Solid lipid nanoparticles and nanostructured lipid carriers: a review of the methods of manufacture and routes of administration

Abstract

The bioavailability of drugs is dependent on several factors such as solubility and the administration route. A drug with poor aqueous solubility, therefore, poses challenges with regards to its pharmaceutical advance and ultimately its biological usage. Lipid nanoparticles have been used in pharmaceutical science due to their importance in green chemistry. Their biochemical properties as ‘green’ materials and biochemical processes as ‘green’ processes mean they can be environmentally sustainable. Generally, lipid nanoparticles can be employed as carriers for both lipophilic and hydrophilic drugs. The proposed administration route for nanoparticles can present advantages and disadvantages which should be considered by a formulator. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are attractive delivery systems because of their ease of manufacture, biocompatibility, biodegradability, and scale-up capacity of formulation constituents. The easy and simple scalability of novel SLNs and nano lipid carriers, along with their various processing procedures, recent developments, limitation and toxicity, formulation optimization and approaches for the manufacture of lipid nanoparticles, lyophilization and drug release are comprehensively discussed in this review. This review also summarizes the research data related to the various preparation methods and excipients used for SLNs and NLCs in recent years.

Keywords:

• Administration route
• hydrophilic drugs
• lipophilic drugs
• solid lipid nanoparticles
• nanostructured lipid carriers
• manufacturing method

1. Introduction

Various drug-delivery technologies have achieved research interest in the last few decades and an exciting section of this has been the improvement of nanomedicine and nano-delivery systems (Patra et al. 2018). Many nanoparticulate drug deliveries can be used to improve drug bioavailability via different mechanisms such as enhancing the permeation of drug or dominating the first-pass effect and, or the efflux of the P-glycoprotein (P-gp) (Ye et al. 2020; Halder et al. 2021). Lipid-based nanoparticles are however non-biotoxic for in vitro/in vivo usages and as such dynamic advancement has been focused in the field of lipid-based DNA/RNA nanocarriers (Duan et al. 2020). Most lipids applied to synthesize lipid nanoparticles are biodegradable and biocompatible with few adverse side effects and chronic toxicity (Xu et al. 2022). Some polymeric nanoparticles have shown toxic effects during in vivo degradation (Cheng et al. 2021). The biocompatibility and physiochemical diversity properties of lipids and their ability to improve drugs bioavailability have offered a promising drug delivery system. Furthermore, lipid-based formulations can improve drug absorption in a variety of different ways such as enhancing membrane permeability, enhancing solubilization capacity, increasing intestinal drug dilution, inhibiting the P-gp efflux transporters, reducing cytochrome P450s (CYPs) enzymatic activity, increasing chylomicron biosynthesis and lymphatic transport rate (Ulldemolins et al. 2021). Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two major kinds of lipid-based nanoparticles.

SLN was presented as the first generation of solid lipid carrier systems in the nanometer dimension, while NLC is often considered the second generation of SLN (Fonseca-Santos et al. 2020). SLNs possess the combinational benefits of different carrier systems which include nanoemulsions, polymeric nanoparticles, and liposomes. SLNs are made from physiologically accepted biocompatible excipients (similar to liposomes and nanoemulsions). Moreover, their solid matrix can successfully keep the loaded active pharmaceutical drugs contrary to enzymatic degradation and can deliver the maximum plasticity to achieve modified release profiles (Kelidari et al. 2015; Khezri et al. 2020). Besides, large industrial-scale production of SLN is possible by several methods such as high-pressure homogenization (HPH) and emulsion (Souto EB et al. 2020).

2. The impacts of green chemistry on the pharmaceutical industry

Pharmaceutical production is the supreme solvent-intensive and the least efficient of all chemical industries causing waste prepared per unit of produce (Rajagopal R 2014). To circumvent this challenge, ‘green’ methods have been developed as a way of decreasing the ecological influence the pharmaceutical industry has. Over the past few decades, the field of green technology, also called sustainable chemistry has expanded. Many independent activities have been carried out in research, science, and industry (Sanjay 2019). Green chemistry has a good plan, production, and use of chemical harvests and facilities which are environmentally safe. Nevertheless, while green chemistry works mainly on technical issues and engineering, sustainable chemistry includes all life cycle phases. Therefore, the physiological lipid component in the fabrication process of SLNs and NLCs makes this drug delivery system one of the most favorable delivery systems. The goal of this review is thus to explicitly describe and highlight the two kinds of novel and simple scaled-up SLN and NLC with their accompanying recent developments, limitation and toxicities, formulation optimization and approaches for the manufacturing of lipid nanoparticles, lyophilization, and pharmaceutical application. This review also presents the research studies reported on the various technique of production and their essential outcomes.

3. Recent progress in SLNs

SLNs are the type of nanosphere that consists of solid lipids with a photon correlation spectroscopy (PCS) between 50 and 1000 nm. These lipidic components can comprise complex mixtures of glyceride, purified triglycerides, or even waxes, that are solid at both the ambient temperature (25 °C) and the human body (around 37 °C), and are dispersed in suitable surfactant(s) (Kanojia et al. 2022). Compared to traditional carriers such as polymeric micro- and nanoparticles, liposomes or emulsions, SLN purports itself as an alternative drug delivery system. SLNs are remarkable lipid-based drug carriers because of many factors which include (I) materials used consisting of biodegradable, low toxicity, and biocompatible components; (II) having an average size from 50 to 1000 nm after drug encapsulation; (III) the lower cost and quick scalability of the particle production process (Mishra V et al. 2018).

As evident in the consequences of current research studies, they have the capacity to carry anti-tumor drugs with contrast agents and deliver simultaneous diagnosis and treatment. Kuang et al. revealed that SLNs with c(RGDyK) were considered as effective carriers to develop the targeted delivery of IR-780 to cancers cell (Kuang et al. 2017). The cRGD-IR-780 SLN considerably enhanced the photothermal therapy and tumor-specific targeting ability along with the ability of imaging of in vivo fate of the SLN combined IR-780 iodide photosensitizer (Kuang et al. 2017).

SLNs have been examined for incorporating various contrasting agents, such as iron oxide (Świętek et al. 2020), technetium-99 (99mTc) (Ghazizadeh et al. 2018), and carbon dots (Arduino et al. 2020). Current treatment possibilities for cancer were achieved by encapsulating an SLN with a quantum dot as a contrast agent (Mussi and Torchilin 2013). Both biomacromolecules and small-sized drug molecules comprising peptides and proteins can be loaded into SLNs for specific purposes. For instance, insulin as proteins/peptides typically suffers challenges in oral delivery as they are degraded during passage through the gastrointestinal tract (GIT) medium. An endosomal escaping agent was thus loaded into an SLNs lipidic core for attaining an endosomal escape for insulin drug delivery (Xu et al. 2018). It was reported that hemagglutinin₂ peptide within SLN enhanced the insulin endosomal escape which protected the biological activity of insulin through the intracellular transport following oral administration. The most beneficial chemotherapeutic agent for colorectal carcinoma is the combination of siRNA and paclitaxel. The solid lipid matrix was integrated with a quantum dot and paclitaxel whereas siRNA was electrostatically attached to the exterior surface of SLN. To achieve the synergistic anticancer activity, dual therapeutic agent siRNA and paclitaxel loaded in SLN effectively accumulated in lung carcinoma. Sun et al. exhibited the effective integration of gadolinium(III) and fluorescein isothiocyanate complexes in SLN, which could be used as a tumor-absorbable contrast agent for the detection of colorectal tumors (Sun et al. 2016).

