Abstract
Lipid nanodispersions are a promising formulation strategy for improving the bioavailability of drugs that are poorly water-soluble but highly lipophilic. Since patients prefer solid dosage forms, further processing of the liquid formulations is necessary. In order to expand the range of applications for drugs formulated in lipid nanodispersions, a high lipid content is required in the solid dosage forms. The aim of the current study was to determine the maximum loading capacity of lipid nanoemulsions and nanosuspensions by embedding the dispersions into orodispersible films and lipid-containing powders using spray drying. Atomic force microscopy enabled an assessment of the particle arrangement in the solid dosage forms and identified a stack-like orientation of the platelet-shaped triglyceride particles when embedded in orodispersible films. During the preparation of the powders by spray drying, a random particle arrangement was achieved, which was caused by the melting of the lipid particles during processing. Furthermore, atomic force microscopic images showed that tristearin particles in the metastable α-modification can exist in elongated to platelet-like shape traced back to the particle formulation and preparation process. The highest loading capacity in the solid dosage forms was achieved when the lipid nanodispersions were embedded in a film-forming matrix of PVA, resulting in lipid contents of up to 47 wt.%. Similar high lipid contents were achieved when lactose was used as the matrix material during spray drying.
Introduction
The number of newly developed but poorly water-soluble drug candidates is steadily increasing, with these poor physical properties mainly attributable to high lipophilicity or/and highly stable crystal lattices of the substances (Bergstrom et al., 2016). A lipid-based formulation approach is a particularly promising strategy for drugs with high lipophilicity (Bunjes, 2010, Quodbach et al., 2025). Thereby, a major advantage of lipid nanocarriers is their improved drug safety. This is because the lipids used are physiological and, thus, tolerated by the human organism, furthermore, no toxic co-solvents or pH adjustments are required to improve the solubility of the drug (Lim et al., 2012). The food-effects that frequently occur when poorly water-soluble drugs are administered perorally could also be reduced when these substances were formulated in lipid-based carriers (Vinarov et al., 2021, Feeney et al., 2016). Two carrier systems that are well known in literature are lipid nanoemulsions and lipid nanosuspensions. A difference between them is the physical state of the used lipids, which additionally affects the localization of the embedded drugs. While in emulsions the drug molecules are located both on the surface and in the core of the lipid droplets, often enabling a higher drug load, in suspensions the drug mainly accumulates on the surface of the crystalline solid lipids (Kupetz and Bunjes, 2014). Regardless of the carrier system used, however, further processing into solid dosage forms is advantageous, as these are better accepted by patients than liquid dosage forms (Stewart et al., 2016).
A further processing of the lipid nanodispersions into a solid form aims to maintain the particle sizes of the nanocarriers even after redispersion of the dosage forms in water. Recent studies have shown that this poses a challenge, as lipid nanoemulsions, for example, tend to coalescent easily (Benita and Levy, 1993, Gupta, 2020). Therefore, sufficient stabilization of the droplets and a supportive matrix material to prevent coalescence during processing are essential. It was shown that good particle size preservation can be achieved when the emulsions are embedded in a matrix e.g. by spray drying (Christensen et al., 2001, Steiner et al., 2022), whereas coalescence occurred when the droplets were embedded in a film-forming HPMC matrix to prepare orodispersible films (ODFs) (Steiner et al., 2022). Lipid nanosuspensions are based on crystalline lipid particle that do not coalesce. This makes them a somewhat simpler system when formulations are to be further processed into solid dosage forms. It has been shown that high lipid contents can be achieved in ODFs, although these depended on the type of lipid embedded in the HPMC matrix (Steiner et al., 2021).
In order to improve the usability of these nanocarriers for less potent and higher-dose drugs, high lipid loads of various carrier systems and different types of lipids in solid dosage forms are essential. Visualization of the nanoparticulate dosage forms could be beneficial in order to better understand the embedding of the nanodispersions in solid matrices. Currently, techniques such as scanning electron microscopy (SEM) or transmission electron microscopy (TEM) are the gold standard for nanoparticular systems. Although these techniques can achieve high resolution, they require a vacuum and complex sample preparation. This can lead to artifacts and changes in the original structure of the samples and is also time-consuming and resource-intense (Sitterberg et al., 2010, Ho et al., 2022). Oil-containing nanoemulsions in particular are very challenging to measure, so cryo-electron microcopy often has to be used (Klang et al., 2012). Atomic force microscopy (AFM) is a promising alternative technique for these nanoparticulate formulations. It can be operated under ambient conditions and requires little sample preparation. Recent studies have shown that various types of lipid carrier systems can be successfully visualized using AFM. Since AFM is the only microscopic technique delivering precise z-axis data, the gradual scanning of the sample with a cantilever can provide additional information such as particle sizes or surface roughness as well as mechanical properties could be obtained (Ho et al., 2022, Wang et al., 2023). In recent studies, solid lipid nanoparticles made from materials such as Compritol® 88 ATO (Mazuryk et al., 2016) and lipid nanoemulsions consisting, for example, of medium-chain triglycerides (MCT) (Preetz et al., 2010) were measured and visualized. AFM has also been used to visualize lipid nanodispersions in gelatin films (Alexandre et al., 2016) or gel matrices made of polyacrylic acid, xanthan, or hyaluronic acid (Shahgaldian et al., 2003). In addition, nanoparticulate systems embedded in ODFs, such as nanoparticles of the drug buspirone hydrochloride (Bharti et al., 2019) or mesoporous silica nanoparticles loaded with prednisolone (Sen Karaman et al., 2018), were characterized using AFM.
This study focuses on the embedding of high contents of different lipid nanodispersions into solid dosage forms and the visualization of the embedded carriers using AFM to identify the orientation of the nanoparticular systems depending on the chosen preparation technique. Various matrix materials are being evaluated to enable a successful embedding of different types of lipid carriers into the solid matrices without loss of their nanoparticulate properties. For this purpose, ODFs and powders prepared by spray drying were selected for closer investigation, as their preparation differs fundamentally in terms of process parameters such as drying temperature and time, but similar matrix materials can be used. This study aimed to evaluate the embedding behavior of drug-free nanoparticulate lipid carrier systems using two different techniques in order to identify carrier formulations and matrix materials that are suitable for high lipid loading, while the additional embedding of drug molecules is part of a future study.
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Materials
Lipid nanodispersions were prepared from the liquid oil MCT (medium chain triglycerides, Miglyol® 812, Caesar&Loretz, Hilden, Germany) and the solid lipids trimyristin (Dynasan 114), tripalmitin (Dynasan 116) and tristearin (Dynasan 118; all IOI Oleo, kind gifts, Hamburg, Germany). The dispersions were stabilized using the additives polyvinyl alcohol (PVA, Kuraray Poval 4-88; Kuraray Europe Hattersheim, Germany), hydroxypropyl methyl cellulose (HPMC, Tylopur 606; Shin-Etsu SE Tylose GmbH, Wiesbaden, Germany; kind gift from Harke Pharma, Germany) and the surfactant sodium dodecyl sulphate (SDS; Carl Roth, Karlsruhe, Germany). Lipid nanodispersions were embedded in the following matrices: lactose (GranuLac® 200, Meggle, kind gift, Wasserburg am Inn, Germany), HPMC (Tylopur 606) and PVA EG-18P (for ODFs, GOHSENOL; Mitsubishi Chemical Group, Tokyo, Japan; kind gift from Harke Pharma, Germany) and PVA 4-88 (for spray drying; Kuraray Europe Hattersheim, Germany). The ODFs also contained the plasticizer glycerol (Carl Roth, Karlsruhe, Germany).
Fabian C. Herrmann, Nicole Hofmann, Fiona Haslacher, Denise Steiner, Embedding lipid nanodispersions in matrices: preparation of solid dosage forms with high lipid content and structural investigations using atomic force microscopy, European Journal of Pharmaceutical Sciences, 2025, 107279, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107279.
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