The need for suitable alternatives to conventional drug delivery systems has led to a rising interest in lipid-based formulations. In particular, lipid nanoparticles (LNPs) are known to have a high drug encapsulation efficiency, high stability and are generally inexpensive to produce [1
]. Additionally, as these lipid systems can be prepared without organic solvents and are made up of lipids similar to those found in the human body, hence they are considered to be biocompatible, biodegradable and non-toxic [1
]. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two main types of LNPs [1
Both lipid systems are prepared using pure lipids or a blend of lipidic compounds (e.g., triacylglycerols, fatty acids and oils), and a single surfactant (or combined with a co-surfactant) surrounding the particles. The formulation technique and lipid structure typically define several LNP characteristics, including the particle size and size distribution, the drug loading capacity and the encapsulation efficiency [3
]. The solid lipid composition (Figure 1
) of SLNs results in their perfect crystalline core, which often results in less space available for drug loading. On the other hand, NLCs are made up of both liquid and solid lipids resulting in a more amorphous matrix and less dense lipid packaging. This allows NLCs to have a higher drug encapsulation, minimal drug leakage and long-term storage stability in comparison to SLNs [4
To date researchers have investigated the potential of LNPs for numerous therapeutic applications, as shown in Figure 2
. For example, Lin et al., 2010 prepared lipophilic calcipotriol and hydrophilic methotrexate loaded NLC’s for the treatment of psoriasis. Their study revealed 2.4 to 4.4 times enhanced skin permeation with negligible skin irritation compared to the control experiment [7
]. NLC’s have also been used for increasing the bioavailability of orally administered drugs by enhancing their uptake through the lymphatic system (M-cells in the intestinal membrane) and bypassing the first pass metabolism [8
]. Chun-Yang Z. et al., 2010 prepared vinpocetine NLC formulation to estimate the potential of NLC as an oral delivery system for poorly water-soluble drugs. Their oral bioavailability study of the formulation, carried out using Wistar rats, revealed a 322% increase in drug concentration compared to the pure drug suspension [9
]. Furthermore, Joshi M. et al., 2008 prepared NLCs containing artemether, a poorly water-soluble antimalarial agent. Their formulation ‘Nanoject’ was investigated in mice which showed significantly higher (p
< 0.005) antimalarial activity as compare to the marketed injectable formulation [10
Usage of the NLCs in ocular drug delivery has also been investigated to enhance pre-corneal retention time. Shen et al. 2010 prepared mucoadhesive NLC’s modified by thiolated agent which resulted in low systemic cyclosporine concentration but significantly higher residence time in aqueous humor, tear and ocular tissues than that of oil solution and non-thiolated NLCs (p
< 0.05) [11
]. Furthermore, Alam et al. 2012 prepared bromocriptine incorporated NLCs for the controlled delivery of drug to provide extended therapeutic effects for the treatment of Parkinson’s disease. Their drug loaded NLCs were found to be longer lasting (5 h more efficacy) compared to the non-encapsulated counterpart. Such beneficial applications of NLC’s also been achieved in the field of pulmonary drug delivery [12
], delivery of chemotherapeutic agent [13
] and gene delivery to actively suppress tumor growth or treat cancer [15
The lipids used to prepare NLCs are usually triglycerides, fatty acids, waxes and partial glycerides. In this work, we prepared NLCs using Compritol®
888 ATO and Miglyol as these are considered GRAS substances and are commonly used to formulate LNPs [4
]. Moreover, both excipients are cheap, widely available, highly biocompatible, highly stable and able to incorporate a range of pharmaceutical actives or cosmetics [17
]. Another reason behind the choice of Compritol®
as the solid lipid was its neutral cytotoxic behavior and its ability to solubilize Olanzapine (OLZ) [18
OLZ was selected as the model drug for encapsulation into the formulated NLCs. OLZ is an essential atypical anti-psychotic agent that is effective in the treatment of schizophrenia [20
]. OLZ is lipophilic, which means that it is highly permeable through biological membranes but suffers from low oral bioavailability due to poor aqueous solubility and extensive first pass metabolism [21
]. Therefore, it is important to design a pharmaceutical system which provides a better dissolution rate and potentially results in higher OLZ bioavailability. Various methods have been investigated to help improve the oral delivery and controlled release of OLZ including the use of lipid-based carriers [21
There are many formulation approaches for LNP formulation including solvent emulsification/evaporation, supercritical fluid extraction of emulsions, high pressure homogenization and spray-drying [24
]. In this study, we employ a combination of high shear homogenization (HSH) and ultrasonication (US) for the production of OLZ-loaded NLCs. Both HSH and US are cost-effective methods that can be easily applied to the production of lipid nanosystems. However, these techniques can have some drawbacks, particularly associated with long processing times [25
]. The impact of processing time on the properties of LNPs (e.g., influence on particle size) when these two techniques are used either in isolation or combination are hard to find. Therefore, the objective of this study was to understand the effect of HSH and US processing time on the physicochemical properties including particle size, polydispersity index (PDI) and surface charge of NLCs so that the production of LNPs can be optimized efficiently.
The aim of this study was to understand the effect of HSH and US on the development of NLCs containing Compritol® and Miglyol and its effect on the particle size and surface charge. The feasibility to encapsulate OLZ into these NLCs was also explored to improve dissolution rate of the drug using these formulations. In this study, Compritol® 888 ATO was used as the solid and Miglyol 812 N as liquid lipid along with the binary mixture of Poloxamer 188 and Tween 80 surfactants.
Spherically shaped and monodispersed NLCs were successfully prepared with C888 (solid lipid) and Mig (liquid lipid) using combination of HSH and US techniques, where processing time and its impact on the properties of NLCs were also investigated. Varying the US processing time between 1 to 15 min allowed the design of particles with different size, PDI and surface charge. The particle size obtained after HSH alone was found to be 148–191 nm depending on the ratio between solid and liquid lipids, that decreased to 118–164 nm after just 1 min of US. There was also an increase in mean diameter with higher liquid lipid content in the NLC. For example, NLCs containing 5% liquid lipid resulted in particles with 118 nm in comparison to 191 nm for formulations containing 50% of Mig. The influence of increasing liquid lipid ratio on the particle size was not considerable when US processing time was extended after HSH. There was a minimal effect of longer HSH time on the properties of NLCs as 15 min of HSH did not result in the further reduction of particle size. On the other hand, US of 5 min was sufficient to reduce the particle size in all cases, further energy input beyond 5 min resulted in the coalescence of smaller particles that was particularly evident for the NLCs with lower Mig ratios.
OLZ was successfully encapsulated by the lipid systems, with little or no effect of increasing Mig ratio on the particle size and PDI of drug-loaded NLCs. An increase in ζ-potential values was observed for OLZ loaded NLCs that indicated incorporation of the drug in the formulation. This may also suggest presence of drug on the particle surface, but lack of diffraction peaks related to OLZ in XRD spectrum suggested otherwise. A steady and continuous release of drug from the OLZ-loaded lipid systems was recorded in PBS at pH 7.4 in 24 h, with a maximum drug release of 89% achieved in formulations prepared with 5% liquid lipid in the formulation that was approximately nine-fold higher than the drug alone. The in-vitro release in this study was performed only in pH 7.4 PBS that provided a general overview of the drug release from formulated NLCs. In future studies, it would be useful to determine the drug release profiles in simulated gastric and intestinal environments to establish the suitability of these formulations for oral administration.
The release data obtained from this work indicated that liquid lipid content in NLCs can influence the release of loaded drugs and it is important to study the processing parameters carefully when using US in combination with HSH whilst developing a protocol for NLP preparation. The NLCs prepared in this study showed good stability at 4 °C for six months as no significant changes in the values of average particle sizes, PDI and surface charge were detected during this period at the chosen condition. It could be of interest to study the stability profile of these formulation at standard ambient temperature (25 °C) to determine their shelf-life at higher temperature. Nonetheless, this could be concluded based on the data obtained from this study that US along with HSH can be an effective and fast method to prepare NLCs of varying particle sizes that can potentially improve the dissolution rate of BCS II drugs.