Formulation of poorly water-soluble drugs in lipid nanocarriers: a suitable approach for taste masking or bitter-taste enhancing?

Abstract

The taste of a drug formulation, especially of orodispersible and liquid dosage forms, is of crucial importance due to its direct contact with the human taste buds. In order to achieve high patient acceptance with these formulations, drugs with an unpleasant, predominantly bitter taste have to be masked. One strategy for masking taste particularly suitable for lipophilic drugs is to dissolve the drug molecules in lipid carrier systems, such as nanoemulsions. Although this strategy has often proven effective as a formulation strategy for improving bioavailability and masking an unpleasant taste, our study indicates that embedding the three poorly water-soluble model drugs fenofibrate, simvastatin, and naproxen in nanoemulsions led to newly created or increased bitterness compared to the non-formulated drug powders. We proved this using both an analytical taste sensor system, specifically an electronic tongue (e-tongue), and a sensory study with a human taste panel. Hereby, complete agreement between the e-tongue measurements and the sensory study was found despite the non-ionic character of fenofibrate and simvastatin. We hypothesize that the changed bitter taste impressions were due to the location of the drug molecules at the oil/water interfaces, which resulted in an increased bitter taste intensity and prolonged duration of the bitter taste. In summary, the study shows that incorporating drugs into lipid nanocarriers tended to worsen the taste rather than mask it.

Introduction

The development of patient-centric dosage forms, especially in geriatric and pediatric populations, has become increasingly important over the last decade. In addition to adjusting the individual drug dose for each patient, consideration should also be given to providing a suitable dosage form, as this can have a significant impact on the patient compliance (Menditto et al., 2020, Stegemann et al., 2022). For vulnerable groups, swallowing a monolithic solid dosage form such as a tablet or capsule can be a major challenge (Schiele et al., 2013). One way to overcome this issue is to formulate orodispersible dosage forms that combine the advantages of solid dosage forms and liquid formulations (Douroumis, 2007). Although these dosage forms disintegrate directly in the mouth and can be swallowed with the saliva, there is one point to consider: a possible interaction between the drug molecules and the taste buds that could lead to an unpleasant taste experience.

The taste of drugs can range from neutral to very unpleasant, with the majority of these substances having an unacceptable taste. Bitter tastes, in particular, are perceived as very disagreeable by patients (Mennella et al., 2013, Nasr et al., 2022). To ensure that drugs with unpleasant tastes are still well accepted, a suitable taste-masking strategy is essential. The most common and most simple method of masking an unpleasant taste is to add sweeteners or flavors to the formulation (Beck et al., 2014, Entrekin and Becker, 1954). However, adding large amounts of sweeteners is not always appropriate, while a strong bitter taste in particular cannot always be masked by flavors (Mennella and Beauchamp, 2008). Another technology used for taste masking involves physically preventing interaction between the drug and the tongue by applying a barrier (Coupland and Hayes, 2014, Douroumis, 2011). While excipients such as polymers or cyclodextrins are often mentioned in the literature (Steiner et al., 2024), lipids can also be used for taste masking of drug substances (Immohr et al., 2017). It has been reported that they are particularly beneficial when the bitter molecules are lipophilic, as they reduce the concentration of the drug in the aqueous phase (Coupland and Hayes, 2014, Tenney et al., 2023). In addition, the use of lipids can further increase the oral bioavailability of the substances when they are dissolved in the lipophilic carrier system (Quodbach et al., 2025).

Several lipid-based formulations have already been used for taste masking, including liposomes, solid lipid nanoparticles, lipid (nano)emulsions, and self-nanoemulsifying drug delivery systems (SNEDDS) (Nasr et al., 2022, Rao et al., 2019). While emulsions especially represent a promising strategy for the formulation of poorly water-soluble drugs, their taste-masking effect would be an advantageous side effect for oral drug formulations. Recent studies have shown that an approach for taste masking could be to combine a bitter drug such as efavirenz (Rao et al., 2019) and paracetamol (Hasan et al., 2015) with a SNEDDS formulation, a sweetener, and aqueous flavorings. Qi et al. indicated that no additional additives are required when masking the taste of ibuprofen using an emulsion. They dissolved the drug in a mixture of orange peel oil and corn oil and demonstrated a taste-masking effect in human subjects and rats, among others (Qi et al., 2021). Similar results were obtained in a study by Bennett et al., in which they masked the taste of ibuprofen with various dairy products. They concluded that as fat content increases, the drug selectively passes into the fat phase, reducing interactions with sensory receptors and decreasing aversive sensations (Bennett et al., 2012). Taking into account other taste experiences, particularly in food studies, it has been shown that reducing bitterness by adding oil could result in an increase of the intensity of salty, sweet, sour and umami flavors (Metcalf and Vickers, 2002).

