity index, and zeta potential before and after simulated intestinal pre-incubation in a simplified SDS-containing intestinal fluid. Intestinal permeation was evaluated ex vivo using porcine gut tissue by analysis of semi-quantitative fluorescence-based permeation readouts (ART) and mean permeation depth (MPD) after 30 and 60 min.

Results: All formulations maintained stable physicochemical properties with particle sizes around 200 nm and negative zeta potentials; pre-incubation increased the negativity of the zeta potential but left particle size unchanged. Despite similar attributes, the formulations differed in intestinal curcumin permeation based on time and composition. At 30 min, nanoemulsions and mixed nanostructured lipid carriers achieved the highest performance. By 60 min, lipid carriers with more liquid lipid significantly increased both the fluorescence intensity and the depth of curcumin permeation, while other systems showed little further improvement.

Conclusions: The intestinal permeation of drug from lipid nanoparticles is governed by the lipid matrix architecture and its interaction with the hydrated intestinal environment, which together affect drug-release kinetics and the ability to sustain a trans-epithelial concentration gradient over time. Thus, optimizing oral lipid nanoparticles requires time-resolved, biologically relevant models rather than physicochemical characterization alone, consistent with observed similar matrix-driven effects in dermal delivery systems.

Introduction

Oral drug delivery remains the most convenient and preferred route of drug administration for patients; nevertheless, inadequate and highly variable bioavailability continues to present significant challenges to the clinical development of numerous drug candidates, particularly those with poor water solubility [1,2]. In addition to drug solubility, these obstacles are attributable to a complex interaction of physiological, biochemical and anatomical factors within the gastrointestinal (GI) tract, such as enzymatic degradation, fluctuating pH levels, limited epithelial permeability, efflux mechanisms and first-pass metabolism [2]. Consequently, a substantial proportion of orally administered drugs—especially Biopharmaceutics Classification System (BCS) Class II and IV compounds such as curcumin—demonstrate insufficient and unpredictable absorption profiles [3,4].

These limitations can compromise therapeutic efficacy and complicate dose optimization, particularly when sustained systemic exposure or local intestinal effects are required [5]. Therefore, effective formulation strategies must not only enhance solubility but also control drug release, intestinal permeation and barrier interactions.

Formulation optimization is a key strategy to improve drug delivery, bioavailability, therapeutic efficacy and safety. In this context, nanocarrier-based systems have gained increasing relevance for oral administration [2,6,7]. Nanoparticles—typically defined as particles ranging from 1 nm to several hundred nanometers—can encapsulate or bind active pharmaceutical ingredients within their core, matrix, or at their surface. Due to their high surface-area-to-volume ratio, these systems facilitate efficient drug loading and promote improved interactions with biological barriers [8]. Additionally, nanoparticulate drug delivery platforms exhibit advantageous pharmacokinetic profiles, including prolonged circulation time, extended half-life, reduced clearance and increased mean residence time [9]. They may also enhance drug uptake in specific intestinal regions or cell populations through several processes, such as size- and charge-dependent interactions with mucus and epithelial surfaces or through active ligand-mediated receptor targeting [6,10,11].

Lipid nanoparticles (LNPs) have emerged as prominent nanocarrier systems in recent decades, with notable independent contributions from Gasco as well as Müller and Lucks [7,12]. The primary categories of LNPs are solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs were developed to address the limitations associated with traditional colloidal carriers, such as emulsions, liposomes and polymeric nanoparticles, by providing enhanced physical stability, controlled drug release, and capabilities for targeted drug delivery [13,14]. Nevertheless, the highly crystalline lipid matrix structure of SLNs poses challenges, including restricted drug loading capacity and increased risk of drug expulsion during storage resulting from polymorphic lipid transitions [15,16].

NLCs were developed to overcome these limitations by incorporating liquid lipids into a solid lipid matrix [13]. This deliberate disruption of crystal order leads to greater imperfections in the lipid matrix, which enhances drug loading capacity and reduces drug leakage during storage. The inclusion of liquid lipids is believed to create nanocompartments within the solid phase, thereby stabilizing the internal structure and limiting changes in lipid crystallinity over time. Consequently, NLCs provide improved physical stability, decreased drug expulsion, and expanded applicability for both lipophilic and hydrophilic drugs. NLCs have demonstrated versatility across multiple administration routes, including oral, parenteral, pulmonary, ophthalmic, dermal and transdermal delivery [17,18,19,20]. For oral administration, lipid-based systems such as self-emulsifying drug delivery systems (SEDDSs/SMEDDSs), nanoemulsions, SLNs, and NLCs have been widely investigated to improve the bioavailability of poorly soluble drugs by enhancing solubilization, promoting intestinal lymphatic transport and limiting pre-absorptive elimination processes [6,11,21]. Biorelevant digestion and lipolysis models, together with cell-based systems, organoids and in vivo pharmacokinetic studies, have shown that the formulation composition, digestion kinetics, matrix-dependent release, and barrier interactions are assumed to influence supersaturation, precipitation, micellar incorporation and absorption [6,10,20,22]. Thus, the internal matrix architecture and drug distribution within the lipid phase may be regarded as important contributors to oral biopharmaceutical performance, complementing standard physicochemical parameters [6,23].

Although lipid nanoparticle (LNP)-based drug delivery systems show considerable promise, their rational optimization remains challenging. Controlled modification of the lipid matrix to enhance biopharmaceutical efficacy is only feasible if the relationship between the matrix composition and biological performance is clearly understood.

To address this question, we previously conducted a dermal penetration study in which the influence of the lipid matrix composition on biopharmaceutical performance was systematically investigated, showing that an increased solid lipid content led to enhanced long-term dermal penetration compared with nanoemulsions and oil-rich formulations [20]. By consistently employing identical lipid excipients, defined solid-to-liquid lipid ratios and comparable production parameters, we were able to directly compare different lipid nanoparticle types—nanoemulsions, SLNs and NLCs—within an ex vivo porcine skin model [20].

Curcumin was selected as a model compound because it is a natural polyphenolic constituent of Curcuma longa with pronounced antioxidant and other biological activities, yet its clinical use is severely limited by extremely low aqueous solubility, poor chemical stability, inadequate tissue distribution and low oral bioavailability [4,24]. These drawbacks make curcumin an ideal probe to study formulation-driven improvements in intestinal permeation and absorption. Lipid nanoparticles, in turn, represent a promising strategy to overcome these limitations and enhance the oral bioavailability of curcumin.

The aim of this study was to determine whether lipid matrix-dependent performance trends previously observed during dermal penetration are conserved under intestinal barrier conditions. For this purpose, curcumin-loaded lipid nanoparticles with identical lipid compositions and production parameters were evaluated in an ex vivo porcine intestinal permeation model to investigate if formulation-related effects can be distinguished from tissue-specific microenvironmental influences [25].

By comparing and evaluating formulation physicochemical properties alongside semi-quantitative permeation metrics, this study aimed to explore possible structure–performance relationships for curcumin-loaded lipid nanoparticles and to assess whether matrix-dependent trends observed in dermal models may also provide insights into intestinal permeation, which could support the future development of oral lipid nanoparticle formulations.

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Materials

Curcumin (Curcuma longa extract containing 80% curcumin) was selected as a model drug to represent BCS-Class IV compounds (low solubility and low permeability) and was obtained from Receptura Apotheke (Cornelius-Apothekenbetriebs-OHG, Frankfurt, Germany). Cetyl palmitate 15 (CP) served as the solid lipid and Miglyol® 812 (medium-chain triglycerides) as the liquid lipid, and both were supplied by Caesar & Loretz GmbH (Hilden, Germany). Plantacare® 818 (BASF AG, Ludwigshafen, Germany), a C8–C16 alkyl polyglucoside, was used as a surfactant to stabilize the lipid nanoparticles. Purified water produced freshly by a PURELAB Flex 2 water purification system (ELGA LabWater, Veolia Water Technologies GmbH, Celle, Germany) was used as the dispersion medium for all samples.

These formulations, comprising the same solid lipid, liquid lipid, and surfactant, were intentionally replicated from our previous dermal penetration study to allow direct comparison of matrix-dependent effects across skin and intestinal barriers without altering the formulation composition [20].

Khan, A.S.; Müller, D.; Keck, C.M. Influence of Lipid Matrix Composition on the Intestinal Permeation of Curcumin-Loaded Lipid Nanoparticles. Pharmaceutics 2026, 18, 1024. https://doi.org/10.3390/pharmaceutics18081024

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