Design and characterization of propofol lipid nanocapsules: proof of concept for hospital preparation

Abstract

The growing discovery of active pharmaceutical ingredients (APIs), most of which being lipophilic, has led to an equally growing interest in vehicles or carriers for these APIs. Formulation of an injectable drug for intravenous administration is more complex for lipophilic APIs. Therefore, the marketed forms available, i.e. liposomes, nanoemulsions (NEs), or lipid-based nanoparticles, are produced only by the pharmaceutical industry. The ability to produce dispersed lipid nanosystems in the hospital, such as NEs, opens a wide range of possibilities for adapting treatments to specific populations (pediatrics, geriatrics…). It also provides an alternative solution in the event of a shortage of essential marketed drugs. The possibility of developing dispersed nanosystems for intravenous delivery of new lipophilic molecules adapted to the patients opens the field of personalized medicine and hospital clinical trials. The “bench to bedside” approach is particularly interesting for accelerating the development of new therapeutics and providing faster access to patients. Rare diseases, for example, could benefit from this accelerated access to a new treatment.

The model drug propofol (PPF) was selected because of its low aqueous solubility, 154 ± 10 µg/mL (Trapani et al., 1996), and a high lipophilicity, with a calculated logP of approximately 4(Thompson and Goodale, 2000). Given the clinical importance of propofol as a rapid and effective anesthetic (Miner and Burton, 2007), other alternatives have been developed, including the use of prodrugs such as fospropofol (2,6-diisopropylphenoxymethyl phosphate) (Pergolizzi et al., 2011, Zhou et al., 2013). However, it has different pharmacokinetics and a delayed effect (Cohen, 2008). Attempts have also been made to solubilize propofol in liposomes (Jensen et al., 2008), inclusion complexes (Trapani et al., 1996), microemulsions (Date and Nagarsenker, 2008, Li et al., 2012), lipid-based self-nanoemulsifying drug delivery systems (Kazi et al., 2025), and polymeric micelles (Chu et al., 2022, Okasaki et al., 2023, Ravenelle et al., 2008).

However, these preparation methods are complex and, at present, cannot be transferred to hospital production. Several formulation trials are found in the literature (Baker et al., 2005), such as the use of non-aqueous solvents, surfactants such as polyoxyethylenated castor oil (Cremophor® EL) or cyclodextrins (Trapani et al., 1996) showing toxicity and/or biodistribution issues or instability during storage. As a result, only the NE formulations have led to marketed drugs (e.g. Diprivan®, Lipuro®…). NEs remain safe vehicles widely used for over 40 years in parenteral nutrition for intravenous lipid delivery. The advantages of NEs include the ability to formulate lipophilic APIs and improve bioavailability. Those marketed forms are obtained by high-energy methods, such as high-pressure homogenization, for which proof of concept for hospital production of PPF-loading NE was recently established (Cèbe et al., 2023). However, using a high-pressure homogenizer in the hospital environment is not straightforward, with GMP and on-site cleaning issues. In addition, an extemporaneous formulation was proposed by adding propofol directly to a commercialized parenteral nanoemulsion (Rooimans et al., 2023). However, this method is more suited to emergency measures as it is difficult to scale up for routine hospital processes and may present stability issues over time due to the formation of large droplets.

This work aimed to develop a lipid nanocarrier for a reference lipophilic drug, propofol, that could be easily transferred to the hospital environment. For this reason, low-energy processes were considered more suitable. These so-called phase inversion processes have been extensively described in the literature (Feng et al., 2020, Komaiko and McClements, 2016, Perazzo et al., 2015, Roger, 2016, Solans et al., 2016). In this case, the driving force responsible for interface formation is not mechanical but results from spontaneous physicochemical interfacial phenomena. By tuning the affinity of the surfactant for the aqueous or oily phases, the interfacial curvature can be spontaneously changed, inducing an inversion from water-in-oil to oil-in-water (and vice versa). This process is typically achieved using a PEGylated surfactant and modifying the hydration state of the polyethylene glycol (PEG) block.

The spontaneous curvature can be modified by modulating the water composition of the system, known as the phase inversion composition (PIC) process (Roger et al., 2011). In the latter, in the absence of water, the system initially consists of inverted surfactant micelles dispersed in a continuous oil phase with their cores containing the collapsed oil-insoluble PEG chains. When added, water quickly diffuses into the oil and accumulates inside the reverse micelles, causing them to swell. The rapid addition of excess water in the organic phase induces the spontaneous inversion of the water–oil interface, leading to the nucleation of nano-sized oil droplets in a continuous aqueous phase.

The obtained nanodroplets have a “core-shell” structure, consisting of (i) a liquid lipid core and (ii) a dynamically arrested shell composed of the PEGylated surfactant and a lipophilic co-surfactant (Rolley et al., 2021). This lack of dynamics makes them highly stable, even below the critical micellar concentration of the surfactants forming the shell. Due to this high stability, the low-energy NEs are also called lipid nanocapsules (LNCs). With drug delivery applications in mind, LNCs were initially obtained by a modified PIC process combining temperature ramps and abrupt cooling with cold water dilution (Heurtault et al., 2002). Their size can be easily tuned from 25 nm to about 150 nm by playing with the relative amount of surfactant and oil (Heurtault et al., 2003, Lefebvre et al., 2017, Roger et al., 2009). They are particularly stable to colloidal aggregation due to their relatively small size in combination with their PEGylated shell (McClements, 2012).

To the best of our knowledge, no LNC has been developed with PPF using PIC low-energy method. In addition, PPF was considered as a worst-case lipophilic model drug for developing LNCs because of its required high final concentration at 2% in the formulation leading to high drug-to-lipid ratio. In addition, we aimed to limit the surfactant’s final concentration as much as possible. In this work, the ability of Kolliphor® HS15-based LNCs to encapsulate PPF was investigated. Several compositions, without or with co-surfactant, have been tested. The formulation showing the highest pharmaceutical potential was then fully characterized in terms of particle size and encapsulation efficiency using a range of complementary techniques, including (i) light scattering (single-angle/multi-angle dynamic light scattering and static light scattering), (ii) nanoparticle tracking, (iii) fractionation (asymmetric flow field flow fractionation), and (iv) tangential flow filtration. The marketed product Diprivan® 2% was used as a reference. The potential of the selected formulation for sterilization and its feasibility for microfluidic-scale production were also evaluated.

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Section snippets

Emilie Tireau, Marie Bonnin, Guillaume Lefebvre, Louise Stinat, Etienne Chevremont, David Dallerac, Nolwenn Lautram, Jean-Christophe Gimel, Brice Calvignac, Frederic Lagarce, Sylvie Crauste-Manciet, Design and characterization of propofol lipid nanocapsules: proof of concept for hospital preparation, International Journal of Pharmaceutics, Volume 692, 2026, 126640, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126640.

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