Oral drug delivery remains indispensable although it presents challenges to poorly soluble drugs. Paradoxically, nanoparticles, especially lipid carriers, provide opportunities for these drugs to achieve maximal therapeutic efficacy as they have the potential to traverse gastrointestinal barriers and deploy in the lymphatic pathway, which aptly, bypasses the first pass effect.
The oral route of delivery remains the most popular and convenient way to get medicines into the body. More than 60 per cent of the drugs are administered orally, representing a global share of 90 per cent of all dosage forms. Based on the Biopharmaceutical Classification System (BCS), oral absorption is mainly governed by two factors: water solubility and permeability (Figure 1) (Khan et al., 2022). However, 70-90 per cent of the newly discovered drugs are poorly soluble (BCS Class II and IV), which greatly challenges oral delivery due to the low absorption and therapeutic effect. For instance, anticancer drugs such as docetaxel, paclitaxel, and antimicrobial agents like colistin and amphotericin B have poor solubility and permeability. Due to their poor solubility, these drugs are eliminated in the gastrointestinal tract (GI) prior to absorption, leading to low bioavailability and therapeutic effects (Tan and Billa, 2021).
With the advent of nanotechnology, it is now possible to formulate drugs into lipid nanoparticles. These lipid nanoparticles hold the key to revolutionising drug delivery systems, offering a safe and targeted approach to the delivery of poorly soluble drugs. Researchers have been captivated by the immense potential of lipid nanoparticles due to their biocompatibility, biodegradability, and wide biomedical applications (Magalhães et al., 2019). From cyclosporine A to lipid-soluble vitamins and protease inhibitors, these lipid nanoparticles have already demonstrated remarkable commercial, pharmaceutical, and therapeutic benefits (Essaghraoui et al., 2019).
What sets lipid nanoparticles apart from other nanoparticulate formulations is their nano-sized dimension and lipidic nature. They exhibit better tolerability in vivo and they can mimic the natural digestive process of dietary fat. Unlike polymer-based nanoparticles, lipid nanoparticles offer safer toxicology profiles, as they eliminate the need for organic solvents during formulation, making them a more desirable choice (Lu et al., 2021). Additionally, the absorption of poorly soluble drugs is enhanced by virtue of stimulation of biliary and pancreatic secretions by the particles, as evidenced by improved bioavailability of lipophilic vitamins (vitamin A, D, E and K), testosterone and halofantrine co-administered with fat-rich diet (Tan and Billa, 2021). The simultaneous absorption of the drug along with the lipids is also known as the “Trojan Horse effect”.
Lipids offer protection to susceptible drugs that degrade via chemical, oxidation, and enzymatic reactions. Moreover, lipid-based nanoparticles can alter the pharmacokinetic profiles of drugs through the manifestation of slow-release behaviour from the delivery system. This, in turn, will minimise an abrupt exposure of high drug concentration in vulnerable organs (Montoto et al., 2020). In this context, the pharmacokinetic profile of the drug is now governed by the particle size, charge, type, and concentration of the lipids rather than the intrinsic physicochemical properties of the drug (Magalhães et al., 2019).
Two notable lipid-based nanoparticles are solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs, the first-generation lipid-based nanoparticles, are colloidal suspensions with particle size range in the order of 40–1000 nm. They remain solid at both room and body temperatures (Montoto et al., 2020). NLCs formulations were developed in 2000 and within five years, two NLCs products were approved for the market (Nanorepair Q10 cream and Nanorepair Q10 serum, Dr. Rimpler, Wedemark, Germany) (Tan and Billa, 2021). NLCs formulations consist of a blend of solid lipids with liquid oil. Despite the presence of liquid oil, the NLCs retain the solid matrix at normal temperature. This unique combination disrupts the crystallinity of the solid lipid matrix and thus, creates imperfections that allow the incorporation of high loads of drugs (Essaghraoui et al., 2019). As a result, NLCs offer significantly increased drug load compared to SLNs, up to five-fold increase observed in retinoids NLCs, opening new possibilities for efficient drug delivery (Jenning and Gohla, 2001).