SLNs suffer from different shortcomings, for example, poor loading efficiency, drug leakage following polymorphic transformation and comparatively large water amount of the dispersions (Jacob et al. 2022). The drug with low entrapment efficiency and loading capacity of the conventional SLN was as a result of a tight packing of the lipid crystal network, the drug solubility in the melted lipid, the polymorphic state of the lipid matrix, and a physical and chemical structure constituent of the solid lipid matrix. The addition of hydrophilic ingredients to the surface of SLNs can modulate the preparation of the ‘protein corona’, i.e. the addition of plasma proteins to the surface of SLNs when they absorb into the bloodstream (Chen et al. 2019). This protein corona preparation exists in various lipid nanoparticles (including SLNs) (Nishihira et al. 2019) and has been confirmed to adjust nanoparticle biodistribution (Chen D et al. 2017). It has been proven that the absorption of polyethylene glycol (PEG) molecules results in a significant reduction in the amount of protein bonds (Partikel et al. 2019). Additionally, incorporating cytotoxic biocides into the SLNs can diminish cytotoxicity in eukaryotic cells while enhancing antimicrobial defense (Sandri et al. 2013). For example, it has been revealed that tilmicosin-loaded castor oil-SLNs can decrease drug side effects, for instance, cardiotoxicity (Xie et al. 2011). Other researchers have attempted to attain selective drug delivery in advanced pH-sensitive SLNs, which can adjust their release kinetics depending on the pH of the environment (Chuang et al. 2017). Mhule et al. incorporated antibiotic drugs into SLNs to improve drug delivery to the infection site (target tissue) (Mhule et al. 2018). Cetyl palmitate-based PEGylated was loaded with sorafenib and paclitaxel through a microfluidic technique. The anti-cancer activity of the SLNs formulation was estimated with 2D and 3D-cell cultures of U87-MG cell line and 2D-cell model of the human alveolar adenocarcinoma cells line (A549) (Arduino et al. 2021). In comparison with a 2D cell model, the 3D spheroid model indicated higher cell viability in terms of both drugs and SLNs. This consequence may be as a result of the minor cell nanoparticle interactions of the cells in the 3D cell cultures versus the traditional 2D cell culture, leading to a reduction of anti-proliferative activities of the cytotoxicity compounds which accomplish more potently on the proliferating (Fröhlich 2018; Figueiredo et al. 2019). The SLN prepared using microfluidics shown here can open a remarkable route for the scale-up of the production and future standardization of these nanosystems within the biomedical field.

Ramasamy et al. (2014) prepared a layer-by-layer doxorubicin–dextran sulfate–SLNs to kill tumor cells. The anionic doxorubicin–dextran sulfate–SLNs were covered with cationic chitosan followed by decorating successively with anionic hyaluronic acid (HA). In this study, a novel approach of polyelectrolyte multilayer was used to facilitate EPR properties and prolong the blood circulation time of the hydrophilic drug. Transferrin (Tf) conjugated with SLNs was prepared to load curcumin for active targeting of prostate cancer cells. In comparison with curcumin-SLNs, prepared Tf-SLNs demonstrated minimal cytotoxicity while Tf-CRC-SLNs showed remarkable in vitro anti-proliferative properties. Cellular uptake of Tf-curcumin-SLNs was reported to be remarkably higher in comparison with pure drug or unconjugated SLNs (Akanda et al. 2021).

4. Recent progress in NLCs

To eliminate the shortcomings of SLN, NLC systems were introduced. The NLCs are formed from a combination of a diverse group of lipid molecules, typically the combination of both solid and liquid lipids as a core matrix. These cause defections in the matrix structure to accommodate other drug molecules as compared to SLNs. Despite the liquid lipid structure, the NLC matrix is solid at both body and room temperatures. NLCs remain in the solid state by adjusting the ratio of liquid lipid to solid lipid. Compared to emulsions, NLCs can effectively prevent particle coalescence through the solid matrix. NLCs have the benefits of SLNs such as sustained drug release capabilities, biodegradation, low toxicity potential, drug protection against harsh environments and prevention of organic solvents during manufacturing (Parvez et al. 2020; Rahman et al. 2020).

Recent research examinations show the significant role of NLC in the field of medicine. Multifunctional nanocarriers of IR 780 and Coumarin 6 fluorescent dye encapsulated CXCR4-targeted NLCs for breast cancer therapy using photodynamic therapy have been reported (Li H et al. 2017). The progressed system was demonstrated to be extremely effective in inhibiting cancer cell progression and metastasis and in parallel permitting imaging (Li H et al. 2017). Olerile et al. fabricated an NLC loaded with quantum dot and paclitaxel that was highly capable of monitoring and following cancer cell growth and simultaneously inhibiting tumor cells in the murine tumor model of hepatocellular cancer (Olerile et al. 2017).

This current study attempted to investigate the co-loaded NLC based on quantum dots and paclitaxel to provide an interpretation essential for a preclinical explanation of the formulation in part. In these experiments, the short-term stability and internalization of co-loaded NLC by HepG2 and MCF-7 cells were examined. It was theorized that the aforesaid investigations would prove that the co-loaded NLC was an effective clinical translation candidate for cancer theragnostic (Olerile 2020).

5. SLN/NLC applications in gene and peptide delivery systems

Nucleic acids and biological macromolecules are not able to diffuse through the mammalian cell membrane due to their highly anionic nature and hydrophilic properties. Their combination with cationic lipid nanoparticles can therefore enhance their intracellular delivery (Algarni et al. 2022). SLNs/NLCs have been recognized as non-toxic and effective lipophilic colloidal carriers for the delivery of drugs and various biological macromolecules such as peptides, DNA, etc. NLCs have significant nanostructures to accommodate drugs as well as genes and therefore attain higher loading capacities. The decorating of NLCs with Tf was prepared for enhanced co-delivery of a green fluorescence protein plasmid. Paclitaxel-loaded Tf-DNA-NLC showed high-efficiency gene transfection, low cytotoxicity, and improved anti-cancer efficacy in both in vitro and in vivo models (Shao et al. 2015). In this self-same research, two different types of nanocarriers (pEGFP and doxorubicin) were loaded on NLCs and SLNs. Tf-decorated doxorubicin and pEGFP-loaded NLCs (T-NLC) showed significantly higher gene transfection activity and improved in vivo anti-cancer efficacy than that of the modified SLNs. T-NLC also indicated a surface charge of +19 mV and an average particle size of 198 nm (Han et al. 2014).

Nanocarriers modified with various ligands were applied for lung cancer gene therapy. The goal of this investigation was to progress dual ligand-modified nanocarriers, which could specifically target cancer cells and increase cellular uptake to enhance the uptake of genetic material. HA and Tf decorating PEG-di-stearoyl phosphatidylethanolamine (HA-PEG-DSPE and Tf-PEG-DSPE) ligands were produced. Unique HA and Tf ligand-modified, plasmid-improved green fluorescent protein decorated NLC (Tf/HA-pDNA NLC) were prepared. The novel fabricated NLCs could effectively load HA, Tf, and gene operated as targeting ligands to enhance the cell-targeting activity (Zhang et al. 2017). Furthermore, cationic SLNs have been commonly applied in gene delivery because of the electrostatic interaction among the positive charges of the lipid and the negative charges of the DNA which cause the preparation of a complex (Dolatabadi et al. 2015). Jin et al. prepared siRNA-PEG/SLN, which can not only cross the blood–brain barrier (BBB) but also be delivered to the tumor environment without obvious systemic toxicity (Jin et al. 2011). SLN decorated with insulin through the micelle-double-emulsion technique was fabricated by Liu et al. In addition to greater stability during nebulization, SLNs presented a higher bioavailability of insulin in the lungs because of the deposition of insulin-SLNs (Liu et al. 2008). The advantages/disadvantages of lipid nanoparticles applied in gene/peptide delivery are presented in Table 1.

Table 1. Advantages/disadvantages of lipid nanoparticles as gene and peptide delivery systems.

Advantages	Disadvantages
Large-scale production from substances generally recognized as safe, good storage stability, the possibility of steam sterilization and lyophilization (Dolatabadi et al. 2015)	Expensive technology (Dolatabadi et al. 2015) The process was dependent on pH Identify by the immune defense and scavenger systems (Dissanayake et al. 2022)

6. Different types of SLN/NLC

Different types of SLNs and NLCs are depicted in Figure 1(a,b). It is crucial to note that the localization of the drug in the SLN/NLC relies on the lipophilicity and the structure of the target molecule (Borges et al. 2020). For example, in SLN type I, in the homogeneous matrix of solid solution, the drug is dispersed in the lipid core whereas in SLN type II, in the drug-enriched shell, a drug-free lipid core is prepared, and an external solid shell with both drug and lipid is prepared. The HPH method is used to produce both types of SLNs. The drug-enriched core model, SLN type III, is achieved when the drug concentration is near to its saturation solubility in the lipid, which results in its precipitation in the core and lipid with extended coverage prepared. It is notable that minor variations in some relevant variables can have an impact on SLN and NLC structure thus changing their applicability. For example, SLN type III is suitable for reaching an extended drug release profile, whereas SLN type I can display a controlled release profile, while SLN type II is not appropriate for this aim (Souto E et al. 2007). Moreover, imperfect crystal, type I NLC, is achieved by using solid lipids and liquid lipids, producing a matrix with many voids and spaces which can carry a payload of drug molecules in amorphous clusters. NLC type II as an amorphous model is achieved when using special lipids (i.e. hydroxyl octacosanyl, isopropyl myristate, dibutyl adipate, or hydroxyl stearate) which do not recrystallize after homogenization and cooling, producing a homogenous amorphous matrix that reduces drug leakage. NLC type III as a multiple model is obtained from liquid lipids moieties which are effectively dispersed in the solid lipid matrix because of the phase separation and it is achieved by mixing higher amounts of liquid lipids with solid lipids where the liquid lipids solubility in the solid lipid is increased. Type III model is acceptable to gain a high drug entrapment efficiency and controlled drug release enhancement that are commonly more soluble in liquid lipids (Ganesan and Narayanasamy 2017).

Figure 1. Types of (a) solid lipid nanoparticles: (i) solid solution, (ii) drug enriched shell, and (iii) drug enriched core; (b) nanostructured lipid carriers: (iv) amorphous type, (v) imperfect type, and (vi) multiple type.

7. Limitations and toxicity of SLNs and NLCs

The main restriction in lipidic nanoparticles is their affinity to fuse, particularly when the average size of synthesized nanoformulation is less than 100 nm. The fusion causes the escape of encapsulated contents from the lipid vesicles and improves dispersity (Carregal-Romero et al. 2018). Nevertheless, this concern can be resolved by covering the lipid nanoparticles surface with PEG coating. Several lipid-based nanocarriers applied for the delivery of chemotherapeutic agents through the parenteral route may have cationic components for the attachment of targeting ligands to specific locations which can lead to an immune response. Similar to all nanoparticles, the evaluation of NLCs toxicity includes the impact of the surface charge, particle size, and other physicochemical features on the product safety (Haider et al. 2020). Other studies have reported that maximum cell lines could tolerate up to 1 mg/mL of lipid doses of drug-free NLCs (Haider et al. 2020). Numerous publications have reported sufficient cellular tolerability for lipid-based nanocarriers synthesized with positively charged cationic surfactants such as cetyltrimethylammonium bromide (CTAB). It was shown that SLNs fabricated with CTAB indicated low toxicity at concentrations above 1 mg/mL (Almeida et al. 2017). It is however important to note that the main risks are related to the usage of CTAB in the fabrication of SLNs as it increases the release of calcium from neutrophils and causes their damage (Hwang, Aljuffali, Hung, et al. 2015). On the other hand, NLCs synthesized using other surfactants such as poloxamer 188 and polysorbate 80, displayed low toxicity and sufficient biocompatibility. It has also been reported that applying a mixture of surfactants to enhance the stability of the product could increase the toxicity risk (Souto EB et al. 2020).

One of the challenges about the safety of NLCs is their affinity to induce oxidative stress. Hyperactivation of cellular defense mechanism in HepG2 liver tumor cells is the mark of oxidative stress activation which is detected after cure with CTAB modified lipid-based nanoparticles (Doktorovova et al. 2014). To reduce the risk of oxidative stress, curcumin or a combination of harmless ingredients such as ethoxylated medium-chain glycerides and hard fats have been used (Kyadarkunte et al. 2015).

Some researchers have also considered the side effects of NLCs on animal health (Carvalho et al. 2020). Indications show that chemotherapeutics agents incorporated into lipid-based nanoparticles are usually harmless after oral, parenteral, dermal, and ocular administration. Most of the detected side effects after administration were mainly attributed to the drug (del Pozo-Rodríguez et al. 2013). Some toxic properties, such as neurovascular injury, neuroinflammation, and microglia activation were injected with SLNs in mice (Hwang, Aljuffali, Hung, et al. 2015). The observed impacts were because of the joining of cationic ingredients or aggregation of the particles when presented to a medium with high ionic strength or proteins. The use of PEG in enhancing SLN’s stability was adequate to inhibit the informed inflammatory reaction (Hwang, Aljuffali, Lin, et al. 2015).

8. Quality by design method to optimize formulations of lipid nanoparticles

Traditional pharmaceutical improvement methodologies depending on quality through testing is outdated. In these techniques, the product quality can be controlled by adjusting the crude materials (e.g. excipients and drugs) and reproducing the procedures. Finalized products must satisfy the regulatory agencies’ specifications or reasons for failure must be established to allow for the process to be restarted. Quality by design (QbD) method has been presented as a way of overcoming these quality control challenges. QbD develops assembling routes and guarantees the safety and ultimately the quality of products (Zhang and Mao 2017; Cunha et al. 2020).

Various statistical tests and mathematical models have been applied in regards to parameters that impact the physical elements of the resulting nanosystems. These consist of differences in composition and manufacturing factors (e.g. homogenization pressure cycles, sonication amplitude time, and emulsification time). These are basic factors that impact nanoparticle/globule polydispersity index, mean size, drug encapsulation efficiency, zeta potential, and in vitro drug release.

Bhatt et al. utilized a QbD approach for the improvement of curcumin loaded in SLNs for controlling breast cancer (Bhatt et al. 2018). Glyceryl monostearate was applied as a core material. The small lipid particles enhanced cellular uptake and instigated superior apoptosis in human breast adenocarcinoma cells compared to its free curcumin counterpart.

9. Regulatory status, commercialization plan and safety of lipidic nanoparticles

Nanomaterials have gained several advantages which make them suitable candidates for a wide range of clinical applications. Though there has been much hype around the emerging field of nanomedicine, there are currently very little official regulations in this field. Many nanomedicines study through direct interaction with biomolecules (e.g. protein, gene, compound, and chemical) are vital for cell division and normal genome function (Zhang et al. 2012), all of which can lead to mutagenicity and genotoxicity. Currently, the specific interactions of biological systems with several nanolipidic are not completely realized thus making the deduction about the toxicological and physicochemical properties of nanomedicines are challenging. The absence therefore of official regulation of nanolipidic production and nanomedicines for health-related applications is a global problem. Some concern is thus imperative in the regulatory plan and is as such presented in Figure 2(a). The main issues faced in the regulation of SLN are described in Figure 2(b). Nevertheless, this over-cautious approach seems to be demonstrating great inertia within the field. However, the standard checks needed for approval are still vague and align with the regulation for small drug molecules (Figure 2(c)) which do not correctly reflect the nanomaterials potential. If the regulation was therefore appropriate and bespoke, it would enable better filtration at preclinical studies, decreasing failure rate either later in the clinical trials or indeed after clinical use and marketing.

Figure 2. (a) Regulatory status of lipidic nanoparticles production. (b) Diagram highlighting the major challenges faced in the regulation of lipidic nanoparticle. (c) Approval process for commercialization plan of small drug molecules. Imaged adapted from Foulkes et al. (2020).

9.1. Commercially available products from lipid-based nanoparticles in market

Most of the commercial lipid nanoparticles products are cosmetic products such as Intensive Serum Nano Repair Q10, NanoLipid Q10 CLR, extra moist softener and extra moist emulsion, IOPE SuperVital cream, serum, eye cream, NLC Deep Effect Eye Serum, NLC Deep Effect Reconstruction Cream, Swiss Cellular White Intensive Ampoules, Olivenöl Augenpflegebalsam Olivenöl Anti Falten Pflegekonzentrat (Pardeike et al. 2009).

10. Approaches of preparation

Many traditional physical methods have been considered for the controlled preparation of nanoparticles. The advantages of these approaches are limited by their energy supplies, lower level of hazardous products and their potential for high performance (Malik et al. 2014). Recently, some lipid-based nanoparticles (SLNs/NLCs) have been prepared via green procedures such as ultra-sonication (Aghazadeh et al. 2021; Boskabadi et al. 2021; Saeedi et al. 2021), supercritical fluid method (Kanwar et al. 2021), ultrafiltration (Passos et al. 2020), flocculation with surfactants (Malik et al. 2014; Li et al. 2021), and HPH (Vinchhi et al. 2021). The mechanisms, advantages, and disadvantages of each method are considered in Table 2.

Table 2. Comparison of different routes applied for the production of SLNs/NLCs.

Mechanism Advantages Disadvantages	HPH (Li and Chen 2020) Shear because of severe turbulent vortices Very impressive dispersing method Tremendously energy severe method Not appropriate for heat-labile drug; high polydispersity
Mechanism Advantages Disadvantages	Hot HPH (Mudshinge et al. 2011) (Figure 3(a)) Severe holes due to the high-pressure drop via the valve Commercially available; scalable The distribution of the drug into the aqueous phase through homogenization; difficulty of nanoemulsion Crystallization step causes many supercooled melts and modifications
Advantages Disadvantages	Cold HPH (Mudshinge et al. 2011) (Figure 3(b)) No temperature obliged degradation of drug or modification of crystalline –
Mechanism Advantages Disadvantages	Solvent emulsification evaporation (Yadav et al. 2013) (Figure 4) Globules emulsification after the evaporation results in precipitation such as small particles size and heat inhabitance Low energy input; an aqueous immiscible solvent which is suitable for thermolabile drugs are used to dissolve in lipids. Emulsion inconstancy; low dispersing phenomenon; insolubility of lipids in organic solvents; toxicological issues; manufacture is not essential for the dispersion of dilute nanoparticles; evaporation or ultrafiltration is necessary; the organic solvent cannot be entirely removed and may stay in the last production.
Mechanism Advantages Disadvantages	Solvent emulsification diffusion (Yadav et al. 2013) (Figure 5) Globules emulsification after the evaporation results in precipitation; benzyl alcohol; tetrahydrofuran, as in moderately miscible solvent, is used to dissolve lipids. Degree of small dispersing; emulsion inconstancy Insolubility of lipids in organic solvents; toxicological issue lyophilization; ultrafiltration methods are essential; excess of organic solvent can keep on in the last production.
Advantages	Solvent injection/solvent movement (Iqbal et al. 2012) (Figure 6) Quick production and informal treatment route; water-miscible solvents such as methanol, acetone, and ethanol, are used to dissolved lipids; no need for sophisticated apparatus.
Mechanism Advantages Disadvantages	Membrane contractor (Yadav et al. 2013) (Figure 7) To produce small droplets; the lipid phase is used over the membrane pores Large-scale manufacture; capability of usage; size regulator; to prepare small droplets, the lipid phase is used by the membrane pores below room temperature through cooling; the lipid nanoparticles repapered by these droplets recrystallize.
Mechanism Advantages Disadvantages	Phase inversion (Iqbal et al. 2012) (Figure 8) A rise in temperature with spontaneous transposal of O/W to W/O transitional emulsion Solvent-free worth for heat-sensitive molecules; low energy severe Combination of extra molecules impact reverse phenomenon; emulsion instability Technique can be cumbersome
Mechanism Advantages Disadvantages	Coacervation (Shah et al. 2015) (Figure 9) Proton switch lipid precipitation is achieved through the reduction in pH of the micellar solution of alkaline salts of fatty acids Appropriate for hydrophobic ion pairs of hydrophilic drugs; appropriate for lipophilic drugs; monodispersity, Solvent-free procedure; modest to scale-up; not suitable for pH-sensitive drugs; to form alkaline salts, lipids are appropriate
Mechanism Advantages	Microemulsion cooling (Koziara et al. 2004) (Figure 10) Globules emulsification after the cooling causes precipitation, i.e. particles. This technique is reproducible, modest, and ordinary to scale up; no organic solvents are applied; all the ingredients are biocompatible.
Mechanism Advantages Disadvantages	Super critical fluid (Chattopadhyay et al. 2007) (Figure 11) Equivalent routes of supercritical fluid extraction of organic solvent prepare emulsions and lipid dissolution; Organic phase expansion; causes lipid crystallization Particles are achieved as a dry powder, inhibit the solvents usage; in distinction to suspensions; slight pressure, and temperature surroundings, CO2 solution is the worthy selection as a solvent Very costly technique
Mechanism Advantages Disadvantages	Ultrasonication (Mei et al. 2005) (Figure 12) Preparation and bubbles implosive collapse because of the cavitation, i.e. ‘the preparation, development, and bubbles implosive collapse in a liquid Low size of the particle; low shear stress Pollution occurs due to metal shading; unproven scalability; severe energy route; the metallic product pollution may happen

11. Lyophilization of lipid nanoparticles

Lyophilization is a favorable method to enhance the physical and chemical stability of SLNs. Moreover, conversion into a solid form avoids hydrolysis reactions and Ostwald’s ripening (Mishra DK et al. 2012; Swathi et al. 2012). Stresses that destabilize the colloidal nanoparticulate suspension are probably produced throughout the freeze-drying process. Irreversible fusion/aggregation of nanoparticles might destabilize the colloidal system of the nanoparticulate. Observably, two additional formulations between the transformations are needed that might be the cause of additional stability challenges. Under vacuum, the primary change is obtained from an aqueous dispersion to a powder containing the water evaporation and the sample freezing. Sample freezing may lead to stability challenges due to the freezing out impact which leads to conversions in the pH and the osmolarity. Resolubilization includes, at least during its primary periods, a condition that considers the aggregation of particles.

To mitigate against this issue, specific excipients must be previously combined before freezing to keep the suspension of the nanoparticulate. Certain excipients with cryoprotectant properties can be added to protect the system from freezing stress and lyoprotectants are added to protect from the drying stress. Adding cryoprotection is essential to reducing the aggregation of SLN and enhancing the redispersion of the dry produce (Campos JR et al. 2019; Amis et al. 2020). Mannose, glucose, sorbitol, polyvinylpyrrolidone, and trehalose have cryoprotective properties. They reduce the crystallization, water osmotic pressure, and the vitreous state of the frozen paradigm (De Jesus and Zuhorn 2015).

12. Patent perspective of SLNs and NLCs

SLNs and NLCs have been examined for numerous usages in topical applications, cosmetics, non-invasive methods, food chemistry as a preservative, targeted delivery of anticancer drugs and the co-delivery of multiple medications (Dhiman et al. 2021). Various approaches of SLNs and NLCs fabrications and or encapsulating therapeutic agents into NLCs or SLNs have been patented. The summary of the patents according to SLN and NLC-based carriers has been indicated in Table 3.

Table 3. List of patents related to pharmaceutical, biomedical, and other applications of SLN and NLC.

Title	Type of compound/drug/excipients	Inventors	Patent number	Year	Ref.
Polymerized solid lipid nanoparticles for oral or mucosal delivery of therapeutic proteins and peptides	Amikacin, gentamycin, /therapeutic protein or peptide insulin hepatitis ‘B’ surface antigen, EPO, typhoid vaccine, G-CSF, factor VIR, interferons, heparin, LHRH analogs, GM-CSF, and cholera vaccine lipids and long-chain fatty acids	Rao, K.K	US20080311214A1	2008	Rao KK (2008)
Solid lipid nanoparticles of roxithromycin for hair loss or acne	Oxithromycin/palmitic acid, stearic acid, cetyl palmitate, poloxamer L 88, phenoxyethanol, glyceryl palmitate, glyceryl behenate, pentylene	Krysztof, C. A. L.	EP2919756B1	2015	Krysztof and Wosicka (2015)
Topical tazarotene solid lipid nanoparticles	Tazarotene/glyceryl behenate, glyceryl dibehenate, myristyl laurate, myristyl myristate	Jesudian, G.	IN149/CHE/2014	2014	Jesudian et al. (2014)
Nanostructured solid lipid carrier coating vitamin A palmitate and preparation method thereof	Vitamin A palmitate/steroid, pentaerythritol stearic acid ester 2 or hard ester alcohol, cetearyl alcohol, castor oil hydrogenated, alcohols, waxiness class, glyceride type, saturated fat acids	Wanping, Z.	CN105496801A	2016	Wanping et al. (2016)
Systems and methods for preparing solid lipid nanoparticles	Fenofibrate/glycerol behenate Cremophor EL, vitamin E TPGS, Tween 80	Repka, M. A.	US20170172937A1	2017	Repka et al. (2017)
Curcumin solid lipid particles and methods for their preparation and use	Curcumin/starches, lecithin, oleic acid, LABRAFAC^®, Gums of phenylated silicones, GELUCIRE^® 43/01, COMPRITOL^® E. CAPRYOL^® 90	Diorio, C.	US10166187B2	2019	Diorio and Lokhnauth (2019)
Nanostructured lipid carriers, methods and uses thereof	Metronidazole and proton pump inhibitor or clarithromycin plus amoxicillin/cetyl palmitate, glyceryl palmitostearate, caprylic/capric triglyceride	Sebra, C. L	WO2018002853A1	2018	Seabra et al. (2018)
Sports fatigue-resistant resveratrol solid lipid nanoparticles and preparation method thereof	Resveratrol/fabaceous lecithin or triacylglycerol, Myrj52 lecithin, stearic acid	Lili, Q.	CN108420801A	2018	Lili et al. (2018)
Nanostructured formulations for the delivery of silibinin and other active ingredients for treating ocular diseases	Silibinin/DETA, calixarenes, chitosan	Blanco, A.R.	AU2021202374A1	2015	Rita et al. (2015)
Nanostructured lipid carriers and stable emulsions and uses thereof	Riboxxol and Riboxxol/Span80, Span 60, diester or trimester, Sorbitan monoester	Khandhar, A. P	WO2018232257A9	2020	Khandhar et al. (2020)
Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms	Cannabinoids/PEG, lecithins	Kaufman, R.C	US10028919B2	2018	Kaufman (2018)

13. Applications of lipid nanoparticles and various routes of administration

Table 4 summarizes various publications which consider the numerous routes of administration such as topical, parenteral, ocular, oral, and brain delivery that have been utilized in the manufacture of lipid nanoparticles.

Table 4. Various loaded active compounds and routes of lipid nanoparticle administration.

Route of administration	Loaded drug	Application	Year	Reference
Oral	Hydrochlorothiazide	Pediatric hypertension	2021	Mura et al. (2021)
	Fluconazole	Candidiasis treatment	2021	Kraisit et al. (2021)
	Ambrisentan	Treatment of pulmonary arterial hypertension	2021	Zancan et al. (2021)
	Heparin	Blood disorder	2021	Maretti et al. (2021)
	L-carnitine	Protective effect against H2O2-induced genotoxicity and apoptosis	2022	Eskandani et al. (2022)
	Coumarin	Cellular permeability	2020	Tzanova et al. (2021)
Ocular	Calcium phosphate	Inhibitor of angiotensin-converting enzyme	2022	Popova et al. (2022)
	Coumarin	Ophthalmic diseases	2017	Liu D et al. (2017)
	Lutein	Limit the retinal damage	2021	Shah S et al. (2021)
	Latanoprost	Glaucoma	2021	Dang et al. (2022)
Parenteral	Melphalan	Human neoplastic disease	2020	Rudhrabatla et al. (2020)
	Tat-peptide	SARS-CoV-2 treatment	2020	Ansari et al. (2020)
	DR5 antibody	Breast cancer	2021	Pindiprolu et al. (2021)
	Acriflavine	Anti-proliferative	2021	Vandghanooni et al. (2021)
Brain	Phenytoin	Status epilepticus	2022	Mohammad et al. (2022)
	Buspirone	Depression	2021	Yasir et al. (2021
	Venlafaxine HCl	Depression	2021	Saeedi et al. (2021)
Pulmonary	SiRNA	Lung diseases	2021	Wang J-L et al. (2021)
	Itraconazole	Antifungal	2021	Shadambikar et al. (2021)
	Insulin	Diabetes	2022	Yadav P and Yadav (2022)
	pp53-EGFP plasmid DNA	Lung cancer	2021	Kumar and Chawla (2021)
Dermal and transdermal	Lawsone	Anti-proliferative	2021	Rasouliyan et al. (2021)
	Vit A	Anti-aging	2021	Boskabadi et al. (2021)

14. The topical route of administration

Skin correlation is a common illness all over the world (Seth et al. 2017). The main challenge for curing this illness is the low efficiency of drugs to permeate through the skin. The stratum corneum is the main skin barrier. This can however be bypassed by changing the permeation from follicles or transcellular to paracellular. SLNs and NLCs have been fabricated to enhance permeation or penetration in the skin. Topical amphotericin B SLNs were prepared by a novel solvent diffusion technique with slight modification and lyophilized with and without cryoprotectants to determine their stability. It was reported that the SLNs particle size considerably enlarged in the SLN formulations lyophilized without cryoprotectants. Lipid nanoparticles have several benefits for manipulating drug delivery profiles (Table 5) (Butani et al. 2016; Chen et al. 2017).

Table 5. Advantages/disadvantages of lipid nanoparticles as topical drug delivery systems.

Advantages

Disadvantages

Improved skin penetration (Garcês et al. 2018) Biocompatible and biodegradable in nature (Jacob et al. 2022) Accumulation and film preparation enhances skin hydration (Patel et al. 2019) Simple preparation route (Ghasemiyeh and Mohammadi-Samani 2018) Enhanced drug solubility (Bhatt S et al. 2018) Avoids systemic absorption and side effects (Khater et al. 2021) Possibility of specific follicular targeting (Lauterbach and Müller-Goymann 2015)

Limited transdermal drug delivery (Weber et al. 2014) Loss of large quantities of the drug (Beloqui et al. 2016) Deficiency of robust controlled drug release (Lauterbach and Müller-Goymann 2015)

14.1. Oral administration

High hepatic first-pass effect and, or partial drug solubility leads to low oral bioavailability which is the most significant challenge in the oral drug delivery system. Enhanced oral bioavailability is obtained by incorporating nanoparticle-based drug delivery systems. The surface modification of nanoparticles with chitosan improved the oral absorption of drugs (Enayatifard et al. 2018; Tan and Billa 2021). NLCs and SLNs indicate the benefit of extended drug release ability to keep a constant plasma concentration. P-glycoprotein efflux pumps and enzymatic or chemical degradation are other central issues in the oral drug delivery system. Lipid nanoparticles could improve lymphatic transport and inhibit the first-pass hepatic effect. For instance, a baicalin-NLC carrier system for oral delivery to improve bioavailability. The NLC was synthesized through emulsion-evaporation and low temperature-solidification technique. The drug loading and entrapment efficiency were 3.54% and 59.51%, respectively (Cirri et al. 2017). Lipid nanoparticles have several advantages/disadvantages when used for the oral route and have been tabulated (Table 6).

Table 6. Advantages/disadvantages of lipid nanoparticles as oral drug delivery systems.

Advantages

Disadvantages

Enhanced oral bioavailability (Nasirizadeh and Malaekeh-Nikouei 2020) Decreased hepatic first-pass metabolism (Poovi and Damodharan 2018) Protects drugs from intra-enterocyte metabolism (Gautam et al. 2020) Avoids undesired plasma peak (Mendoza-Muñoz et al. 2021) Modulated and controlled drug release (Rajagopal V et al. 2022) Enhanced AUC and MRT values (Asif et al. 2022) Shorter onset of action and a longer duration time (Cirri et al. 2017)

Lipid dispersions comprise of a high volume of water (Beloqui et al. 2014) Drug expulsion during storage (Beloqui et al. 2014) Inhibited loading capacity for hydrophilic drugs (Zhang et al. 2016) Polymorphic transitions (Pandita et al. 2014) Particle size progression during storage time (Rao S and Prestidge 2016) Gelation of lipid dispersions (Tran et al. 2014)

14.2. Ocular administration

Ocular drug delivery has several drawbacks due to the physiological and anatomical characteristics of the eyes. Drug delivery is often to the eye’s frontal segment. Conjunctival blood flow, ocular blood barrier, corneal epithelium, and tear drainage are often challenges that have to be overcome. Lipid nanoparticles can cross the ocular blood barrier, control drug release, and protect drugs from lacrimal enzymes. In gene therapy, non-viral gene delivery containing SLNs and NLCs have been used for retinal targeting in retinal diseases. Indomethacin (IN)-SLNs and NLCs were formulated to examine their potential usage in topical ocular delivery. IN-loaded SLNs were fabricated through a hot homogenization technique. The surface modification of the SLNs with chitosan improved the ocular penetration of IN. IN SLNs (0.1% w/v) and NLCs (0.8% w/v) were successfully achieved (Chetoni et al. 2016). A summary list of advantages/disadvantages of this administration method is detailed in Table 7.

Table 7. Advantages/disadvantages of lipid nanoparticles as ocular drug delivery systems.

Advantages

Disadvantages

High encapsulation efficiency (Campos J et al. 2020) High ocular permeability (Tan F et al. 2021) Sufficient pharmacokinetic features (Nair et al. 2021) Extended and controlled release (Khames et al. 2019) Swelling ocular bioavailability and distribution (Nair et al. 2021) Inhibits ocular toxicity (Bonilla et al. 2021) Positively charged lipid nanoparticles have a longer ocular retention time because of close contact with negatively charged mucous (Başaran et al. 2010) Good stability and biocompatibility (El-Emam et al. 2021)

Preliminary burst release from SLNs (Attama et al. 2008) Low drug loading capacity (Chetoni et al. 2016) Formulation and most of the reported studies were just in vitro valuation (Sánchez-López et al. 2017) Lipid nanoparticles toxicity on retinal cells have not been extensively studied (Seyfoddin et al. 2010)

14.3. Parenteral administration

Lipid nanoparticles’ advantages/disadvantages are summarized in Table 8. Drug-loaded lipid nanoparticles can be injected intramuscularly, subcutaneously, intravenously, and directly adjacent to the target organs. In this manner, NLCs are suitable alternatives whereas SLNs are not appropriate carriers because of their inadequate drug loading. Carvacrol NLCs were prepared using a warm microemulsion technique and considered the effect of lipid matrix and concentration of components on the NLCs formation. The NLCs formulation with the lowest particle size (98 nm), highest encapsulation efficiency and narrowest size distribution, was optimized by using surfactant and beeswax (HLB = 9) as solid lipid and 5% of lipids (Galvão et al. 2020).

Table 8. Advantages/disadvantages of lipid nanoparticles as parenteral drug delivery systems.

Advantages

Disadvantages

Scale-up achievability (Santonocito and Puglia 2022) Long physical stability Organized and extended drug release (Elbrink et al. 2021) Increase in drug plasma peaks (Rizvi et al. 2019) Lower clearance rate and smaller volume of distribution (Ajorlou and Khosroushahi 2017) Inhibited side effects (Joshi and Müller 2009) Good potential as vaccine adjuvants (Tretiakova and Vodovozova 2022) Longer drug circulation time (Rudhrabatla et al. 2020) Lower cytotoxicity (Galvão et al. 2020) Enhancing drug bioavailability (Hosseini et al. 2016) Improving drug permeation (Bhise et al. 2017)

Drug burst release by erosion mechanism (Wissing et al. 2004) Lack of wide clinical studies (Wong et al. 2007) Low drug load for hydrophilic drugs (Attama 2011) Drug expulsion (Wissing et al. 2004) RES clearance for systemic cytotoxic drug delivery(Selvamuthukumar and Velmurugan 2012) Accumulation of lipid in the liver and spleen may cause pathological alteration (Prasad and Chauhan 2014)

14.4. Pulmonary delivery

For both systemic and local management, the pulmonary drug delivery system is a non-invasive method of drug delivery. Through this direct delivery profile, drug amount may be reduced, subsequently decreasing the drug adverse effects. Among delivery systems, lipid nanoparticles containing SLNs and NLCs for the pulmonary delivery systems have been examined. For instance, phosphodiesterase type 5 inhibitors – among which sildenafil citrate – show a key role in the cure of pulmonary hypertension. SLNs were prepared using a modified melt emulsification method. A sustained release and high encapsulation efficiency (88–100%) of the cargo above 24 h was observed. Besides, sterilization via autoclaving and nebulization with a jet nebulizer affected the drug entrapment and the colloidal stability of SLNs, demonstrating their potential as a pulmonary delivery system (Makled et al. 2017). A summary list of the advantages/disadvantages of this method can be found in Table 9.

Table 9. Advantages/disadvantages of lipid nanoparticles as pulmonary drug delivery systems.

Advantages

Disadvantages

Enhanced biopharmaceutical features (Gordillo-Galeano et al. 2021) Extended drug release (Haque et al. 2018) Improved bioavailability (Hidalgo et al. 2015) Extended drug residence time in the lung (Abdelaziz et al. 2019) Potential in lung cancer treatment (Wang J et al. 2021) Potential gene delivery of cationic SLNs (Abdelaziz et al. 2019) Prevention of adverse drug effects (Paranjpe and Müller-Goymann 2014) Low toxicity (Pardeike et al. 2011) Enhanced patient compliance (Ahmed et al. 2020) Long dosing intervals (Yue-Xing et al. 2018) Mucoadhesiveness (Ahmad et al. 2020) Inhibiting immature peptide degradation and proteins in pulmonary systemic drug delivery systems (Weber et al. 2014)

Alteration in drug release patterns due to lipase degradation in some lipid matrix compositions (Cipolla et al. 2014) Toxic effects may be achieved from burst drug release of these nanocarriers (Xiang et al. 2007) Rapid clearance (Hidalgo et al. 2015) Not appropriate for deep lung delivery due to their small particle size (Cipolla et al. 2014) Loss of loaded drug for the duration of nebulization (Weber et al. 2014)

14.5. Brain delivery

Drug delivery to the brain is one of the significant challenges due to the BBB. Nanoparticles are appropriate as brain drug delivery candidates because they can subsequently pass the reticuloendothelial system (RES). Inadequate permeation of drugs across the BBB and transported drugs efflux from the brain to blood circulation are two main challenges in brain drug delivery. To address these concerns, SLNs and NLCs as colloidal drug delivery systems have been employed. Novel levofloxacin/doxycycline (LEVO/DOX)-loaded SLNs were synthesized via an emulsification method through high-speed homogenization followed by ultrasonication. The results of the pharmacokinetic study of the optimized SLN-HPMC gel in plasma and the brain showed a considerable increase in the brain peak concentration and the AUC_0–360 min in comparison to the intranasal LEVO/DOX free solution (Hady et al. 2020). The advantages/disadvantages of lipid nanoparticles used in brain drug delivery systems are documented in Table 10 (Tosi et al. 2016).

Table 10. Advantages/disadvantages of lipid nanoparticles as brain drug delivery systems.

Advantages

Disadvantages

Enhancement in brain uptake of drugs (Hady et al. 2020) Biocompatibility, biodegradability, and low cytotoxicity(Dal Magro et al. 2017) Bypassing blood–brain barrier (BBB) (He et al. 2019) Enhancing drug retention time in the brain (Blasi et al. 2007) Prevention of efflux system (Tosi et al. 2016) Controlled drug release (Blasi et al. 2011) Non-invasive brain drug delivery(Trapani et al. 2021) Possibility of both hydrophilic and lipophilic drug encapsulations (Kaur et al. 2008) Possibility of site-specific brain targeting (Teixeira et al. 2022) Lipid nanoparticles with particle size less than 100 nm (Ganesan et al. 2019)

The possibility of the detection of lipid nanoparticles through RES cells (Blasi et al. 2007) Rapid clearance of IV administered drug-loaded SLNs from the systemic circulation (Dal Magro et al. 2017)

15. Nanomedicines approved for clinical use

A variety of nanotechnologies and nanomaterials have already achieved regulatory approval and some are in the clinical setting for further investigation. These include anticancer drugs such as doxorubicin, cemiplimab, paclitaxel (Kemp and Kwon 2021) and antifungals such as amphotericin B (Patra et al. 2018), ambisome (Foulkes et al. 2020), and natamycin (Chandasana et al. 2014). At the time of writing this review, a search was performed on the website www.clinicaltrials.gov, and a number of relevant consequences corresponding to the keywords ‘nanoparticles’ and ‘lipid’ were determined and some of them are presented in Table 11.

Table 11. Lipid nanoparticle drug delivery systems on currently active clinical trials.

Track number	Status	Drug	Disease	Route of administration
siRNA therapy
NCT01437007	Phase I	TKM-080301	Colorectal cancer with hepatic metastases, pancreas cancer with hepatic metastase, gastric cancer with hepatic metastase, breast cancer with hepatic metastase, ovarian cancer with hepatic metastase	IA injection
NCT03159416	Phase I	Inclisiran	Renal impairment	SC injection
NCT01960348	Phase III	Patisiran (ALN-TTR02)	hTTR-mediated amyloidosis	IV infusion
NCT01858935	Phase I	ND-L02-s0201	Hepatic fibrosis	IV infusion
NCT03060577	Phase II	Inclisiran, evolocumab	Cardiovascular disease, type 2 diabetes	SC injection
NCT02227459	Phase I	ND-L02-s0201	Hepatic fibrosis	IV infusion
mRNA therapy
NCT05057182	Phase IV	BNT162b2	COVID 19	IM injection
NCT04416126	Phase I	ARCT-810	OTC deficiency	IV infusion
NCT04638400	Phase IV	Simvastatin 40 mg, ezetimibe 10 mg	Inflammation, atherosclerosis, hypercholesterolemia	Oral
NCT04442347	Phase I	ARCT-810	OTC deficiency	IV infusion
NCT03323398	Phase I Phase II	mRNA-2416, durvalumab	Relapsed/refractory solid tumor malignancies or lymphoma, ovarian cancer	Intratumoral injection
NCT04283461	Phase I	mRNA-1273	COVID-19	IM injection
Others
NCT02971007	Phase II	CAMB	Vulvovaginal candidiasis	Oral
NCT02629419	Phase II	CAMB	Mucocutaneous candidiasis	Oral
NCT04148833	Phase II Phase III	Paclitaxel	Aortic and coronary atherosclerotic disease	IV injection
NCT03823040	Phase I	Oxiconazole	Tinea pedis/tinea versicolor/tinea circinate	SLNs loaded gel for topical application

CAMB: encochleated amphotericin B; HSP47: heat shock protein; IM: intramuscular; IV: intravenous; OTC: ornithine transcarbamylase; PLK1: polo-like kinase-1; TTR: transthyretin.

16. Conclusions

Compared to other colloidal and polymeric nanocarriers, lipid nanoparticles are novel drug delivery systems that present several benefits. Ease of scalability, biodegradability, biocompatibility, and ability to achieve controlled release profiles are some of the most advantageous qualities that these lipid carriers present. An understanding of the two kinds of lipid nanoparticles (SLN and NLC) allows for targeted drug delivery using various methods of administration. Cytotoxicity of SLN/NLC has been considered in several publications via using various combinations of surfactants and lipids on different cell lines. In many examinations, the consequences demonstrate low levels of cytotoxicity. Furthermore, there is limited information associated with unwanted side-effects linked to the administration of lipid particles. It is therefore essential to consider the issues related to the physical instability of the nanoparticles, chiefly the formation of unexpected gelation or aggregates during administration, which can be hazardous at the time of usage. In a few cases, the reason for the observed side effect could perhaps be related to the choice of excipients. An appropriate selection of SLN/NLC dose and selection of excipients are therefore the most critical items for SLN and NLC safety. The concept of surface modification is also very promising in a bid to moderate these challenges. PEG coatings on nanoparticles shield the surface from aggregation, RES and prolonging systemic circulation time in the bloodstream. Additionally, formulations attributed to the stabilization of particles via the use of surfactants have been reported to demonstrate less toxicity in comparison to their lipid alone nanoparticles. For example, for poloxamer 188 and polysorbate 80, two commonly used surfactants in SLN and NLC formulations, sufficient evidence of their safety has been confirmed. Possible deficiency for SLN and NLC is that they have the potential to induce oxidative stress, hence induction of inflammatory response. Nevertheless, the evidence is still restricted. SLN and NLC are attractive candidates that will permit effective and targeted delivery of hydrophilic and hydrophobic drug compounds. Intracellular entry of drugs and its extended-release profile are the main properties of SLN/NLC drug delivery mechanisms that can diminish side effects and provide treatment of the root cause of the illness rather than the symptoms of the illness. Lipid nanoparticles are therefore considerable drug delivery systems for the delivery of different types of pharmaceutically active ingredients from small molecules to proteins and potentially genes.

Figure 3. Preparation of solid lipid nanoparticles by (a) hot homogenization and (b) cold homogenization techniques.

Figure 4. Emulsification-solvent evaporation procedure to prepare solid lipid nanoparticles.

Figure 5. Emulsification solvent diffusion method to prepare solid lipid nanoparticles.

Figure 6. Solvent injection method to develop solid lipid nanoparticle.

Figure 7. Membrane contactor method to manufacture solid lipid nanoparticles.

Figure 8. Preparation of solid lipid nanoparticles through phase inversion temperature method.

Figure 9. Preparation of solid lipid nanoparticles via coacervation method.

Figure 10. Preparation of solid lipid nanoparticles by microemulsion method.

Figure 11. Supercritical fluid method to manufacture solid lipid nanoparticles.

Figure 12. Combination of high shear homogenization and ultrasonication methods to manufacture solid lipid nanoparticles.

Abbreviations
99mTc	=	technetium-99
AUC	=	area under the curve
BBB	=	blood–brain barrier
CTAB	=	cetyltrimethylammonium bromide
CYPs	=	cytochrome P450s
DTX	=	docetaxel
EPR	=	enhanced permeability and retention
HPH	=	high-pressure homogenization
IN	=	indomethacin
LEVO/DOX	=	levofloxacin/doxycycline
MRT	=	mean residence time
NLCs	=	nanostructured lipid carriers
PCS	=	photon correlation spectroscopy
PEG	=	polyethylene glycol
P-gp	=	P-glycoprotein
QbD	=	quality by design
RES	=	reticuloendothelial system
SLNs	=	solid lipid nanoparticles
Tf	=	transferrin

Disclosure statement

No potential conflict of interest was reported by the author(s).