Nanostructured lipid carriers and their potential applications for versatile drug delivery via oral administration

Enteral administration is the most convenient route despite the gastrointestinal physiological barriers. Nanostructured lipid carriers (NLCs) have emerged as a promising strategy for improving therapeutic compound oral bioavailability, not only due to nanomaterial advantages, but also due to lipid ingredients themselves, such as preventing enzyme degradation, taste masking, and especially favorable uptake by chylomicron pathways to the lymphatic drainage system. Therefore, NLCs have been employed for systemic absorption improvement, site-specific treatment of the digestive system, and especially targeting delivery to the liver, brain, cancer ulcer, and so on through oral uptake. Lipids, surfactants, and other materials like lipophilic counter ions or coating polymers are considered for oral NLCs formulation design. A variety of NLCs fabrication methods and stability enhancement techniques by transforming NLCs into powder form or hydrophobic -ion pairing are discussed. Hence, this review aims to provide an overview of the current state of the art of NLCs and their modern techniques and applications in oral drug administration, which will advocate their extended use in the future.

Highlights

• Advantages of NLCs for oral administration: NLCs absorption mechanism, sensory masking, enzyme degradation prevention, P-glycoprotein (P-gp) efflux circumvention
• Methods to improve oral NLCs drug loading, targeting effect and stability: hydrophobic ion pairing, surface modification for target position, transformation into powder form
• Site specific delivery and organ/cancer targeting of NLCs through oral administration

1. Introduction

Oral route is the most accepted drug uptake option due to its ease of administration, providing patient compliance, the simplest use, and the safest means of administration. It offers systemic effects through absorption in the gastrointestinal tract, thereby being chosen as the uptake route for common treatments, even for long-term treatment of some chronical diseases involving diabetes, hypertension, cardiovascular ailments, and cancer. However, oral administration may result in low bioavailability and a slow onset of action. Besides, the hindrance of the physiochemical nature of drugs that are either or both low solubility and low permeability [1] in the gastrointestinal tract (GIT) leads to poor absorption and, subsequently, insufficient therapeutic action in the targeting site. There are several hurdles from the physiology of GIT challenging drugs to overcome before reaching the systemic circulation. Firstly, the physiological lumen fluid is prone to multi-pH and food enzyme intervention can cause drug degradation chemically, which alters unpredictably the pharmacological effects.

Secondly, the physical barriers to absorption, including mucus, unstirred water layer, and gut wall cell line membrane, are semipermeable, which only allows selective molecules to penetrate during the short dosage transit throughout GIT. Thirdly, despite successful delivery through these barriers, drugs encounter pre-systemic metabolism by the liver or by enzymes, present in the intestinal and colon mucosa. The CYP3A4 family of enzymes, for example, dominates drug metabolism. Lastly, drugs across the membrane are prevented from intercellular transport by P-glycoprotein (P-gp), highly expressed on the apical surface of columnar cells in the jejunum and tumor cells, pumping drugs back into the intestinal lumen or out of cancer cells. Furthermore, the absorption also varies, depending on other non-disease factors such as age and sex as well as the disease status of patients [2, 3]. Therefore, these above factors should be taken into account to provide enough therapeutic effects in order to improve the bioavailability of oral drug carriers.

Scientists concentrate on ideal strategies for drug transport. From the early 1900s, with the proliferation of nanotechnology, several colloidal delivery vehicles on a nanoscale incorporating drugs have been broadly researched, including polymeric nanoparticles, liposomes, niosomes, and lipid-based nanoparticles (LBNs), including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) [4]. With the combination of natural lipids and surfactants as main ingredients, LBNs shed light on encapsulated drug delivery systems, especially for overcoming GIT hurdles. They are considered to possess more advantages than other nanoparticles (NPs) due to their organic solvent-free preparation and also their ability to withstand factorial degradation [5, 6]. SLNs were first introduced in the 1900s [7], and the first generation of lipid nanocarriers were made of solid lipids, dispersed in water and stabilized by the addition of surfactants or co-surfactants, resulting in nanosized vesicles with drugs encapsulated inside 8, 9, 10. SLNs are capable of conveying hydrophilic molecules, even peptides, genes, and vaccines. When they were first introduced, SLNs got more attention than other lipid-based colloidal carriers because they are biocompatible and easy to scale up in mass production while keeping a low cost of ingredients [5, 11]. However, the crystalline nature of solid lipids at ambient temperature presents limitations to this carrier. Their bulk structure of the carrier system is like a “symmetric brick wall”, in which just a few available spaces for free molecules are embbed in, and consequently unsatisfying drug loading efficacy [12]. Furthermore, they will rearrange the crystalline lattice to get more stable and form gelation in the dispersed phase. This leads to drug leakage out of carriers and particle aggregation during storage time [13, 14].

Because of these drawbacks of SLNs, further studies to modify them finally led to the introduction of the next LBNs generation – nanostructured lipid carriers (NLCs). NLCs share a fundamental identity with SLNs, a colloidal system of lipids dispersed in a watery phase with the help of emulsifiers. The distinguishing point is that a part of solid lipids is replaced by liquid lipids, resulting in the lipid matrix still being liquid or amorphous at room temperature and physiological temperature [5, 15]. The addition of liquid lipids alters the core structure of NLCs. Besides the presence of crystal-like solid lipid composition, liquid lipids cause disruption partly in the lattice structure and form crystal imperfection structures in NLCs. The integrated drugs are distributed more in oil, and the imperfect structure of NLCs is capable of encapsulating more drugs. As a result, the amount of drug loading in NLCs would be significantly higher than in SLNs [12]. This lipid matrix also prevents polymorphic changes of solid lipids by lowering the level of recrystallization to get more stable after a long storage time, which then limits drug extrusion. The amorphous clusters of the NLCs could carry active pharmaceutical ingredients (APIs) molecules better inside [16]. Like SLNs, NLCs show substantial favorability for lipophilic drugs due to the hydrophobic nature of the carrier [17]. The process of adding more methods, like conjugation, would make it easier to put hydrophilic drugs into LBNs [18].

In this review, novel LBNs, a combination of solid and liquid lipid into a promising vehicle named nanostructured lipid carriers (NLCs) are described in detail about their formulations and superior characteristics, especially the high drug payload features of NLCs due to the presence of liquid lipid solubilizing drugs, when compared to parent lipid-based carriers, that is, solid lipid nanoparticles (SLNs). The utilization of NLCs has been an all-around approach for optimizing carriers due to supreme drug entrapment and for both local treatments, targeting action sites to organs like the brain [19], liver [20], kidney [21] and even cancer, or simply intensifying the effectiveness of bioactive agents via oral means. This paper briefly discusses a succinct introduction of NLCs involved in components and their integration with various techniques and highlights outstanding applications that illustrate the tremendous potential of incorporating drugs into NLCs for oral drug delivery systems.

List of excipients of NLCs