In the quest for effective drug delivery, lipid nanoparticles have emerged as a promising solution. However, their successful systemic delivery relies on navigating various barriers within the GI tract. One of the obstacles is the protective mucosal layer that lines the GI tract, acting as a shield for the underlying epithelia. To counteract the dislodging forces exerted by GI motility, lipid nanoparticles possess a unique ability to adhere to the mucosal layer. Smaller particle sizes exhibit increased mucoadhesion, allowing them to remain attached for longer periods, effectively overcoming the challenge of GI shear stress (Liu et al., 2021).
Additionally, due to the lipidic nature, the lipid-based nanoparticles permit the absorption of drugs through the lymphatic pathway. The lymphatic system serves as an additional pathway for the absorption of lipid nanoparticles or other lipophilic compounds (e.g., long-chain fatty acids, cholesterol esters and fat-soluble vitamins) (Montoto et al., 2020). This is in contrast to most orally administered drugs, which are transported mostly via the portal blood vein before reaching the systemic circulation. The lymphatic system consists of lymph, capable of maintaining homeostasis through the regulation of extracellular fluid and helps in the body’s defence system by transporting immune cells to injury sites.
Lipid nanoparticles that are absorbed by the intestinal lymphatics are transported through the mesenteric lymph duct that enters the thoracic duct and empty in the systemic circulation via left jugular and subclavian veins. The lymphatic system is a formidable absorption pathway for drug delivery because it (i) bypasses the first-pass metabolism that increases drug bioavailability, (ii) has prolonged drug delivery due to the longer duration of drug transport and (iii) offers the possibility of targeting drugs to lymph, potential application in lymphatic cancers and relevant infections such as leishmaniasis, malaria and AIDS (Tan and Billa, 2021).
Lymphatic absorption of lipid nanoparticles has been extensively explored as a viable means for delivering poorly soluble drugs. Shackleford et al. (2003) demonstrated that the lymphatic pathway played a significant role in the absorption of testosterone dissolved in oleic acid (Andriol®), accounting for the majority (91.5 per cent) of its overall absorption. Additionally, the incorporation of methotrexate into SLNs resulted in a 10-fold increase in bioavailability, hypothesised to be predominantly attributed to enhanced lymphatic absorption. (Paliwal et al., 2009). Furthermore, that vincopecetineloaded NLCs also observed a twofold increase in the maximum concentration obtained compared to pure vinpocetine solution (Khan et al., 2013). The lymphatic pathway was hypothesised to be the main transportation route for the NLCs as opposed to the solution, which suffered a significant first pass effect in the liver.
Lipid nanoparticulate carriers provide a means for deploying drug cargoes systemically, when delivered orally, by virtue of lymphatic uptake of the particles. In this regard, the bioavailability of several class III or IV drugs has been improved when formulated as orally administered lipid-based nanoparticles. Additionally, the systemic bioavailability of those drugs can be further attained through the incorporation of mucoadhesive polymers, coating the lipid-based nanoparticles.
As a result, the mucoadhesive lipidbased nanoparticles can adhere to the mucous layer of the GI epithelia, and thus, effectively prolonging the residence time of the formulation at the absorption site as depicted in Figure 2 (Tan and Billa, 2021). This intimate contact with the epithelium confers a higher permeation propensity which subsequently increases the systemic bioavailability of the drugs. Although lipid-based nanoparticulate delivery systems are inherently muco-adhesive, this property may be enhanced further by coating the particles with appropriate polymers. Such coated particles also protect labile drugs from the GI milieu so that unaltered form of the drugs traverses across the epithelia.
The utilisation of lipid-based nanoparticles introduces a groundbreaking avenue for enhancing the systemic bioavailability of poorly soluble drugs, revolutionising their delivery following oral administration and GI absorption. By overcoming the barriers faced by poorly soluble drugs, these nanoparticles provide a game-changing solution, unlocking the full potential of therapeutic agents that were previously hindered by their low bioavailability. As the field of pharmaceutical science continues to advance, the utilisation of lipid-based nanoparticles promises to reshape the landscape of drug development and patient care, ushering in a new era of enhanced drug efficacy and improved treatment options.
Tan, S.L.J., Billa, N., 2021. Improved bioavailability of poorly soluble drugs through gastrointestinal muco-adhesion of lipid nanoparticles. Pharmaceutics 13, 1–19; https://doi.org/10.3390/pharmaceutics13111817
The authors declare no conflict of interest.