The most direct method for evaluating whether a bitter taste can be successfully masked is to perform a sensory evaluation using trained panelists. This scientific analytical evaluation has long been applied and is well established in food science for both bitter substances (Ferrer-Gallego et al., 2014, Guinard et al., 2007) and food products (Oladokun et al., 2017, Sokolowsky and Fischer, 2012). The so-called time-intensity evaluation method thereby allows a focused assessment of the bitterness over a defined time period, with trained participants rating the intensity continuously. This allows for a quantitative description of taste perception over time with the study design controlling for inter-individual variability to isolate product-related effects (Wang et al., 2024). Parameters like the maximum intensity, time to start, or duration of taste event enable continuous monitoring and thus evaluation of changes in the taste experience caused by taste-masking approaches (Cliff and Heymann, 1993). Particularly for dispersed systems, where it is difficult to assess the drug concentration in the different phases, this scientific sensory approach allows for quantifying taste-masking effects.

Another objective approach to quantify the bitter taste of a dispersed system are electronic taste sensor arrays, such as electronic tongues. Furthermore, these systems are often considered more ethically acceptable (Steiner et al., 2024). Although literature discusses that the active ingredients should apparently have ionic properties in order to achieve reliable e-tongue signals (Oman et al., 2007, Woertz et al., 2011), initial findings performed in our study indicated different results for such drugs, which we aimed to prove by the human sensory approach.

The present study therefore investigates the taste of three poorly water-soluble model drugs, namely fenofibrate, naproxen, and simvastatin, incorporated in a lipidic nanocarrier. Fenofibrate and simvastatin were selected as non-ionic model drugs that had previously been reported to require taste masking for orally disintegrating tablets (Kumar et al., 2009) or have a bitter taste (Datir et al., 2020). Naproxen is an anionic drug also known for its bitter and unpleasant taste (Stange et al., 2014). These model drugs were used to investigate the possibility of masking their bitterness by incorporating the drug molecules into different lipid nanoemulsions made of various oils. First, a formulation screening was carried out to identify an appropriate formulation for the nanoemulsions and suitable oils for further processing. The selected formulations were then investigated in more detail using in vitro and in vivo taste assessment methods: e-tongue measurements and a sensory study of the bitter taste using time-intensity analysis. While the results of the e-tongue measurements were initially discussed individually, correlations between the e-tongue response and the human taste perception were subsequently identified. These results provided valuable insights into the taste profiles of the formulations studied.

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Materials

Micronized fenofibrate (Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China: kind gift), simvastatin, and naproxen (both Fagron GmbH, Glinde, Germany) were used as poorly water-soluble model drugs. Selected physicochemical properties of the drugs are summarized in Table 1. For preparation of lipid nanoemulsions different oils were used: medium chain triglycerides (MCT), refined soybean oil, refined sunflower oil, refined peanut oil (all Gustav Heess, Leonberg, Germany; kind gift), native linseed oil (Caelo, Hilden, Germany), and tricaprylin (Tokyo Chemical Industry, Tokyo, Japan). The composition of the oils is displayed in Table 2. The emulsions were stabilized using polyvinyl alcohol (PVA; Parteck MXP 4-88, Merck, Darmstadt, Germany; kind gift), poloxamer 188 (P188; Lutrol F68, BASF SE, Ludwigshafen, Germany), and sodium dodecyl sulfate (SDS; Carl Roth GmbH, Karlsruhe, Germany). Furthermore, hydroxypropyl-β-cyclodextrin (HP-β-CD; Wacker Chemie AG, München, Germany) was used. All formulations were prepared with purified water.

Julia Scholten, Miriam Pein-Hackelbusch, Martina Sokolowsky, Julien Park, Denise Steiner, Formulation of poorly water-soluble drugs in lipid nanocarriers: a suitable approach for taste masking or bitter-taste enhancing?, International Journal of Pharmaceutics, Volume 699, 2026, 126993, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126993.

Read also our introduction article on Taste Masking here: