Nanostructured lipid carrier system: A compendium of their formulation development approaches, optimization strategies by quality by design, and recent applications in drug delivery
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Shamama Javed
,
Bharti Mangla
Abstract
The lipid-based colloidal carriers, such as nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), nanocapsules, liposomes, and microemulsion, are the latest and significant entrants in the development of drug delivery systems owing to their myriad advantages. The NLCs are second-generation SLNs having unstructured matrix, have high drug loading, and provide long-term drug stability in comparison to SLNs and other colloidal systems, which show lower drug loading and experience burst release/drug expulsion during storage. This review is aimed to summarize the formulation development and optimization strategies for NLCs as reported in the literature collected from authentic databases. Various types of NLCs, formulation components, methods of preparation, characterization parameters, optimization (statistical designs) strategies, toxicity, regulatory aspects, and their applications in oral, parenteral, ocular, pulmonary, nose-to-brain, tumor targeting, and transdermal drug delivery have been dealt in detail. Patents granted on the NLCs have also been enlisted.
1 Introduction
The versatility in the field of nanomedicine is evolving with passing time and extensive investigations are being performed by scientists worldwide. The nano-drug delivery systems are classified as polymeric systems, such as nanocapsules, nanospheres, nanofibres, and nanodiscs, and lipid-based systems, such as liposomes, transferosomes, ethosomes, niosomes, virosomes, phytosomes, micelles, solid lipid nanoparticles (SLNs), and nanostructured lipid carrier (NLC) systems.
Lipid nanoparticles (LNPs) gained attention in the early 1990s when the first-generation SLNs were created [1]. The SLNs created a lot of interest worldwide and quite several research groups started working on SLNs in the first years of their discovery, and to date, SLNs remain an alternative approach to current conventional carriers, such as emulsions, liposomes, and polymeric nanoparticles [2,3]. The SLNs are within the range of submicron (50–1,000 nm) and the appropriate selection of lipids and surfactants will affect particle size (PS), long-term storage stability, drug loading (DL), and release behaviors [4,5]. Their major benefit is the prospect of their large-scale industrial development [6,7]. Possible SLN-related problems, such as restricted DL capacity, change in drug release profile, and expulsion of drugs during storage, are either avoided or minimized using the new-generation NLCs [8].
NLCs are the second generation of SLNs, composed of a binary mixture of solid lipid and liquid lipid, the average size in the range of 10–500 nm [9]. Here, the solid lipid is mixed with the liquid lipids preferably in a ratio of 70:30 up to 99.9:0.1. They contain a special nanostructure, which results in the improvement in DL as well as firm incorporation of the drug inside increasing the storage time. The NLCs can be administered to the patients using oral, topical, intravenous (IV), as well as ocular routes [10]. The advantages associated with NLCs include easy scale-up, drug targeting, controlled drug release profile, longer stability profile, high DL, biocompatible, biodegradable, and nontoxicity [11]. The selection of drugs, lipids (solid and liquid), surfactants, and cryoprotectants is crucial in their development and optimization [12,13].
The quality-by-design (QbD) approach has attracted much attention recently for the optimization of manufacturing variables to achieve safe and effective pharmaceutical formulations. It has been applied successfully in the optimization of SLNs and NLCs for the screening of excipients used and in the study of drug–lipid compatibility. Using the QbD, the quality target product profile (QTPP) and critical quality attributes (CQAs) of the product are identified followed by the evaluation of critical material attributes (CMAs) and critical process parameters (CPPs) to ensure the quality of the finished product [14]. Several mathematical models and statistical tests are available to apply to the parameters that influence the physical characteristics of the nanoformulations. These parameters include the variation in the composition of lipids, emulsifiers, and the manufacturing parameters including time and rate of emulsification, time and amplitude of sonication, pressure, and number of cycles of homogenization, etc. The effect of these critical parameters on the PS, polydispersity index (PDI), zeta potential (ZP), drug encapsulation efficiency (EE), and in vitro drug release was studied [14].
This review is aimed to summarize and highlight the preparation and characterization techniques of NLCs along with their applications in the biomedical field. The toxicity profile, recent patents, and the regulatory considerations associated with NLCs are also covered.
2 Types of NLCs
The NLCs can be divided into three types: imperfect, amorphous, and multiple oil-in-solid fat-in-water (O/F/W) based on differences in their lipid and oil composition.
2.1 Imperfect NLCs
The preparation of imperfect NLCs requires the mixing of structurally dissimilar lipids, such as glycerides and fatty acids, creating imperfections in the crystal order.
2.2 Amorphous NLCs
In the amorphous form of NLCs, lipids are combined in such a way that they cannot crystallize and a structure-less amorphous matrix is obtained. Special lipids, such as hydroxyoctacosanyl hydroxystearte or isopropyl myristate, are mixed with the solid lipid. Consequently, NLCs exist in an amorphous state instead of the ordered one preventing drug exclusion due to β modifications during its storage.
2.3 Multiple O/F/W NLCs
Generally, the solid matrix of many O/F/W-type NLCs contains distributed nanosized liquid oil compartments, which increases the DL as the drug solubility is increased due to these nanosized compartments [15,16]. Preferentially, these lipid particles are suited for the incorporation of lipophilic drugs and the hydrophilic drugs can only be incorporated in low concentrations. In certain cases, a water-insoluble lipid conjugate is formed from the water-soluble drugs by conjugating it with lipids using covalent linkage or salt formation. These lipid conjugates can be melted and processed to afford the lipid–drug conjugate nanoparticles and these lipidic conjugates can have 30–50% DL for water-soluble drugs [17].
3 Components of NLCs
The major components of NLCs include solid lipids, liquid lipids, surfactants, and surface modifiers [18]. Solid lipids form the solid lipid core of the NLCs and act as the matrix-forming lipids. Various solid lipids along with their melting point and compositions used in the NLC formulations are given in Table 1. On the other hand, liquid lipids (oils) are the lipophilic excipients that are used to integrate the solid lipid core and to reduce its crystallinity [19]. In the preparation of NLCs, two types of oils are used: natural oil or synthetic oil, and most of the drugs are dissolved in synthetic oils [20]. Various types of synthetic and natural oils used in the formulation of NLCs along with their examples are summarized in Table 2.
List of solid lipids, their melting points, and compositions used in the NLC formulations
| Solid lipids | Melting point (±5°C) | Compositions used |
|---|---|---|
| Stearic acid/octadecanoic acid/cetylacetic acid | 69.6 | Stearic acid + palmitic acid + small concentration of oleic acid (HLB value = 15) |
| Glyceryl monostearate (GMS) | 57–65 | Monoglycerides + diglycerides of fatty acids (HLB value = 3.8) |
| Glyceryl monostearate polyoxylethylene stearates (Gelot™ 64) | 55–62 | Mixture of glycerol monostearate and PEG-75 (MW 3,500) stearate (C18) (HLB value = 10) |
| Carnauba wax | 82 | Hydroxy acid aliphatic ester + p-methoxy cinnamic acid aliphatic ester + p-hydroxy cinnamic acid aliphatic diester + oxy-polyhydric alcohol (HLB value = 12) |
| Cetyl palmitate | 54 | Ester derived from hexadecanoic acid and hexadecanol (HLB value = 10) |
| Glyceryl palmitostearate (Precirol® ATO 5)/glyceryl distearate | 50–60 | Mono- + di- + triglycerides of C16 and C18 fatty acids (HLB value = 2) |
| Glyceryl behenate (Compritol® 888 ATO)/glycerol dibehenate | 65–77 | Mono- + di- + triesters of behenic acid (HLB value = 2) |
| Compritol® HD5 ATO/behenoyl polyoxyl-8 glycerides | 60–67 | Mono- + di- + triglycerides of PEG8 and mono- + diesters of behenic acid (HLB value = 5) |
| Geleol™ mono- and diglycerides NF/mono- and diglycerides | 54–64 | Mono- + di- + triesters of palmitic acid (C16) and stearic acid (C18) (HLB value = 3) |
| Grades of Softisan – it is a mixture of triglycerides graded based on even-numbered, saturated, and non-branched natural fatty acids of chain length C8–C18 and are of vegetable origin | ||
| Softisan 100 | 33–35 | Hydrogenated co-glycerides + mixture of C10–C18 fatty acid triglycerides |
| Softisan 154 | 53–58 | Hydrogenated palm oil + mixture of C10–C18 fatty acid triglycerides |
| Softisan 142 | 42–44 | Mixture of C10–C18 fatty acid triglycerides of |
| Softisan 138 | NA | Mixture of C10–C18 fatty acid triglycerides and diglycerides |
| Softisan 645 | NA | Mixture of diglycerol with caprylic, isostearic, capric, stearic, and adipic acid |
| Softisan 378 | 38 | Mixture of caprylic/capric/myristic/stearic triglycerides |
| Softisan 601 | 40–45 | Hydrogenated coconut oil + ceteareth-25 + triglycerides (glyceryl cocoate) |
| Softisan 649 | 35 | Mixture of diglycerol, caprylic, isostearic, capric, stearic acid, hydroxystearic, and adipic acid |
| Grades of Witepsol® – synthetic hard wax, available in different series | ||
| Witepsol®H (5,12,15,19,32,35,37) | 31–38 | Mixture of triglycerides + diglycerides (15%) + monoglycerides (1%) with low hydroxy value |
| Witepsol® W (32,25,35,45) | 32–35.5 | Mixture of triglycerides (65–80%) + diglycerides (10–35%) + monoglycerides (1–5%) with high hydroxy value |
| Witepsol® S (51,55,58) | 30–35.5 | Non-ionic ethoxylated emulsifier |
| Witepsol® E (75,76,85) | 37–44 | Series E are hard fats having melting point more than the body temperature |
| Imwitor grades | ||
| Imwitor 372P | 62 | Glyceryl stearate citrate, HLB = 12 |
| Imwitor 491 | 66–77 | Mixture of GMS and monoglycerides with HLB value 4 |
| Imwitor 900K | 61 | Glycerol monostearate (40–55%, type I), HLB = 3 |
| Imwitor 928 | 34 | Mixture of glyceryl cocoate and medium-chain partial glycerides |
| Dynasan grades | ||
| Dynasan® 116 | 63–68 | Tripalmitin |
| Dynasan® 118 | 72 | Glyceryl tristearate/triglycerides |
| Dynasan® 114 | 55–58 | Solid triglycerides (triglycerides/trimyristin) |
| Others | ||
| Lauric acid (dodecanoic acid) | 43.2 | Mixture of saturated fatty acid with a 12-carbon atom chain |
| Apifil® CG/PEG-8 Beeswax | 59–70 | It is a polar beeswax derivative by esterification of beeswax with polyethylene glycol (PEG). PEG group imparts hydrophilic properties to beeswax. |
| Tefose® 63 | 49 | Mixture of ethylene glycol palmitostearate + PEG-6 palmitostearate + PEG-32 palmitostearate (HLB value = 9.5) |
| Tristearin/glyceryl tristearate | 54–72 | It is derived from three units of stearic acid |
Synthetic and natural oils used for the formulation of NLCs and their examples
| Types of oil used | Examples |
|---|---|
| Synthetic oils | |
| Medium-chain mono- and diglycerides of caprylic/capric acid | Capmul MCM |
| Imwitor | |
| Propylene glycol (PG) fatty acid esters including PG monolaurate | Lauroglycol FCC |
| Capmul PG-12 | |
| Lauroglycol 90 | |
| PG diester of caprylic/capric acid | Labrafac PG |
| PG dicaprylate | Miglyol 840 |
| Medium-chain triglycerides and their esters including capric/caprylic triglycerides | Akomed R, Akomed E, Miglyol 810, Captex 355, Crodamol GTCC, Neobee M5 |
| Fractionated coconut oil | Miglyol 812, Triacetin, Labrafac CC, Captex 300 |
| Long-chain monoglycerides, such as glyceryl monolinoleate | Maisine 35 |
| Glyceryl monooleate | Peceol, Capmul GMO |
| Capric/caprylic/diglyceryl succinate | Miglyol 829 |
| Fatty acids, such as oleic acid and caprylic acid | Crossential O94 |
| Fatty acid esters | Ethyl butyrate, ethyl oleate (Cardamol EO), isopropyl myristate, ethyl butyrate, isopropyl palmitate |
| Mineral oil | Liquid paraffin |
| Vitamins | Vitamin E/α-tocopherol |
| Diethylene glycol monoethyl ether | Transcutol HP |
| Natural oils | |
| Fixed oils | Sunflower oil, shark liver oil, palm oil, sesame oil, olive oil, rice bran oil, margosa oil, mustard oil, jojoba oil, cod liver oil, cottonseed oil, arachis/peanut oil, castor oil, soyabean oil, chaulmoogra oil |
| Essential oils | Pumpkin seed oil, lemon grass oil, cinnamon oil, peppermint oil, citronella oil, lavender oil, clove oil, garlic oil, geranium oil |
The entrapment efficiency, stability, drug-loading capacity, and the controlled release behavior of NLC formulations are influenced by their lipid component [4]. These lipids are well-tolerated physiologically and are approved as generally regarded-as-safe (GRAS) compounds. Although there are no specific guidelines as such for their selection, however, the drug solubility in lipids is one of the criteria to select an appropriate lipid. The third component surfactant is often a polymeric material that is used to provide stability to the lipid crystal suspension, maintain uniform PS distribution, and prevent particle growth. Various properties of NLCs, such as the viscosity and water-solubilizing capacity, are determined by the surfactants and they play a crucial role in the formulation development. They also prevent the agglomeration and dispersibility of the particles and provide stability to the formulation.
Surfactants are amphiphiles that reduce the surface tension and therefore facilitate the partition of particles between the two phases. The hydrophilic head of the surfactants remains oriented toward the aqueous phase and the lipophilic groups get oriented toward the lipid [21]. Surfactants are selected based on the chosen lipid component as they should be physico-chemically compatible with each other. Other factors that determine the selection of surfactants include the route of administration and the hydrophilic–lipophilic balance (HLB) value of the surfactant. Another compound, known as the co-surfactant, is used to further decrease the interfacial tension and to enhance the drug solubility in SLNs/NLCs to a value lesser than that of the surfactants alone. A few examples of surfactants and co-surfactants used in the preparation of NLCs are listed in Table 3 [22].
Various surfactants, co-surfactants, and surface modifiers used in the formulation of NLCs
| Agents | Examples |
|---|---|
| Surfactants/co-surfactants | Soy lecithin (Lipoid S 75, Lipoid S 100), phosphatidyl choline 95% (Epikuron 200), Poloxamer-188 (Pluronic F-68), egg lecithin (Lipoid E 80), Cremophor EL, Poloxamer 407, lecithin, Poloxamine 908, Solutol HS 15, Tyloxapol, Polysorbate 20 (Tween® 20), Polysorbate 60 (Tween® 60), Polysorbate 80 (Tween® 80), sodium cholate, taurodeoxycholic acid sodium, sodium glycocholate, butyric acid and butanol, sodium dodecyl sulfate, cetylpyridinium chloride, polyvinyl alcohol, and sodium oleate |
| Surface modifiers | Folate, PEG 2000, biotin, ferritin, transferrin, β-d-galactosides, mannose, l-arginine, oligo-chitosan, hyaluronic acid, wheat germ agglutinin |
Another important component of NLCs includes the surface modifiers, which are the ingredients that add special properties to the formulation and influence the in vivo effects of NLCs. Several surface modifiers are used to modify the NLCs and a few of them are listed in Table 3. These surface modifiers may be attached with some linkage, such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG, succinic acid-PEG 2000, folate-PEG-Chol, and mannan-PEG-phosphatidylethanolamine. The surface modifications of SLNs are generally inspired by the methods used for the functionalization of liposomes. Special functionalized lipids are included in the SLNs/NLCs’ formulation using the post-insertion method. Another feasible approach to modify the surface of SLNs/NLCs is by linking the coating agent used in the formulation to an excipient, which is an integral part of the formulation. This is done by using N-hydroxy succinimide/1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide chemistry forming covalent bonds and is a well-validated approach in designing polymeric particles systems [23,24].
4 Methods of preparation of NLCs
Techniques used in the preparation of SLNs can also be used for the preparation of NLCs [25]. These preparation techniques are divided into three major categories: high-energy approaches, low-energy approaches, and approaches with organic solvents. Various critical aspects in the formulation development of NLCs are discussed henceforth [26] and are depicted in Figure 1. Various advantages and disadvantages are associated with different techniques and the selection of appropriate methods for the preparation of NLCs depends upon the characteristics of the drug and the PS required. For instance, the high-pressure homogenization (HPH) technique utilizes both high pressure and high temperature and is the most commonly employed method for NLCs’ preparation. It has the advantage of utilizing high temperature, which decreases the viscosity of mixed liquids and thereby reduces the PS; however, the disadvantage associated with this method is the probability of degradation of drug and carrier due to higher temperature [27]. Therefore, this method is more suitable for highly lipophilic and insoluble drugs and not for hydrophilic ones. Other advantages of this technique are the avoidance of organic solvents and the scale-up suitability. On the other hand, the emulsion evaporation technique includes evaporation of the oil phase by heating under reduced pressure; therefore, the advantage of this technique is the avoidance of heat; however, the major disadvantage is the use of solvents, which may lead to toxicity due to solvent residues. Similarly, the advantages of the solvent dispersion technique include speed, simplicity, and avoidance of major instruments; however, this method is not suitable for the preparation of NLCs at an industrial scale and also is associated with chances of solvent residue in the final product. The microemulsion technique has the advantage of the usage of a small amount of drug and simplicity; however, it requires high concentrations of emulsifiers.
Methods of preparation of NLCs. (a) Hot homogenization technique, (b) cold homogenization technique, (c) phase inversion temperature (PIT) technique, (d) coacervation technique, (e) supercritical fluid (SCF) technique, (f) high shear homogenization/ultrasonication technique, (g) double emulsion technique, (h) microemulsion technique, (i) membrane contactor technique, (j) emulsification–solvent evaporation technique, (k) emulsification solvent diffusion technique, and (l) solvent injection technique.
4.1 High-energy approaches
4.1.1 HPH technique
The HPH technique remains one of the most preferred methods owing to the shorter production time in comparison to other techniques, easier scale-up, and lack of solvents [27]. HPH methods can be divided into hot HPH and cold HPH protocols [28]. The hot HPH process includes melting solid lipids first followed by mixing them with liquid lipids and drugs. This dispersion is then mixed with hot surfactant solution in water resulting in a pre-emulsion, which upon homogenization at up to three cycles at 500 bar at high temperature gives SLNs/NLCs as the end desired product. Generally, the high temperature reduces the PS by decreasing the viscosity of lipids; however, the chances of drug or carrier system degradation increase. Whereas, in cold HPH, the lipid blend is melted and mixed to form lipid microparticle dispersion, which is then mixed with a cold surfactant solution to form a pre-suspension, which upon homogenization at up to 5–10 cycles at 1,500 bar at room temperature gives SLNs/NLCs as the end product.
4.1.2 Melt emulsification homogenization technique
In this technique, the solid lipid, the liquid lipid, and the drug are mixed and dispersed into the aqueous surfactant solution using the probe sonication method. The mixture is then cooled to a low temperature to afford solid NLCs. The important advantage associated with this technique is the avoidance of heat.
4.2 Low-energy approaches
4.2.1 Microemulsion technique
In this technique, the lipid carrier is melted just above its melting point followed by the addition of a drug, auxiliary emulsifier, and deionized water (preheated to the same temperature) to yield a transparent mixture with thermodynamic stability similar to oil-in-water type microemulsion. The obtained mixture is dispersed immediately in ice-cold water (0–4°C) with gentle mechanical stirring forming dispersion of NLCs. The temperature difference between the microemulsion and cold water is the key factor in determining the size of nanoparticles as the rapid cooling prevents the aggregation of these particles resulting in smaller size NLCs. While method simplicity is its advantage, the abundant use of emulsifiers and auxiliary emulsifiers is its disadvantages.
4.2.2 Membrane contractor technique
Lipid is transported through the pores of a membrane at a pressure that keeps the system above the melting temperature of the lipid, resulting in the creation of tiny droplets. The aqueous phase, on the other hand, is cycled within the membrane, and droplets generated at the holes are swept along with it. When the preparation is cooled to room temperature, LNPs are formed. The size and lipid influx of LNPs are influenced by aqueous phase flow velocity, lipid and aqueous phase temperature, membrane pore size, and lipid phase pressure.
4.2.3 Phase-inversion temperature technique
The phase inversion from O/W to W/O emulsion is used in this process, which is a unique, cost-effective, and solvent-free method for the synthesis of LNPs. Step 1 comprises optimizing the quantities of lipid, surfactant, and water, followed by a 4°C increase in temperature from room temperature to 85°C. To achieve the phase inversion zone, the system is subjected to three temperature cycles. The addition of cold water (0°C) in step 2 produces an irreversible shock to the system, causing nanocapsule production.
4.2.4 Coacervation technique
This is a revolutionary solvent-free approach that can even include thermosensitive pharmaceuticals without the use of expensive equipment or hazardous solvents. In the presence of an appropriate amphiphilic polymeric stabilizing agent, a Micellar solution of a fatty acid sodium salt interacts slowly with an acid solution (coacervating solution).
4.2.5 Double emulsification technique
This method, which is based on the solvent emulsification–evaporation process, is mostly used to make LNPs that are loaded with hydrophilic medicines. The medication and the stabilizer are enclosed in the W/O/W double emulsion’s inner aqueous phase. Due to their higher PS than SLNs, these formulations are referred to as lipospheres.
4.3 Approaches with organic solvents
4.3.1 Solvent emulsification evaporation technique
The lipid is dissolved in a water-immiscible organic solvent, such as cyclohexane or chloroform, and then emulsified with continuous stirring in an aqueous phase containing surfactants, resulting in an O/W emulsion. Solvent evaporation and lipid precipitation result from evaporation at decreasing pressure. Although the approach eliminates heat stress, it does have one drawback: the use of an organic solvent.
4.3.2 Emulsification solvent diffusion technique
This approach is similar to the “solvent emulsification–evaporation” method, except that the lipid is dissolved in a somewhat water-miscible organic solvent, such as benzyl alcohol or ethyl formate. The transitory oil-in-water emulsion is poured into the water with constant stirring, causing the dispersed phase to solidify and form LNPs due to organic solvent diffusion. The lipid solidifies as the solvent diffuses to the liquid phase.
4.3.3 Evaporation solvent injection technique
A water-miscible solvent, such as acetone, ethanol, methanol or isopropyl alcohol, or a water-soluble solvent mixture, is used to solubilize lipid, which is quickly injected into an aqueous surfactant solution while being stirred constantly. Excess fat is removed from the resulting dispersion by filtering. This approach has the advantages of being simple to use, efficient, versatile, requiring no specialized equipment (such as a high-pressure homogenizer), and using authorized organic solvents.
4.3.4 Supercritical fluid technique
This technique involves solubilization of the lipid material with the drug in an organic solvent, such as chloroform by adding a suitable surfactant resulting in an organic solution. The organic solution is disseminated in the aqueous phase (that may or may not contain a co-surfactant) and the combination is then homogenized at high pressure to generate an O/W emulsion. The O/W emulsion is injected at a constant flow rate from one end of the extraction column (typically the top), and the supercritical fluid (kept at constant temperature and pressure) is introduced at a constant flow rate counter currently. Continuous extraction of solvent from the O/W emulsions is used for the formulation of LNP dispersions.
5 Lyophilization of NLCs
Lyophilization (freeze-drying) method has been the technique to stabilize the NLCs. One of the purposes of lyophilization is to prolong the product storage duration and preserve it from chemical and physical degradation. Therefore, a solid-state material is easy to obtain using the lyophilization technique and it would readily re-disperse when required. Lyophilization, in general, is based on the sublimation principle (dehydration process) where the water goes straight from a solid state (ice) to a gaseous state without going through a liquid state [29]. During the lyophilization process, cryoprotectants or lyoprotectants are used as stabilizers, which protect the formulation during freeze-drying (cryoprotectant) against the freezing and drying stresses (lyoprotectant). To protect the product from the high stress created during the lyophilization process, cryoprotectants, such as mannitol, trehalose, fructose, sorbitol, lactose, glucose, sucrose, and aerosil, are added in 5–15% w/w concentration [30].
It is the most dependable drying procedure since it does not alter the product’s molecular structure. Cryoprotectants are also known to vitrify at a certain temperature, Tg. Nanoparticles can be immobilized inside a glassy cryoprotectant matrix to avoid the aggregation and protect them from the mechanical stress of ice crystals. Cryoprotectants not only improve the long-term stability of NLCs during storage, but they also serve as bulking agents (which add bulk to the formulation, especially when the product concentration to freeze dry is low) and tonicity adjusters [31]. Surfactant-stabilized NLCs created by an appropriate approach might retain good stability. However, in aqueous solutions, it can have poor chemical and physical stability.
During storage, however, aggregation or other unforeseeable adverse effects may develop. As a result, boosting the stability of NLCs and maintaining their physical qualities is increasingly important. Cryoprotectants were used to lyophilize the NLC solution and protect it against agglomeration during storage, according to many investigations. Tilmicosin NLC suspension was lyophilized using mannitol as a cryoprotectant after being produced by heat homogenization with Compritol 888 ATO, sesame oil, Poloxamer 407, and Tween® 80. The lyophilized products were shown to be more stable over a longer period [32]. NLCs containing lopinavir (LPV) and verapamil were produced utilizing Compritol 888 ATO® and oleic acid as solid and liquid lipids using a hot high-shear homogenization technique. PS and PDI were used to screen many cryoprotectants, including mannitol, sorbitol, sucrose, and trehalose. Trehalose was shown to be superior at preventing LPV-NLC aggregation and improving stability throughout the freeze-drying process. Trehalose has several benefits in comparison to cryoprotectants, such as lesser chemical interactions and a higher glass-transition temperature, both of which may aid nanoparticle stability [33,34]. Rifabutin (RFB)-NLCs for the treatment of tuberculosis were prepared with the help of miglyol-812 (liquid lipid) and Precirol® ATO 5 (solid lipid) via high-shear homogenization and ultrasonication techniques. Aerosil was used as a cryoprotectant and made a stable formulation at 2% w/w of its concentration [35]. Olmesartan NLCs prepared by Precirol ATO 5 and Capmul MCM were lyophilized by mannitol as it resulted in the formation of voluminous, easy to redisperse cake with redispersibility index close to one, and ultimately their long-term stability [36]. Mannitol as a cryoprotectant for the preparation of exemestane NLCs using ultrasonication technique is also reported. Flaxseed oil was used as liquid lipid and Precirol ATO 5 was used as solid lipid for the preparation of the NLCs. NLCs’ lyophilized formulation showed better stability as compared to their suspension throughout the storage period [37].
6 Characterization of NLCs
Owing to the tiny size of the particles and the intricacy of the system, the characterization of NLCs can be challenging. PS and size distribution, ZP, surface charge, particle morphology, polymorphism, thermal behavior of lipids, degree of crystallinity, and lipid modification are relevant parameters to be considered [38]. The PS and size distribution of NLCs are the most essential characteristics that determine their stability, solubility, release rate, and in vivo performance; hence, their accurate measurement is critical [15]. Photon correlation spectroscopy (PCS) and laser diffraction are the most promising and extensively used methods for the PS assessment of LNPs [39,40]. NLCs are generally polydispersed in nature; therefore, the measurement of PDI is vital to understand the size distribution of the nanoparticles. The nanoparticle dispersion is considered to be more monodispersed when the PDI value is low. The majority of studies consider a PDI value of less than 0.3 to be optimal [41,42]. PCS using a Zetasizer NanoZS at 25°C may be used to detect PDI and ZP [43]. The second most essential characteristic parameter is DL and EE, which may be assessed by calculating the amount of drug encapsulated within the nanoparticles. In a nutshell, NLC dispersion is placed in a centrifugal tube and centrifuged for 30 min at 5,000 rpm, after which the quantity of drug in the aqueous phase is evaluated using HPLC [44,45,46]. The following formulae can be used to compute drug EE and DL:
Because these factors are significantly connected with drug incorporation and release rates, determining the degree of lipid crystallinity and the alteration of the lipid are also key components of characterizing NLCs. Lipid crystallization and modification modifications may be greatly slowed due to the tiny size of the particles and the presence of emulsifiers. To assess the state of lipids, differential scanning calorimetry (DSC) and X-ray scattering are commonly utilized [47,48,49]. Varied lipid changes have different melting temperatures and melting enthalpies, which DSC makes use of. The length of the long and short spacing of the lipid lattice may be measured using X-ray scattering. Infrared and Raman spectroscopy are important methods for studying lipid structural characteristics, but their use in characterizing NLC dispersions has yet to be determined [50,51,52,53,54].
7 Optimization of NLCs
Experimental design via the QbD system helps develop a design space statistically, which offers approaches to address the formulation-related problems and it is helpful in improving and validating formulation for better efficacy and patient care [55]. In QbD, we combine experimental data and mechanistic knowledge to predict performance, as it allows us to achieve optimal product design by balancing high-risk and medium-risk to low-risk variables. ICH-Q8 (pharmaceutical development), ICH-Q9 (quality-risk management), ICH-Q10 (pharmaceutical quality system), and ICH-Q11 (development and production of pharmacological substances) are some of the ICH recommendations that focus on the conceptual views of QbD and give some support to manufacturers [56,57,58,59]. The adoption of the QbD approach in the formulation optimization process has led to statistically designed experiments (DOEs) for determining the impact of multiple parameters and their interactions on the product profile. In the process of optimizing NLCs via the QbD approach, much importance is given to develop a relationship between process variables and the method and it involves multiple steps, such as defining the purpose and objectives, QTPP, identifying CMAs, screening of CPPs, identifying working design space, and analyzing CQAs.
At this stage, the QTPP must be well defined through research literature and field experience systematically assessed under the quality risk management strategy, which helps to reduce time and waste of resources. For the NLCs’ preparation, QTTP is set for the improvement of its biopharmaceutical performance to provide therapeutic benefits to the patients. CMAs and CPPs are referred to as independent variables defined by simulation and specific statistical techniques [60]. NLC formulations optimized via basic knowledge of these process parameters with the aid of appropriate experimental design are a must otherwise undesirable outcomes will be achieved (Figure 2). For the nanolipid carrier system, CMAs include API composition, solid lipid concentration, liquid lipid concentration, excipient ratio, surfactant concentration, drug–lipid ratio, types of solvent ratio, polymer concentration, the ratio of a binary mixture, etc. CPPs may include stirring time, homogenization time, preparation technique, temperature, sonication time, lipid type, etc. CQAs are PS distribution, phase separation, EE, polydispersibility index, ZP, pH, in vitro release, dissolution efficiency, DL, and enthalpy. Table 4 shows all the NLC formulations optimized by various statistical designs along with detailed information for the researchers.
Ishikawa design for production of optimized NLCs.
Statistical designs applied to NLCs’ formulation development and optimization
| Drug-loaded NLCs with technique | Lipids used (solid lipid:liquid lipid) | Independent variables applied | Dependent variables applied | No. runs | Characterization parameters | Delivery route | Important conclusions of the study |
|---|---|---|---|---|---|---|---|
| Central composite designs are among the most commonly used optimization designs as they have five levels of each independent variable with a limited number of required experiments | |||||||
| Gypenosides–sodium glycocholate-NLCs/hot melting, HPH method [61] | GMS: Labrafil M1944 CS and Maisine 35-1 | Total lipid concentration (%), ratio of liquid lipid to total lipid (%), surfactant concentration (%) | PS, encapsulation efficiency (EE), DL | 20 | DSC, TEM, in vitro dissolution, XRD, accelerated stability studies. in vivo imaging, pharmacokinetics, and in situ intestinal perfusion study | Oral | Improved oral absorption of drugs |
| Atazanavir NLCs/emulsification–HPH process [62] | — | CMAs and CPPs | PS, PDI, ZP | — | DSC, powder X-ray diffraction, FT-IR analysis | Lymph targeting | Improved drug bioavailability and avoiding first-pass metabolism |
| Curcumin-NLCs/ultrasonication method [63] | Compritol ATO 888: Olive oil | Liquid lipid concentration, vitamin E tocopheryl polyethylene glycol succinate (TPGS), Poloxamer 188 | Speed, sonication time | 15 | Photon correlation microscopy, TEM, in vitro transcorneal release, corneal hydration, corneal histology, stability studies | Ocular | Enhanced the curcumin permeation across corneas |
| Exemestane-NLCs/ultrasonication technique [64] | Precirol® ATO 5: flaxseed oil | Sonication time (min), weight of solid lipid (mg), weight of surfactant (mg) | PS, EE, PDI | 20 | SEM, TEM, DSC, XRD, in vitro release, DL, ex vivo gut permeation study, confocal laser scanning microscopy (CLSM) | Oral | Promising approach for the management of breast cancer |
| Dihydroartemisinin-NLCs/solvent diffusion method [65] | GMS:Miglyol 812N | Drug concentration (%), lipid concentration (%), ratio of liquid lipid to total lipid | PS, DL, EE | 20 | ZP, PDI, stability study, TEM, in vitro release | Parenteral | Prolonged plasma level of drug |
| Beta-carotene-NLCs/solvent diffusion method [66] | Palmitic acid:corn oil | Liquid lipid-to-total lipid ratio (%), lipid phase concentration, surfactant concentration (%), aqueous phase temperature | PS and b-carotene degradation | 30 | TEM | Oral | Enhanced bioavailability |
| Nepafenac-NLCs/melt-emulsification and ultra-sonication techniques [67] | GMS:Miglyol 812N | Drug concentration (%), Miglyol 812N concentration (%), ratio of Cremophor EL/soy lecithin | PS, PDI, EE | 20 | Morphological studies, DSC, in vitro release cellular uptake, cell cytotoxicity assay on human corneal epithelial cells (HCECs) | Occular | Promising approach for the management of inflammation |
| Econazole nitrate-NLCs/solvent injection method [68] | Precirol ATO 5:oleic acid | Solid lipid concentration (5), liquid lipid concentration (%), Poloxamer 407 (% w/v) | PS, PDI, EE, and ZP | 15 | In vivo permeation study by CLSM, recrystallization index, TEM, stability study | Topical | Effective delivery for deep-seated fungal infection |
| Linalool-NLCs/HPH [69] | GMS:decanoyl/octanoyl-glycerides | Solid lipid (%), liquid lipid concentration, Span 80, Tween® 80 | PS | 30 | ZP, TEM, XRD, DSC, and in vitro release study | Oral | Sustained release and enhanced the bioavailability of the drug |
| Ifosfamide-NLCs/solvent diffusion technique [70] | GMS:oleic acid | Drug/lipid ratio, organic/aqueous phase ratio, surfactant concentration | PS, DL, EE | 20 | TEM, DL, EE, ZP, DSC, FT-IR, XRD, in vitro release, stability studies | Oral | Successfully developed NLCs with high entrapment efficiency and stability |
| Box Behnken design requires three stages of each variable and all combinations of treatments include at most one midpoint of space design edges and the preparation of NLC-loaded drugs showed that it is a suitable instrument establishing the relationship among factors and expected attributes | |||||||
| Nobiletin-NLCs/melt-emulsification technique and HPH [71] | Geleol mono- and bi-glycerides NF:Labrafac WL 1349 | Emulsifier-to-lipid ratio, lecithin-to-Poloxamer 188 ratio, and liquid lipid-to-solid lipid ratio | PS, EE | 17 | FT-IR, DSC, XRD, PDI, ZP | Oral | Enhanced bioavailability |
| Glibenclamide-NLCs/emulsion-solvent diffusion and evaporation method [72] | GMS:Capryol 90 | Surfactant (Tween® 80), total lipid, liquid lipid/total lipid | PS, EE, DL | 17 | Zeta potential, DSC, TEM, in vitro skin permeation study, CLSM | Topical | Enhanced bioavailability and better permeation of drug through rat skin |
| UcuubaNLCs/emulsification, homogenization and solidification technique [73] | Ucuuba fat: Capryol 90 | Surfactant concentration (% w/v), liquid lipid concentration (% w/v), solid lipid concentration (% w/v) | PS, PDI, EE | 17 | ZP, TEM, in vitro release, DSC, XRD, FT-IR | Topical | Successfully developed NLCs and showed antifungal efficacy against onychomycosis |
| Lurasidone hydrochloride-NLCs/solvent evaporation method [74] | Gelot64:Capryol 90 | Total lipid (%), surfactant (%), sonication time (min) | PS, EE, drug release | 15 | PDI, TEM, SEM, DSC, in vitro release, in vivo pharmacokinetic and stability study | Intranasal | Promising approach for the management of schizophrenia through intranasal route |
| Ticagrelor-NLCs/hot melt emulsification ultrasonication method [75] | GMS:Capmul MCM | Total lipid amount, liquid lipid/total lipid, surfactant (%) | PS, PDI, EE | 17 | Cytotoxicity, cellular uptake, pharmacokinetic study, pharmacodynamic study | Oral | Promising approach for antiplatelet activity and improved oral bioavailability |
| Triamcinolone Acetonide-NLCs/hot homogenization method [76] | Spermaceti:soybean oil | Solid lipid (g), liquid lipid (g), Tween® 80 (g) | PS, EE, ZP | 17 | Field emission scanning electron microscope, energy-dispersive X-ray spectroscopy, in vitro release, in vitro permeation studies | Buccal | Promising efficiency approach for the buccal drug delivery system |
| Salicylic acid-NLCs/emulsification method using high-speed homogenization [77] | Stearic acid:Lexol GT-865 (mixture capric/caprylic triglyceride) | Total lipid concentration (%), solid lipid-to-liquid lipid ratio, surfactant concentration (%) | PS | 17 | SEM, DSC, EE, PDI, ZP | Oral | Reduced side effect and improved efficiency of salicylic acid |
| Luliconazole-NLCs/sonication technique [78] | NLC (lipids) hydrogel excipients | Lipid content, surfactant concentration, and sonication time | PS, % EE | 17 | Occlusivity, spreadability, and extrudability | Topical | Increased antifungal activity of the drug, increased patient compliance by reducing the frequency of application |
| 20(S)-Protopanaxadiol-NLCs/melt emulsification method [79] | Cetylpalmitate:Miglyol 812N | Drug concentration, volume of the liquid lipid, and the amount of the surfactant | PS, PDI, EE | 15 | TEM, XRD, in vitro deposition of the drug into human cadaver skin, in vivo human skin irritation study | Topical | NLC formulation did not cause any skin irritation, it could be used to enhance the topical skin deposition of 20(S)-Protopanaxadiol |
| Fenofibrate NLCs/hot homogenization – ultrasonication [80] | Solid: liquid lipid | Drug concentration, ratio of solid lipid/liquid lipid, and percentage of emulsifier | PS, % EE | 17 | DSC, in vitro release, in vivo studies | Oral | Enhanced dissolution and bioavailability of fenofibrate |
| Rivastigmine-NLCs/ HPH technique [81] | GMS:castor oil | Solid to liquid lipid, ratio of Tween® 80 and span 80, number of HPH cycles | PS, PDI, Z, EE | 17 | ATR, TEM, DSC, in vitro release, skin irritation study, pharmacokinetic study | Topical | Promising approach for the dementia management |
| Butenafine HCl-NLCs/HPH method [82] | Compritol 888 ATO 5:Labrasol | Liquid content, surfactant concentration (Tween® 80), and homogenization cycle | PS, EE | 17 | In vitro drug release studies, ex vivo drug permeation study | Topical | Enhanced bioavailability of the drug in the treatment of fungal infections |
| Olmesartan minoxidil-NLCs/homogenization method [83] | Precirol® ATO 5: Capmul MCM | Amount of liquid lipids (mg), amount of total lipids (mg), drug concentration (mg), surfactant concentration (%) | PS, PDI, EE | 30 | DSC, XRD, SEM, TEM, in vitro drug release, cellular uptake, pharmacokinetics study | Oral | Enhanced oral bioavailability of the drug |
| Full factorial three-level statistical design involves two or three input factors with more experiments are needed | |||||||
| Carvedilol-NLCs/HPH method [84] | GMS:oleic acid | Total lipid concentration, liquid lipid concentration, surfactant concentration | PS, EE | 8 | DL, FT-IR, DSC, SEM, in vitro release, XRD, accelerated stability study | Oral | Enhanced oral bioavailability of the drug |
| Repaglinide-NLCs/emulsification and ultrasonification technique [85] | GMS:oleic acid | Liquid lipid ratio, surfactant concentration | PS, ZP, EE | 9 | In vitro release, TEM, DSC | Oral | Promising carrier for the controlled release of Repaglinide |
| Febuxostat NLCs/high shear homogenization [86] | Stearic acid:oleic acid | Liquid-to-solid lipid ratio, surfactant concentration | PS, % EE | 12 | PDI, ZP | Oral | This system seemed to be suitable for oral delivery of febuxostat for gout treatment |
| Raloxifene-NLCs/solvent diffusion method [87] | GMS:Capmul MCM C8 | Solid-to-liquid lipid ratio (%), concentration of stabilizer (%) | EE | 9 | DL, in vitro drug release studies, FT-IR, DSC, PS, ZP, TEM, XRD, stability study, pharmacokinetic study | Oral | Enhanced oral bioavailability of the drug |
| 5-Flurouracil-NLCs/solvent diffusion method [88] | Cholesteryl stearate:oleic acid | Octanol, oleic acid, cholesteryl stearate (%) | DL, EE, PS, drug release | 12 | Atomic force microscopy | Oral | A useful optimization method for the production of NLCs |
| Plackett–Burman designs (unique types of two-level fractionate designs) that analyze N − 1 input variables with N number of experiments; this N should be multiplied by 4. This design is seldom used, but this DOE was proved to be more efficient and logical in the optimization of formulations. | |||||||
| Olmesartan Medoxomil-NLCs/hot-microemulsification homogenization followed by ultrasonication [89] | Stearic acid:oleic acid | Solid lipid concentration, liquid lipid concentration, surfactant concentration | PS, EE | 13 | ZP, in vitro release with model kinetics, TEM, stability study | Oral | Successful development of NLCs using multivariate statistical approaches for improved product and process understanding |
| Isradipine-NLCs/solvent evaporation with probe sonication [90] | Emulcire61:Capryol 90 | Total lipids (% w/v), solid lipid: liquid lipid, surfactant (% w/v); surfactant: co-surfactant, stirring speed (rpm), sonication time (min), temperature (°C), drug (mg) | PS, EE, drug release | 12 | DL, TEM, DSC, ZP, FT-IR, stability study, CLSM, in vitro permeation study | Oral | This study improved the lymphatic uptake and biodistribution of drugs, thereby promising the approach as in vivo prospect and clinical efficacy |
| Colombian propolis-NLCs/emulsification–diffusion technique [91] | Labrafac:LipophileWL 1349 | Polyvinyl alcohol (%), caprylic/capric triglycerides (%), Poloxamer concentration of sesame oil (%), emulsification time (min), emulsification stirring rate (rpm) | PS, PDI | 12 | DSC, XRD, FT-IR, NMR, SEM, cytotoxicity, neutral red uptake assay | Cosmetics | This approach can be used pharmaceutical or cosmetic industries for developing innovative products |
| Mixture designs are used while the total compositions of independent variables are fixed, and variable ratios are often not independent of each other. The proportion of the other components will decrease if the number of one component increases. | |||||||
| Zingiber zerumbet-NLCs/emulsification method [92] | GMS:coconut oil (virgin) | Zingiber zerumbet oil, solid lipid, liquid lipid | PS, PDI, ZP, EE | 11 | Penetration study | Topical | NLCs prepared with DOE showed a stable formulation and provide a promising future in various applications, such as drug delivery, food, textile, and cosmetics |
8 Applications of NLCs
The NLCs can be used in a wide variety of drug delivery systems by different routes including oral, transdermal, ocular, pulmonary, and IV delivery systems. Some of the pharmaceutical applications of NLCs are summarized in Figure 3.
Various pharmaceutical applications of NLCs.
8.1 Oral drug delivery
Drug delivery through the oral route is the well-received and cost-effective way of drug administration, with the greatest patient adherence. However, high hepatic first-pass effect, restricted drug solubility and/or efflux pumps of P-glycoprotein (P-gp), and enzymatic and chemical deterioration all contribute to low oral bioavailability, which must be overcome [93,94]. LNPs, including NLCs and SLNs, have the benefit of being able to maintain steady plasma levels due to their potential for sustained drug release. Because of their larger specific surface area and saturation solubility, they dissolve quickly, hastening the start of pharmacological action. P-gp efflux pumps can be inhibited by certain lipids and surfactants employed in the synthesis of these LNPs. Drugs are less likely to be degraded chemically or enzymatically because they are incorporated in the lipid matrix [95]. According to the diagrammatic representation in Figure 4, lymphatic transport can be increased by LNPs and can bypass the liver, avoiding the hepatic first-pass effect. As a result, adding bioactives into NLCs may aid in improving therapeutic effectiveness and extending release time from these nanocarriers [96].
![Figure 4
Schematic representation of the absorption of drugs from NLCs in the lymphatic portal system. Drugs incorporated in the NLCs bypass the first-pass metabolism in the liver resulting in increased effectiveness [97].](/document/doi/10.1515/ntrev-2022-0109/asset/graphic/j_ntrev-2022-0109_fig_004.jpg)
Schematic representation of the absorption of drugs from NLCs in the lymphatic portal system. Drugs incorporated in the NLCs bypass the first-pass metabolism in the liver resulting in increased effectiveness [97].
Piazzini et al. reported the synthesis of silymarin (SLM) NLCs for optimal oral absorption and in vivo effectiveness in a type 2 diabetes and metabolic syndrome model. Through energy-dependent processes, the formulations were successful in boosting transport through the Caco-2 cell layer. SLM-NLC formulation showed a considerable reduction in blood glucose and lipid levels when compared to free SLM [98]. To improve the oral bioavailability and extend the action and effectiveness of the anti-hyperlipidemic medication simvastatin (SIM), NLCs were synthesized using an emulsification–solvent evaporation method followed by ultrasonication. In contrast to SIM suspension, a single dosage of SIM-NLC resulted in a 4-fold increase in bioavailability, making NLCs a viable drug delivery method in the control of hyperlipidemia [99]. According to other researchers, atorvastatin (AT)-loaded NLCs released more drugs than the drug solution. In comparison to AT suspension and Lipitor, the oral bioavailability of NLC formulation (NLC-1) rose by 3.6 and 2.1 times, respectively. The nanosized formulation, which may have enhanced lymphatic absorption, was implicated in the high plasma levels of AT from NLCs [100].
NLCs of the poorly soluble drug raloxifene hydrochloride (RLX) were prepared in a study using a hot homogenization procedure followed by an ultrasonication technique. In female Wistar rats, high entrapment efficiency of over 90%, sustained drug release, and a 3.19-fold increase in bioavailability of RLX-NLC were indicated when compared to a plain drug suspension, indicating its possibilities as a potential carrier for RLX oral delivery in osteoporosis treatment [101]. Likewise, for the oral administration of docetaxel (DTX), cysteine-modified NLCs (cNLCs) were synthesized and evaluated against unmodified NLCs. In total intestinal segments, the intestinal absorption of cNLCs was significantly enhanced as compared to unchanged NLCs and DTX solution, which can be related to changed cNLCs’ increased mucoadhesion capabilities [102]. Finally, the emulsion–evaporation and low temperature–solidification approaches were used to effectively manufacture baicalin-loaded NLCs (BA-NLCs). When compared to BA suspension, BA-NLCs could significantly enhance baicalin bioavailability following oral administration (1.9-fold) [103].
8.2 IV drug delivery
The IV method is typically used for medications that are unable to absorb through the digestive tract or injected into muscles or other tissues [104]. From the IV route, drug directly goes into the blood system for systemic action bypassing the first-pass metabolism and absorption phase, making it a reliable quicker route [105,106]. Drugs with short half-lives or duration of action are more suitable to be given via this route as they could be delivered at a more uniform rate, and bioavailability of 100% could be achieved. Moreover, IV is a better option for patients who are uncooperative, unconscious, or likely to vomit upon oral administration of a drug [107]. Few significant studies performed on NLCs for their delivery by IV route are enlisted here. Mupirocin-loaded NLCs (M-NLCs) for IV administration were prepared recently, which enhanced the antibacterial activity of the drug. By the storage of almost 3 months at 25°C, all formulations of NLC demonstrated sustained drug release and acceptable physical properties. M-NLC-1 was shown to be safe in rats at a dosage of 250 mg/kg and to have a considerable rise in plasma concentration in rabbits after IV injection, indicating a better pharmacokinetic profile than free drug [108]. In another study, genistein-loaded NLCs for IV administration were prepared and optimized by the QbD approach for higher entrapment (92.8%) and the ZP of −21.25 mV with excellent stability of the formulation [109]. Recently, commercial artesunate was used to prepare and test intravenously delivered artemether NLCs (ARM-NLCs) for in vivo pharmacodynamic effectiveness. In a mouse model, both formulations were shown to be efficient in lowering parasitemia, with ARM-NLC outperforming the others [110]. Furthermore, DTX-loaded NLCs were manufactured using a simplified film ultrasonication–dispersion process to minimize harmful effects and increase therapeutic effectiveness, making them a viable cancer drug delivery system [111].
8.3 Ocular drug delivery
The eyes are very sophisticated and complex organ of the body. Ocular delivery is difficult due to distinct physiological and anatomical aspects of the eyes, as well as many restrictions that must be addressed to attain specific ocular tissue. To eliminate these hurdles and increase ocular tissue bioavailability, LNPs were used as a new innovative drug delivery method [112]. The most frequent route of medication delivery to the anterior portions of the eyes is by topical application to the eyes. The blood ocular barrier, corneal epithelium, conjunctival blood flow, and tear drainage are main hurdles in this system. LNPs can cross the blood–ocular barrier as they are a unique technology and achieve sustained and regulated drug release, prevent medicines from lacrimal enzymes, and extend drug deposition and resident duration in the eyes [113]. Ocular problems, particularly in the posterior region of the eyes, are challenging to cure. When it comes to targeting intraocular tissues, the topical method is not always considered the best option.
Transscleral administration (subconjunctival and retrobulbar injection), intravitreal route, and subretinal injection, among others, are being investigated [114]. Because the majority of these methods are painful, LNPs are an excellent alternative drug delivery strategy for the treatment of ocular disorders. Gene therapy for retinal disease targeting employing non-viral vector gene delivery, such as SLNs and NLCs, has also been suggested as a viable therapeutic strategy for retinal illnesses [115]. For ocular biodistribution, amphotericin B (AmB)-loaded PEGylated NLCs have just recently been developed and improved. In both wild-type and AmB-resistant Candida bacteria, AmB-PEG2K-NLCs had considerably superior antifungal efficacy (p < 0.05) and were equivalent to, or better than, commercially available parenteral AmB formulations [116]. Melt-emulsification along with ultra-sonification was used to synthesize novel hybrid Genipin-crosslinked dual sensitivity hydrogel/NLCs of baicalin (BN) (BN-NLCs). In comparison to BN eye drops and BN-NLCs, the in vitro release investigation revealed that BN-NLC gel enhanced BN release. As a result, this new hydrogel with a lengthy precorneal residence duration has the potential to be used in ocular medication administration [117]. Last to mention here, Timolol maleate™ and Brinzolamide-loaded NLCs were designed to enhance the bioavailability, permeation, and precorneal residence time of these drugs that would result in efficacious treatment of glaucoma. There was a remarkable enhancement in the release pattern and permeation of both the drugs from NLCs as compared to that from their suspension [118].
8.4 Pulmonary drug delivery
A new method of drug delivery used by the researchers is pulmonary drug delivery associated with many advantages, such as non-invasiveness for both local and systemic administration, high drug accumulation in the target site, accelerated onset of action by direct inhalation, the large surface area of pulmonary system, high drug permeability through thin alveolar epithelium, reduction in drug dosage, and consequently reduced drug adverse effects [119,120]. LNPs have been considered for pulmonary delivery as these have shown good results in comparison to the conventional formulations, such as sustained drug release, biodegradability, low toxicity, higher stability, and biocompatibility [121,122]. Here, we have summarized a few marvel research studies performed under this category for the understanding of pulmonary delivery of drug-loaded nanoparticles.
For intramuscular and pulmonary delivery, sodium colistimethate-loaded NCLs (SCM-NLCs) were prepared [123]. Nanoparticles inhibited eight drug-resistant P. aeruginosa strains with a minimal inhibitory concentration of 1–2 mg/L in vivo. SCM-NLC had much fewer CFU/g lung than saline and was comparable to free SCM, despite the fact that the dosage in the SCM-NLC group was lower than free SCM. The treatment procedures did not cause any tissue injury. After pulmonary or intramuscular injections, SCM-NLC was effective against P. aeruginosa in vivo, was nontoxic, and transported effectively to the liver and lungs [123]. Lipid nanocarrier systems were prepared and evaluated to selectively deliver the RFB to alveolar macrophages to alveolar macrophages. These nanoparticles were engineered to be absorbed by alveolar macrophages, transported to acidified phagosomes and phagolysosomes, and released bactericidal quantities of the antituberculosis drug intracellularly using both mechanisms of passive and active targeting. By using the pulmonary route of delivery, the proposed nanocarrier can be studied as a viable transporter for the safer and more effective treatment of TB [124]. Recently, Montelukast-loaded NLCs (M-NLCs) for pulmonary delivery were developed and tested in vitro for aerodynamic evaluation and in vivo evaluation done in Wistar rats for pulmokinetics. When compared to the Montelukast-aqueous solution, the pulmonary pharmacokinetic analysis revealed prolonged drug residence in the lungs with better bioavailability and a targeting value of 11.76 for M-NLCs. The research showed that Montelukast lipidic nanoparticulate preparation had the potential to increase efficacy while reducing toxicity, resulting in improved medication performance as M-NLC-DPI for inhalation administration [125]. The literature also suggested that the delivery through the pulmonary route was possible for NLC formulation for beclomethasone dipropionate (BDP). NLC was effectively nebulized, resulting in aerosols with a PS adequate for BDP deep lung administration. The findings showed that LNPs are potential nebulized carriers for BDP, creating opportunities for nebulized lipophilic drug-targeting techniques [126].
8.5 Nose-to-brain drug delivery
The brain is one of the most essential organs and its homeostasis is very critical. The flow of endogenous and exogenous chemicals between the peripheral blood and the cerebrospinal fluid (CSF) is controlled by barriers, which is necessary for appropriate brain function [127]. Due to its anatomy and physiological obstacles, such as the blood–brain barrier (BBB), which is the primary barrier to active molecules entering the central nervous system (CNS) [128], drug delivery to the brain is the most difficult task. Due to the difference in the physicochemical properties from those required for molecular entrance into the CNS, most active CNS medicines (98%) are unable to get through this barrier [129]. Drugs that pass through the BBB are lipophilic drugs with a log P-value of 1.5–2.7 and a molecular weight of less than 600 Da [130]. A variety of transporters are present in the BBB including P-gp efflux transporter, which restricts drug entrance into the CNS. One of the delivery approaches for overcoming BBB is nose-to-brain drug delivery. Its benefit is patient compliance, to avoid hepatic first-pass metabolism, and non-invasiveness [131]. There are three ways through which NLCs are transported from the nose to the brain. They include the olfactory pathway, the trigeminal nerve pathway, and the systemic pathway. Blood circulation is also involved in drug absorption into the brain from the nasal cavity [132]. The distribution of active agents happens throughout the systemic circulation, entering nasal blood arteries before being swiftly transported to the carotid artery blood supply to the brain and spinal cord [133].
8.6 Brain drug delivery
In contrast to oral drug delivery, brain targeting enhances the drug’s concentration in the CSF, reduces dose frequency, has fewer adverse effects, avoids first-pass metabolism, and has a faster onset of action [134]. The two primary difficulties are decreased drug penetration through the BBB and efflux of delivered medicines from the brain to the blood circulation [135]. The main benefits of LNPs are their high drug encapsulation and small size. That is why they are an ideal choice for targeting specific tissues of the brain. Colloidal drug delivery systems, including SLNs and NLCs, have the benefit of enhancing the retention time of drugs in the blood of brain capillaries and triggering a drug gradient from blood to brain tissues, widening tight junctions to promote entry from BBB and transcytosis of drug-loaded LNPs via the endothelium layer, and increasing the retention time of drug in blood of brain capillaries. Furthermore, they can accommodate both hydrophilic and lipophilic drugs [136].
Because of their bio-acceptability, quick absorption by the brain, and biodegradability, NLCs may be regarded as one of the key techniques for drug administration without any alteration to the drug molecule. Furthermore, the ease with which they may be scaled up and the lack of a burst effect make them ideal drug delivery vehicles. Over the last few years, a growing number of research papers have been published in this area, showing NLCs as a potential method in brain delivery. An increasing number of studies have been reported in this regard over the past decade establishing the NLCs as a promising tool in brain delivery. The recent development is of almotriptan maleate (ALM) mucoadhesive chitosan-coated NLCs for the treatment of migraine since ALM has poor solubility, poor penetration, and low concentration in brain regions, demanding repeated oral administration. Experiments conducted on albino rabbits for in vivo pharmacokinetics revealed that the optimized ALM-NLCs (1.54 mg/mL) had a considerably greater C max in plasma than ALM solution (0.25 mg/mL) and ALM oral marketed tablet (0.58 mg/mL). Because NLCs are flexible and lipophilic, they may be a viable technique for drug transport to the brain [137]. The in vivo anticonvulsant effect of carbamezipine-loaded NLCs (CBZ-NLCs) in a PTZ-induced seizure model demonstrated a considerable rise in the starting date (134.0 s) and a decrease in the length (17.2 s) of tonic-clonic seizure compared to CBZ dispersion (75.4 and 37.2 s), respectively [138]. Apart from these, NLCs of lurasidone hydrochloride for the treatment of schizophrenia [139], artemisinin NLCs for the treatment of brain tumors and malaria [140], and baclofen NLCs for targeted delivery to the brain [141] are also reported in the literature for their improved brain delivery.
8.7 Transdermal drug delivery
The transdermal drug delivery system (TDDS) has been used for centuries to transfer medications and therapeutics through various layers of the skin, including the surface, epidermis, dermis, and hypodermis, for therapeutics effects [142]. Moreover, it is essential to handle various issues with traditional skin preparations, including skin barrier impermeability, limited effectiveness, and excessive application frequency [143]. One of the many advantages of NLCs is the presence of biologically active and biodegradable lipids, which show less toxicity and provide adhesiveness, skin hydration, lubrication, smoothness, emollience, skin penetration enhancement, and modified drug release characteristics. For increasing progress in the cosmetic and pharmaceutical sector, researchers are currently focusing on manipulating topical and dermal applications of NLCs [144]. The small size of NLCs ensures enhanced skin penetration of active compounds through contact with the stratum corneum and few mechanisms are available in the literature related to it [145].
Understanding the transport pathways that are vital since drug transit through skin necessitates greater lipophilicity. The process of transport of a hydrophilic drug through the skin from NLCs differs from that of a hydrophobic drug. It is predicted that unless water from the NLCs readily penetrates transdermally, a hydrophilic medication would not be accessible for percutaneous transport from NLCs. As a result, significant water mobility within the NLC vehicle and for percutaneous transmission through the skin barrier is proposed [146]. NLCs are also effective in delivering hydrophobic drugs transdermally to the systemic circulation [147]. The major concerns across the world are skin disorders, both infectious and non-infectious. Skin disorders are difficult to treat because of therapeutic limitations, such as limited medication effectiveness due to inadequate skin penetration of drugs from standard formulations. Drug permeation is limited by the stratum corneum of the epidermis, which must be overcome by switching the penetration channel from transcellular to paracellular or follicles [148]. The rapid emergence of LNPs (SLNs and NLCs) had remained successful to increase the skin penetration of drugs as these formulations are prepared by mixing LNPs with the conventional formulations [149]. Biodegradability, adhesiveness, close contact with skin, biocompatibility, regulated drug release profile, hydration of skin, and film formation to enhance skin penetration effects are benefits of LNPs for topical dermal administration [150].
For the treatment of vitiligo, topical SIM-loaded NLCs were produced and proved to be safe, with the drug entrapment of 99.27% and adequate long-term stability [151]. Febuxostat-loaded NLC gel was formulated for the topical treatment of gout. The NLC gel formulation showed 87% release within 6 h in a controlled manner [152]. According to a recent discovery, for skin regeneration in tissue engineering, a new gelatine/hyaluronic acid/polycaprolactone nanocomposite scaffold containing 54.1 wt% AT-loaded NLCs was tested as a suitable target [153], optimized NLC-loaded Apremilast showed PS 157.91 ± 1.267 nm, % entrapment efficiency 69.14 ± 0.278%, and ZP −16.75 ± 1.40 mV, respectively. It was suggested to be explored for topical delivery of drugs for the treatment of psoriasis [154].
The NLC gel of repaglinide (RG), an effective anti-diabetic drug, was formulated to improve the bioavailability by the transdermal route. The optimized gel system (RG-NLC gel) showed sustained release up to 24 h and two times improvement in the bioavailability in comparison to the marketed oral tablet in the rat model [155]. Likewise, NLC-based gel was produced for improved skin administration of donepezil-free base. In Alzheimer’s disease, because of many disadvantages of the oral administration of this drug, patients are less likely to stick to their treatment regimen. Drug skin penetration from the new gel was boosted in the in vitro skin permeation studies, and lipid nanocarriers provided an additional boosting impact to enhance drug permeability over the skin [156]. An NLC gel loaded with tripterine (TRI) for transdermal delivery was developed in another research.
In another study, NLC gel loaded with TRI for transdermal administration was formulated. Sustained-release properties of the drug are demonstrated by in vitro drug release from the TRI-NLC-gel. The penetration of NLC into the deep skin layers was discovered through dermatokinetic studies and histopathological studies showed that treated skin remained intact indicating better compatibility of the novel gel [157]. It is also important to note that topical administration in the treatment of rheumatoid arthritis, triptolide-loaded NLCs reduced knee edema transdermally by lowering inflammation and modulating TNF-, IL-1, and IL-6 levels, making the drug-NLC system a viable delivery strategy [158].
In contrast to the Exelon® patch, the NLC transdermal system had a remarkable increase in bioavailability and sustained release of rivastigmine. The designed NLC-based transdermal patch was shown to be nonirritating in skin irritation tests. The higher Cmax and AUC0–72 in plasma treated with NLC-loaded transdermal patches compared to standard patches suggested that NLC-based transdermal patches might be used as a possible carrier for improving rivastigmine bioavailability for improved dementia therapy [159].
8.8 Tumor targeting by NLCs
In recent times, tumor targeting has become one of the most important parts of drug delivery. The development of a new carrier system for the transport of numerous anti-cancer medications is still a subject of discussion, and it is a vital step toward the improvement of drug entrapment and tumor targeting [160]. NLCs as nanocarriers can be the drug delivery choice for certain anti-cancer drugs upon proper research by improving their drug release, chemical stability, and cytotoxicity. In a research study, it was revealed that encapsulating camptothecin and topotecan in the NLC system was found to have higher cytotoxicity and cell uptake against melanoma and leukemia cells. To provide a long circulation impact and excellent tumor targeting, they can be coupled with an amphiphilic copolymer, folate poly PEG-cyanoacrylate-co-cholesteryl cyanoacrylate [161].
To combat multidrug resistance and improve cancer treatments, NLCs co-loaded with arginyl-glycyl-aspartic acid were used to co-deliver doxorubicin and sildenafil citrate. In contrast to individual treatment and administration, co-delivery of drugs enhanced uptake and accumulation via integrin-mediated endocytosis and potential ABC transporter blockage, making co-delivery an efficient strategy for inducing apoptosis [162]. The capability of multifunctional NLCs in the management of non-small-cell lung carcinoma was recently discovered by the researchers, and the findings have had a substantial impact on the field of drug delivery to enhance the effectiveness of lung cancer therapy [163]. To improve cytotoxic effects in MCF-7 breast cancer cells, researchers developed chrysin-loaded NLCs of doxorubicin. A significant rise in the percentage of apoptosis was observed in chrysin-loaded NLCs from 21.11 ± 5.72% to 27 ± 3.13% (P < 0.05). In comparison to the control group, the quantities of mRNA expressions of Nrf2, NQO1, HO1, and MRP1 were significantly lower. As a result, it is possible that delivering chrysin with NLCs could improve doxorubicin effectiveness by inhibiting drug efflux pumps [164]. In animal models, novel NLC-based formulations of di-indolylmethane (DIM) derivatives DIM-10 and DIM-14 increased oral bioavailability and antitumor activity significantly. The anticancer properties of both derivatives were shown to be better than those of free drug-treated groups, indicating that they had promising capabilities for clinical purposes [165].
9 Toxicity studies on NLCs
The rapid emergence of nanomaterials has led to an exponential resurgence of drug delivery systems in the field of pharmacy and medical science. Equipped with useful characteristics, such as being biodegradable, biocompatible, and stable profile, makes NLCs a very suitable drug delivery system [166]. LNPs (both SLNs and NLCs), due to their ability to incorporate lipophilic drugs and maintain their controlled drug release, have garnered a lot of attention recently. It is therefore required to sufficiently investigate their toxicity owing to their extensive applications [167]. The toxicity studies performed on various NLC formulations are summarized in Table 5. The acute toxicity research for Zerumbone (ZER)-loaded NLCs (ZER-NLC) was carried out by orally administering a single dosage of water, olive oil, ZER, NLC, or ZER-NLC to BALB/c mice for 14 days [168]. Clinical and behavioral problems, toxicological effects, feed consumption, and gross appearance were identified in the animals. MMP decrease, lysosomal membrane destabilization, and lipid peroxidation were restored by quercetin-loaded NLCs, which also prevented paraquat-treated change in Bax and Bcl2 gene expression [169]. In rabbits and rats, intravaginal administration of 0.5% podophyllotoxin-NLCs (POD-NLCs) induced only minor discomfort with no evidence of acute or chronic damage to the vaginal mucosa [170].
Various drug-loaded NLCs tested using animal models (ex vivo and in vivo studies)
| Drugs | Animal/test model | Outcomes | Ref. |
|---|---|---|---|
| Tocopherol | Skin irritation testing/three-dimensional tissue culture model EpiDerm | Histological evaluation revealed that the prepared tocopherol-loaded NLCs were nontoxic and nonirritant with a relative % cell viability of 92.7% | [171] |
| Calcipotriol + Methotrexate | Skin irritation testing on female nude mice | Prepared NLCs showed non-significant or negligible skin irritation | [172] |
| Huperzine A | Draize patch test for skin irritation on albino rabbits | The primary skin irritation index or the irritation score was found to be zero even after 24 h | [173] |
| Tretinoin | Skin compliance test on female Laca mice | No visual or microscopical signs of irritation were observed with the prepared NLCs, however, the marketed formulation showed signs of marked inflammation | [174] |
| Cyclosporine A | Cytotoxicity studies on human corneal epithelial cell lines | Cell viability increased upon incubation for 12 h | [175] |
| Flurbiprofen | Ocular tolerance analysis/Eytex® system | Ocular tolerance analysis/Eytex® system | [176] |
| Levofloxacin | Modified egg chorion of hen/ocular tolerance test | Absence of irritation | [177] |
| Cyclosporine A | Ocular irritation/tolerance study | No significant signs of ocular irritation | [178] |
| Flurbiprofen | Ocular irritation/tolerance study | No evidence of inflammation or tissue edema | [179] |
| Bixin | Bixin 2.5 mg/kg given to Wistar rats p.o. | The treated group showed better protection against the Paracetamol-induced lipo-oxidation as well as reversal of AST and ALT liver enzymes to normal level | [180] |
| Halofantrine | Halofantrine given to Swiss albino mice p.o. in different doses | Normal glomerulus, normal peri-portal mononuclear infiltration | [181] |
| Artemether | Swiss albino mice | No change in the morphology of kidney and liver tissues | [182] |
| DTX | Administered to ICR mice IV | Showed signs of shortness of breath for 1–2 min immediately after drug administration which came back to normal after 5 min | [183] |
10 Stability and safety of NLCs
The SLNs have problems with stability; however, other lipid-based nanoformulations, such as NLCs, have been developed to alleviate the problems associated with SLNs. NLCs are sometimes referred to as new unstructured-matrix SLNs. It is a misconception to assert that NLCs will not be employed in the future; every problem has a remedy. The HPH process utilized for the preparation of NLCs can be easily transferred from a small-batch production to a large-batch production in the pharmaceutical industry while avoiding the use of any organic solvent in their preparation [184]. Altogether, the use of GRAS components, the large-scalable production methods for their preparation, and the improved drug safety demonstrated by the use of lipid-based nanocarriers make NLCs an ideal drug delivery system candidate for the pharmaceutical market.
The long-term physical stability of NLCs has some issues owing to the presence of water content in it. However, there are now a plethora of options for preserving them, such as freezing the suspension to turn it into a solid. A freeze-dried nanoparticle should ideally preserve stability while keeping the fundamental nanoparticle characteristics and maintain water in the dispersion and include a preservative. Moreover, NLCs are considered generally safe nanocarriers for oral, dermal, pulmonary, and ocular administration due to the presence of biodegradable and physiological lipids, which have been shown to be well tolerated in both in vitro and in vivo investigations [185]. NLCs contain lesser quantities of surfactants and cosurfactants when compared to emulsions, which further improve their safety profile.
11 Patents on NLCs
In this section, recent patents concerning NLCs over a period of time are summarized. The nanosized NLC formulations for dermal, nasal, topical, and those directed toward the CNS and peripheral nervous system have already been patented. The enhanced bioavailability, ease of crossing BBB, and stability as compared to the conventional formulations have them interesting enough for their patentability. Table 6 summarizes the recent patents of NLCs for various drug delivery applications. Chen et al. developed cationic charged LNPs, which delivered major active biomolecules including proteins, peptides, vitamins, antibodies, and nucleic acids [186]. Keck and Muchow prepared testosterone undecanoate NLCs using stearic acid as solid lipid. These prepared NLCs enhanced the oral bioavailability of the drug as compared with the marketed product. Furthermore, these NLCs can be used for dermal or nasal delivery [187]. DTX NLCs with reduced Ostwald ripening were developed by Singh using whey protein as an emulsifier. A specific characteristic of this patent was lactoglobulin/albumin, immunoglobulin, and bovine serum albumin, which was used as whey protein (emulsifier) [188].
Patents granted on NLCs in the field of applications in drug delivery
| Patent number | Title of patent | Inventors | Ref. |
|---|---|---|---|
| US20080020058-A1 | Lipid nanoparticles-based compositions and methods for the delivery of biologically active molecules | Chen et al. | [186] |
| EP2229936-A1 | Nanonized testosterone formulations for improved bioavailability | Keck and Muchow | [187] |
| US20090238878-A1 | Solid nanoparticle formulation of water-insoluble pharmaceutical substances with reduced ostwald ripening | Singh | [188] |
| US20100047297-A1 | Nano-crystals for use in topical cosmetic formulations and method of production thereof | Petersen | [189] |
| US20100247619-A1 | Nano-structured lipid carriers containing Riluzole and pharmaceutical formulations containing said particles | Bondi et al. | [190] |
| US20110059157-A1 | Anionic lipids and lipid nano-structures and methods of producing and using the same | Awasthi and Lagisetty | [191] |
| US20110097392-A1 | Antibody bound synthetic vesicle containing molecules for delivery to central and peripheral nervous system cells | Wang et al. | [192] |
| WO2011116963-A2 | Lipid nanoparticle capsules | Petit et al. | [193] |
Petersen developed rutin nanoparticles with size 300–800 nm and demonstrated that nanodelivery, such as liposomes, NLCs, and SLNs, was significantly long term and electrolyte stable in contrast to existing conventional formulations [189]. Bondi et al. prepared riluzole in NLCs using compritol for the amyotrophic lateral sclerosis (neuroprotective action) treatment. The size of prepared NLCs was found to be less than 100 nm, which can easily cross BBB and showed clinical signs of allergic encephalomyelitis in rats as compared with the group treated with the free riluzole [190]. Awasthi and Lagisetty claimed the novel NLCs’ preparation using cholesteryl hemisuccinate, 2-carboxyheptadecanoylheptadecylamide, 1,4-dipalmitoyl-tartarate-2,3-diglutaric acid, and 1,4-dipalmitoyl-tartarate-2,3-disuccinic acid as solid lipid and vitamin E as liquid lipid [191]. Wang et al. prepared nanoparticles, such as NLCs, of biotinylated protein for targeting CNS or PNS neuronal cells. NLC-loaded protein recognizes a receptor expressed on a neuronal cell’s surface [192]. There are few references related to the use of LNPs to deliver peptides/proteins because of the matrix’s hydrophobic nature. Proteins/peptides containing LNPs provide proteolytic degradation protection in the GIT. Petit et al. improved protein/peptide delivery with the use of polymeric-coated NLCs or SLNs. These polymer-coated nanoparticles provided extra protection by enhancing their stability against chemical degradation and have a greater capacity for skin penetration than conventional LNPs [193]. Lutz et al. filed a patent on the process and method for the development of NLCs. They prepared NLCs using murumuru seed butter and bisdiglyceryl polyacyladipate-2 and have been used in cosmeceutical and skincare industries [194].
12 Regulatory considerations and marketed formulations
The main objective of keeping a vigilant eye on any formulation by the regulatory bodies is to ensure, promote, and protect public health. Important commodities, such as pharmaceuticals, foods, medical devices, in vitro diagnostics, biological, nutritional products, veterinary medicines, cosmetics, and agrochemicals, are under mandatory and strict control of regulatory bodies to ensure their safety and efficacy. In the case of polymeric nanoparticles, sometimes the excipients used do not belong to the GRAS category as they are not regulatorily accepted by the FDA. They might give good experimental results but cannot be used in products in the market [195]. Regulatory bodies ensure that pharmaceutical companies perform all sorts of toxicity studies on any new drug or new polymer before creating formulations from them and there should not be any hindrance in the development of a new drug delivery system [196]. All the emerging nanocarrier systems, such as nanoparticles, dendrimers, carbon nanotubes, liquid crystals, and others, have raised the importance of regulations for a new pharmaceutical product [197]. All the ingredients, components, and constituents of NLCs, such as lipids and emulsifiers, are considered to be physiologically safe, nontoxic, non-immunogenic, biodegradable, and biocompatible in nature and easily fit in the category of GRAS by the regulatory authorities. They are already being used in the food industry and sometimes for encapsulating pharmaceutical compounds in a safe and accepted range [198,199,200]. Minor regulatory obstacles are the significant reason for the wide acceptance and commercial success of the NLCs.
Several products containing NLCs received regulatory approval and are available on market. A few of them are summarized in Table 7 along with other marketed lipid-based formulations, excipients used in the preparation, and surfactants.
Marketed NLCs containing formulations, excipients, and surfactants
| Marketed products | Country |
|---|---|
| Products containing NLC | |
| Cutanova Nanorepair Q10 cream | France |
| FloraGlo® | Netherlands |
| NanoLipid Restore CLR® | France |
| NLC deep effect eye serum | Germany |
| extra moist softener | Korea |
| Cutanova Nanovital Q10 cream | France |
| Lipid-based formulations | |
| Sandimmune® | United States |
| Sandimmune Neoral® | United States |
| Norvir® | United States |
| Fortovase® | Switzerland |
| Marketed excipients used for NLC formulation | |
| Solid lipids | |
| Xifaxan® | United States |
| Azelex® | Ireland |
| Viokace™ | United States |
| Survanta® | United States |
| Liquid lipid | |
| Avodart™ | United Kingdom |
| Lipofen® | Canada |
| Terramycin® | United States |
| Baycip® | Germany |
| Surfactants | |
| Targretin® | California |
| Rapamune® | United States |
| Oxidize® | Romania |
| Dermazene™ | United States |
| Kaletra® | United States |
13 Recent advancements of NLCs in delivering diverse therapeutics
13.1 Anticancer agents
In contrast to pure drug, the design and preclinical testing of microneedle-assisted Resveratrol NLCs for localized administration to breast cancer treatment revealed greater anticancer efficacy and improved internalization of MDA-MB-231 breast cancer cells [201]. The hot microemulsion technology was used to deliver sorafenib and ganoderic acid NLCs for hepatocellular cancer, and the dual drug-loaded NLCs beat the plain medicines in chemoprotection, signaling superior activity [202]. Miltefosine given via NLCs in vivo in tumor-bearing BALB/c mice for the breast cancer treatment showed antitumor potential, improved pharmacokinetics, and higher apoptotic effects [203]. In MCF-7 cells, NLCs loaded with imatinib were produced and their in vitro effectiveness was assessed. The cytotoxicity of the optimized drug–NLC combination (IC50 = 6 M) was found to be 8.75 times higher than that of the drug alone (IC50 = 52.5 M) [204]. In another study, nanoencapsulated resveratrol possessed anticancer and apoptotic effects on cell proliferation and exerted a protective effect against cytotoxicity induced by paraquat [205]. A multi-component cancer-targeting delivery system was recently reported for the treatment of non-small-cell lung cancer by NLCs enclosing luteinizing hormone-release hormone (cancer-targeting moiety), gefitinib (EFG-TK inhibitor), paclitaxel (anticancer drug), siRNA targeted to EGF receptor mRNA as an EGF receptor suppressor, and rhodamine (imaging agent).
In comparison to the individual components used accordingly, the system has dramatically improved anticancer action [206]. Cabazitaxel (CAB) was created using expert design, NLCs of a taxane derivative, and the anti-microtubule compound, and different formulation features including the ratio of liquids and concentration of surfactants, homogenization speed, and time were adjusted. The NLCs were successful in delivering the extremely lipophilic medication CAB as a potential drug carrier in the treatment of breast cancer [207]. Folic acid-conjugated NLCs were described as an effective delivery approach for doxorubicin targeted to breast cancer cells [208]. Optimized dual drug-loaded NLCs of quercetin and piperine were found to be effective against oral squamous cell carcinoma [209]. Co-delivery of rituximab-conjugated NLCs of curcumin and imatinib in the treatment of non-Hodgkin lymphoma is reported recently [210]. Optimized NLCs of 5-Fluorouracil were prepared using a QbD approach using a 32 factorial design as effective chemotherapy for colon cancer. The oral administration of drug-loaded NLCs had higher bioavailability as compared to drug solution [211].
13.2 Phytochemicals
Active plant constituents have manifested their pharmacological activities against many diseases from time immemorial, but due to their physicochemical properties, they often have solubility, permeability, and poor bioavailability issues. Such phytoconstituents require an advanced and novel lipid carrier as a formulation to improve their biopharmaceutical problems. NLCs have been formulated for active plant constituents and these lipid-based nanocarriers have emerged as novel drug delivery systems [212]. Development of 1′-acetoxychavicol acetate NLCs for prostate cancer [213], naringenin-loaded NLCs against non-alcoholic fatty liver disease [214], cannabidiol NLCs for nasal administration for the treatment of neuropathic pain [215], nanolipoidal α-terpineol in combating keratitis induced by Pseudomonas aeruginosa [216], and bergamot oil NLCs was seen as promising means for photothermal treatment of vitiligo [217]. Curcumin-NLCs improved the neuroprotective effect of curcumin as a therapeutic for anxiety and depression [218], magnetic curcumin NLCs reported no mitochondrial toxicity when tested in vitro [219], NLCs were able to improve stability and release profile of lycopene from watermelon extract [220], and NLCs of nicergoline, a semi-synthetic ergot alkaloid based on sesame oil for intranasal delivery for brain targeting, showed augmented neuroprotective action for the treatment of dementia [221].
Curcumin-loaded NLC smart gels with the encapsulation efficiency of 72.15% and ZP of −21.67 mV were found to be biocompatible and effective for the treatment of rheumatoid arthritis [222]. Corylin-NLC gel was prepared and was found to be a promising strategy for the treatment of UV-induced skin aging [223]. Heparin-decorated NLCs of artemether-protoporphyrin IX-transferrin combinatorial delivery system were made for the treatment of malaria [224]. To address the failure of single antibiotic therapies, co-delivery of hesperidin and clarithromycin in NLCs was tried against Helicobacter pylori. NLCs were reported to interact with the microorganism membrane by adhering to the outer cell membrane and causing leakage of cytoplasmic contents [225]. Very recently, puerarin-loaded NLCs were prepared by a solvent evaporation method. This system showed an enhanced therapeutic effect on alcohol-induced cell injury of BRL-3A cells. The optimized NLC composition consisting of GMS, olive oil, poloxamer, and puerarin has an average PS (159 ± 1.1 nm), %EE (92.16%), DL (5.75%), and ZP (−28.3 mV), respectively [226]. Biotin-conjugated NLCs for oral delivery of chrysin distinctly improved the biopharmaceutical performance of chrysin, a vital flavonoid from nature [227].
13.3 Therapeutics
Miltefosine-loaded NLCs for the treatment of cutaneous leishmaniasis orally are recently prepared for a better safety profile and reduced hemolytic potential [228]. The oral bioavailability of perphenazine-loaded NLCs was enhanced as NLCs showed the potential to surmount the oral delivery drawbacks of this poorly water-soluble drug [229]. The low solubility and poor stability issues of hydrochlorothiazide suitable for pediatric oral therapy were tackled by formulating it into SLNs and NLCs. The NLCs showed better performance than SLNs, with 90% entrapped drug compared to 80% in SLNs. The NLC formulation showed good physical stability during 6-month storage at 4°C (vs SLNs) [230]. Eplerenone-loaded NLCs were successful as oral targeting delivery carriers in the treatment of chronic serous chorioretinopathy. The optimized drug-loaded NLCs showed a PS (134 nm), PDI (0.31), %EE (76 ± 6.56% w/w), and ZP (−32.37 mV) [231]. The oral bioavailability of nintedanib esylate in NLC was ameliorated over 26.31-fold compared to drug suspension resulting in increased oral bioavailability of the drug via lymphatic uptake [232]. Incorporation of olanzapine in mesoporous NLC showed a significant improvement in the oral bioavailability of olanzapine over the plain drug suspension [233]. Mannosylated NLCs of clofazimine can be used as a promising carrier for the safe delivery of drugs via inhalation route for the treatment of tuberculosis disease. A two-fold greater bioavailability was seen compared to drug dispersion [234].
Novel inhalable ciprofloxacin-NLCs formulated into nanocomposite microparticles emerged as a new approach to improve the targetability of ciprofloxacin in noncystic fibrosis bronchiectasis, thereby overcoming poor lung targeting issues of the drug after oral inhalation [235]. Itraconazole PEGylated NLCs for the treatment of pulmonary aspergillosis via inhalational delivery are reported [236]. NLC of BDP for pulmonary drug delivery via medical nebulizers is reported [237]. Intranasal administration of NLCs of Artesunate was reported to have great potential and a satisfactory alternative to parenteral administration in the treatment of severe and cerebral malaria in remote areas of sub-Saharan Africa [238]. Transferrin-functionalized curcumin NLCs were found to be promising in brain delivery [239].
14 Conclusions
In the present pharmaceutical world of research and development, numerous sophisticated nano-scaled drug delivery systems are being explored both on the laboratory and industry scale extensively. The nanosized drug delivery system offers a good stability profile to both the drug and the carrier system giving them desirable characteristics in the dosage form development. NLCs are the latest and new-generation LNP formulations, poised with flexibility in DL, modulation of their release profiles, and improved pharmaceutical performances. These special characteristic features of NLCs are attributed to their unique composition, which is the blend of solid and liquid lipids. In this review, we have tried to sum up all the information regarding the newest LNPs aka the NLCs. We have managed to throw light on all the aspects, such as components of NLCs, their preparation techniques, characterization parameters, and their optimization process, by giving numerous examples at each step for the complete understanding of the young formulator/researcher. The NLCs offer a wide range of applications in the field of medical science for the treatment of various diseases as they can administer both the hydrophilic and hydrophobic drugs by different routes, such as oral, parenteral, topical, ocular, pulmonary, and drug delivery, to the brain very efficiently. Their nontoxicity upon systemic exposure can open their new role as diagnostic tools in the field of imaging. Their specificity and targeting ability make them a very promising nanosized drug delivery system of the present times. The design and development of multifunctional NLCs loaded with combinations of drugs and biological actives and targeting them specifically to the required site will soon open better research options for the scientists and researchers worldwide in the fields of the cosmetic and pharmaceutical industry, which will be a successful step toward a new technological era in human clinical trials. Some key advantages of these nanosized carrier systems are decreased drug payload, enhanced patient compliance, reduced toxicity of the drug, cheap large-scale production, biocompatibility, biodegradability of their constituents, ease of manufacturing, and improvised chemical stabilization of the active ingredients making them even more promising and near to perfect all-rounded nanocarriers in their generation.
Acknowledgments
The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, for funding this research work under the project number: ISP20-15.
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Funding information: This work was funded by the Deputyship for Research & Innovation, Ministry of Education, Saudi Arabia (project no. ISP20-15).
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Author contributions: SJ and BM developed the concept of the manuscript; literature survey was conducted by SJ, BM, YA, MHS, and WA; methodology and data curation were done by SJ, MHS, YM, and WA. SJ and BM wrote the draft manuscript; and while writing, review, and editing were performed by YA, MHS, and WA. YA and MHS supervised the work. All authors have accepted responsibility for the entire content of this article and approved its submission.
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Conflict of interest: The authors state no conflict of interest.
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Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
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© 2022 Shamama Javed et al., published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
Articles in the same Issue
- Research Articles
- Theoretical and experimental investigation of MWCNT dispersion effect on the elastic modulus of flexible PDMS/MWCNT nanocomposites
- Mechanical, morphological, and fracture-deformation behavior of MWCNTs-reinforced (Al–Cu–Mg–T351) alloy cast nanocomposites fabricated by optimized mechanical milling and powder metallurgy techniques
- Flammability and physical stability of sugar palm crystalline nanocellulose reinforced thermoplastic sugar palm starch/poly(lactic acid) blend bionanocomposites
- Glutathione-loaded non-ionic surfactant niosomes: A new approach to improve oral bioavailability and hepatoprotective efficacy of glutathione
- Relationship between mechano-bactericidal activity and nanoblades density on chemically strengthened glass
- In situ regulation of microstructure and microwave-absorbing properties of FeSiAl through HNO3 oxidation
- Research on a mechanical model of magnetorheological fluid different diameter particles
- Nanomechanical and dynamic mechanical properties of rubber–wood–plastic composites
- Investigative properties of CeO2 doped with niobium: A combined characterization and DFT studies
- Miniaturized peptidomimetics and nano-vesiculation in endothelin types through probable nano-disk formation and structure property relationships of endothelins’ fragments
- N/S co-doped CoSe/C nanocubes as anode materials for Li-ion batteries
- Synergistic effects of halloysite nanotubes with metal and phosphorus additives on the optimal design of eco-friendly sandwich panels with maximum flame resistance and minimum weight
- Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model
- Controllable morphology of Bi2S3 nanostructures formed via hydrothermal vulcanization of Bi2O3 thin-film layer and their photoelectrocatalytic performances
- Development of (−)-epigallocatechin-3-gallate-loaded folate receptor-targeted nanoparticles for prostate cancer treatment
- Enhancement of the mechanical properties of HDPE mineral nanocomposites by filler particles modulation of the matrix plastic/elastic behavior
- Effect of plasticizers on the properties of sugar palm nanocellulose/cinnamon essential oil reinforced starch bionanocomposite films
- Optimization of nano coating to reduce the thermal deformation of ball screws
- Preparation of efficient piezoelectric PVDF–HFP/Ni composite films by high electric field poling
- MHD dissipative Casson nanofluid liquid film flow due to an unsteady stretching sheet with radiation influence and slip velocity phenomenon
- Effects of nano-SiO2 modification on rubberised mortar and concrete with recycled coarse aggregates
- Mechanical and microscopic properties of fiber-reinforced coal gangue-based geopolymer concrete
- Effect of morphology and size on the thermodynamic stability of cerium oxide nanoparticles: Experiment and molecular dynamics calculation
- Mechanical performance of a CFRP composite reinforced via gelatin-CNTs: A study on fiber interfacial enhancement and matrix enhancement
- A practical review over surface modification, nanopatterns, emerging materials, drug delivery systems, and their biophysiochemical properties for dental implants: Recent progresses and advances
- HTR: An ultra-high speed algorithm for cage recognition of clathrate hydrates
- Effects of microalloying elements added by in situ synthesis on the microstructure of WCu composites
- A highly sensitive nanobiosensor based on aptamer-conjugated graphene-decorated rhodium nanoparticles for detection of HER2-positive circulating tumor cells
- Progressive collapse performance of shear strengthened RC frames by nano CFRP
- Core–shell heterostructured composites of carbon nanotubes and imine-linked hyperbranched polymers as metal-free Li-ion anodes
- A Galerkin strategy for tri-hybridized mixture in ethylene glycol comprising variable diffusion and thermal conductivity using non-Fourier’s theory
- Simple models for tensile modulus of shape memory polymer nanocomposites at ambient temperature
- Preparation and morphological studies of tin sulfide nanoparticles and use as efficient photocatalysts for the degradation of rhodamine B and phenol
- Polyethyleneimine-impregnated activated carbon nanofiber composited graphene-derived rice husk char for efficient post-combustion CO2 capture
- Electrospun nanofibers of Co3O4 nanocrystals encapsulated in cyclized-polyacrylonitrile for lithium storage
- Pitting corrosion induced on high-strength high carbon steel wire in high alkaline deaerated chloride electrolyte
- Formulation of polymeric nanoparticles loaded sorafenib; evaluation of cytotoxicity, molecular evaluation, and gene expression studies in lung and breast cancer cell lines
- Engineered nanocomposites in asphalt binders
- Influence of loading voltage, domain ratio, and additional load on the actuation of dielectric elastomer
- Thermally induced hex-graphene transitions in 2D carbon crystals
- The surface modification effect on the interfacial properties of glass fiber-reinforced epoxy: A molecular dynamics study
- Molecular dynamics study of deformation mechanism of interfacial microzone of Cu/Al2Cu/Al composites under tension
- Nanocolloid simulators of luminescent solar concentrator photovoltaic windows
- Compressive strength and anti-chloride ion penetration assessment of geopolymer mortar merging PVA fiber and nano-SiO2 using RBF–BP composite neural network
- Effect of 3-mercapto-1-propane sulfonate sulfonic acid and polyvinylpyrrolidone on the growth of cobalt pillar by electrodeposition
- Dynamics of convective slippery constraints on hybrid radiative Sutterby nanofluid flow by Galerkin finite element simulation
- Preparation of vanadium by the magnesiothermic self-propagating reduction and process control
- Microstructure-dependent photoelectrocatalytic activity of heterogeneous ZnO–ZnS nanosheets
- Cytotoxic and pro-inflammatory effects of molybdenum and tungsten disulphide on human bronchial cells
- Improving recycled aggregate concrete by compression casting and nano-silica
- Chemically reactive Maxwell nanoliquid flow by a stretching surface in the frames of Newtonian heating, nonlinear convection and radiative flux: Nanopolymer flow processing simulation
- Nonlinear dynamic and crack behaviors of carbon nanotubes-reinforced composites with various geometries
- Biosynthesis of copper oxide nanoparticles and its therapeutic efficacy against colon cancer
- Synthesis and characterization of smart stimuli-responsive herbal drug-encapsulated nanoniosome particles for efficient treatment of breast cancer
- Homotopic simulation for heat transport phenomenon of the Burgers nanofluids flow over a stretching cylinder with thermal convective and zero mass flux conditions
- Incorporation of copper and strontium ions in TiO2 nanotubes via dopamine to enhance hemocompatibility and cytocompatibility
- Mechanical, thermal, and barrier properties of starch films incorporated with chitosan nanoparticles
- Mechanical properties and microstructure of nano-strengthened recycled aggregate concrete
- Glucose-responsive nanogels efficiently maintain the stability and activity of therapeutic enzymes
- Tunning matrix rheology and mechanical performance of ultra-high performance concrete using cellulose nanofibers
- Flexible MXene/copper/cellulose nanofiber heat spreader films with enhanced thermal conductivity
- Promoted charge separation and specific surface area via interlacing of N-doped titanium dioxide nanotubes on carbon nitride nanosheets for photocatalytic degradation of Rhodamine B
- Elucidating the role of silicon dioxide and titanium dioxide nanoparticles in mitigating the disease of the eggplant caused by Phomopsis vexans, Ralstonia solanacearum, and root-knot nematode Meloidogyne incognita
- An implication of magnetic dipole in Carreau Yasuda liquid influenced by engine oil using ternary hybrid nanomaterial
- Robust synthesis of a composite phase of copper vanadium oxide with enhanced performance for durable aqueous Zn-ion batteries
- Tunning self-assembled phases of bovine serum albumin via hydrothermal process to synthesize novel functional hydrogel for skin protection against UVB
- A comparative experimental study on damping properties of epoxy nanocomposite beams reinforced with carbon nanotubes and graphene nanoplatelets
- Lightweight and hydrophobic Ni/GO/PVA composite aerogels for ultrahigh performance electromagnetic interference shielding
- Research on the auxetic behavior and mechanical properties of periodically rotating graphene nanostructures
- Repairing performances of novel cement mortar modified with graphene oxide and polyacrylate polymer
- Closed-loop recycling and fabrication of hydrophilic CNT films with high performance
- Design of thin-film configuration of SnO2–Ag2O composites for NO2 gas-sensing applications
- Study on stress distribution of SiC/Al composites based on microstructure models with microns and nanoparticles
- PVDF green nanofibers as potential carriers for improving self-healing and mechanical properties of carbon fiber/epoxy prepregs
- Osteogenesis capability of three-dimensionally printed poly(lactic acid)-halloysite nanotube scaffolds containing strontium ranelate
- Silver nanoparticles induce mitochondria-dependent apoptosis and late non-canonical autophagy in HT-29 colon cancer cells
- Preparation and bonding mechanisms of polymer/metal hybrid composite by nano molding technology
- Damage self-sensing and strain monitoring of glass-reinforced epoxy composite impregnated with graphene nanoplatelet and multiwalled carbon nanotubes
- Thermal analysis characterisation of solar-powered ship using Oldroyd hybrid nanofluids in parabolic trough solar collector: An optimal thermal application
- Pyrene-functionalized halloysite nanotubes for simultaneously detecting and separating Hg(ii) in aqueous media: A comprehensive comparison on interparticle and intraparticle excimers
- Fabrication of self-assembly CNT flexible film and its piezoresistive sensing behaviors
- Thermal valuation and entropy inspection of second-grade nanoscale fluid flow over a stretching surface by applying Koo–Kleinstreuer–Li relation
- Mechanical properties and microstructure of nano-SiO2 and basalt-fiber-reinforced recycled aggregate concrete
- Characterization and tribology performance of polyaniline-coated nanodiamond lubricant additives
- Combined impact of Marangoni convection and thermophoretic particle deposition on chemically reactive transport of nanofluid flow over a stretching surface
- Spark plasma extrusion of binder free hydroxyapatite powder
- An investigation on thermo-mechanical performance of graphene-oxide-reinforced shape memory polymer
- Effect of nanoadditives on the novel leather fiber/recycled poly(ethylene-vinyl-acetate) polymer composites for multifunctional applications: Fabrication, characterizations, and multiobjective optimization using central composite design
- Design selection for a hemispherical dimple core sandwich panel using hybrid multi-criteria decision-making methods
- Improving tensile strength and impact toughness of plasticized poly(lactic acid) biocomposites by incorporating nanofibrillated cellulose
- Green synthesis of spinel copper ferrite (CuFe2O4) nanoparticles and their toxicity
- The effect of TaC and NbC hybrid and mono-nanoparticles on AA2024 nanocomposites: Microstructure, strengthening, and artificial aging
- Excited-state geometry relaxation of pyrene-modified cellulose nanocrystals under UV-light excitation for detecting Fe3+
- Effect of CNTs and MEA on the creep of face-slab concrete at an early age
- Effect of deformation conditions on compression phase transformation of AZ31
- Application of MXene as a new generation of highly conductive coating materials for electromembrane-surrounded solid-phase microextraction
- A comparative study of the elasto-plastic properties for ceramic nanocomposites filled by graphene or graphene oxide nanoplates
- Encapsulation strategies for improving the biological behavior of CdS@ZIF-8 nanocomposites
- Biosynthesis of ZnO NPs from pumpkin seeds’ extract and elucidation of its anticancer potential against breast cancer
- Preliminary trials of the gold nanoparticles conjugated chrysin: An assessment of anti-oxidant, anti-microbial, and in vitro cytotoxic activities of a nanoformulated flavonoid
- Effect of micron-scale pores increased by nano-SiO2 sol modification on the strength of cement mortar
- Fractional simulations for thermal flow of hybrid nanofluid with aluminum oxide and titanium oxide nanoparticles with water and blood base fluids
- The effect of graphene nano-powder on the viscosity of water: An experimental study and artificial neural network modeling
- Development of a novel heat- and shear-resistant nano-silica gelling agent
- Characterization, biocompatibility and in vivo of nominal MnO2-containing wollastonite glass-ceramic
- Entropy production simulation of second-grade magnetic nanomaterials flowing across an expanding surface with viscidness dissipative flux
- Enhancement in structural, morphological, and optical properties of copper oxide for optoelectronic device applications
- Aptamer-functionalized chitosan-coated gold nanoparticle complex as a suitable targeted drug carrier for improved breast cancer treatment
- Performance and overall evaluation of nano-alumina-modified asphalt mixture
- Analysis of pure nanofluid (GO/engine oil) and hybrid nanofluid (GO–Fe3O4/engine oil): Novel thermal and magnetic features
- Synthesis of Ag@AgCl modified anatase/rutile/brookite mixed phase TiO2 and their photocatalytic property
- Mechanisms and influential variables on the abrasion resistance hydraulic concrete
- Synergistic reinforcement mechanism of basalt fiber/cellulose nanocrystals/polypropylene composites
- Achieving excellent oxidation resistance and mechanical properties of TiB2–B4C/carbon aerogel composites by quick-gelation and mechanical mixing
- Microwave-assisted sol–gel template-free synthesis and characterization of silica nanoparticles obtained from South African coal fly ash
- Pulsed laser-assisted synthesis of nano nickel(ii) oxide-anchored graphitic carbon nitride: Characterizations and their potential antibacterial/anti-biofilm applications
- Effects of nano-ZrSi2 on thermal stability of phenolic resin and thermal reusability of quartz–phenolic composites
- Benzaldehyde derivatives on tin electroplating as corrosion resistance for fabricating copper circuit
- Mechanical and heat transfer properties of 4D-printed shape memory graphene oxide/epoxy acrylate composites
- Coupling the vanadium-induced amorphous/crystalline NiFe2O4 with phosphide heterojunction toward active oxygen evolution reaction catalysts
- Graphene-oxide-reinforced cement composites mechanical and microstructural characteristics at elevated temperatures
- Gray correlation analysis of factors influencing compressive strength and durability of nano-SiO2 and PVA fiber reinforced geopolymer mortar
- Preparation of layered gradient Cu–Cr–Ti alloy with excellent mechanical properties, thermal stability, and electrical conductivity
- Recovery of Cr from chrome-containing leather wastes to develop aluminum-based composite material along with Al2O3 ceramic particles: An ingenious approach
- Mechanisms of the improved stiffness of flexible polymers under impact loading
- Anticancer potential of gold nanoparticles (AuNPs) using a battery of in vitro tests
- Review Articles
- Proposed approaches for coronaviruses elimination from wastewater: Membrane techniques and nanotechnology solutions
- Application of Pickering emulsion in oil drilling and production
- The contribution of microfluidics to the fight against tuberculosis
- Graphene-based biosensors for disease theranostics: Development, applications, and recent advancements
- Synthesis and encapsulation of iron oxide nanorods for application in magnetic hyperthermia and photothermal therapy
- Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect
- State-of-the-art review of fabrication, application, and mechanical properties of functionally graded porous nanocomposite materials
- Insights on magnetic spinel ferrites for targeted drug delivery and hyperthermia applications
- A review on heterogeneous oxidation of acetaminophen based on micro and nanoparticles catalyzed by different activators
- Early diagnosis of lung cancer using magnetic nanoparticles-integrated systems
- Advances in ZnO: Manipulation of defects for enhancing their technological potentials
- Efficacious nanomedicine track toward combating COVID-19
- A review of the design, processes, and properties of Mg-based composites
- Green synthesis of nanoparticles for varied applications: Green renewable resources and energy-efficient synthetic routes
- Two-dimensional nanomaterial-based polymer composites: Fundamentals and applications
- Recent progress and challenges in plasmonic nanomaterials
- Apoptotic cell-derived micro/nanosized extracellular vesicles in tissue regeneration
- Electronic noses based on metal oxide nanowires: A review
- Framework materials for supercapacitors
- An overview on the reproductive toxicity of graphene derivatives: Highlighting the importance
- Antibacterial nanomaterials: Upcoming hope to overcome antibiotic resistance crisis
- Research progress of carbon materials in the field of three-dimensional printing polymer nanocomposites
- A review of atomic layer deposition modelling and simulation methodologies: Density functional theory and molecular dynamics
- Recent advances in the preparation of PVDF-based piezoelectric materials
- Recent developments in tensile properties of friction welding of carbon fiber-reinforced composite: A review
- Comprehensive review of the properties of fly ash-based geopolymer with additive of nano-SiO2
- Perspectives in biopolymer/graphene-based composite application: Advances, challenges, and recommendations
- Graphene-based nanocomposite using new modeling molecular dynamic simulations for proposed neutralizing mechanism and real-time sensing of COVID-19
- Nanotechnology application on bamboo materials: A review
- Recent developments and future perspectives of biorenewable nanocomposites for advanced applications
- Nanostructured lipid carrier system: A compendium of their formulation development approaches, optimization strategies by quality by design, and recent applications in drug delivery
- 3D printing customized design of human bone tissue implant and its application
- Design, preparation, and functionalization of nanobiomaterials for enhanced efficacy in current and future biomedical applications
- A brief review of nanoparticles-doped PEDOT:PSS nanocomposite for OLED and OPV
- Nanotechnology interventions as a putative tool for the treatment of dental afflictions
- Recent advancements in metal–organic frameworks integrating quantum dots (QDs@MOF) and their potential applications
- A focused review of short electrospun nanofiber preparation techniques for composite reinforcement
- Microstructural characteristics and nano-modification of interfacial transition zone in concrete: A review
- Latest developments in the upconversion nanotechnology for the rapid detection of food safety: A review
- Strategic applications of nano-fertilizers for sustainable agriculture: Benefits and bottlenecks
- Molecular dynamics application of cocrystal energetic materials: A review
- Synthesis and application of nanometer hydroxyapatite in biomedicine
- Cutting-edge development in waste-recycled nanomaterials for energy storage and conversion applications
- Biological applications of ternary quantum dots: A review
- Nanotherapeutics for hydrogen sulfide-involved treatment: An emerging approach for cancer therapy
- Application of antibacterial nanoparticles in orthodontic materials
- Effect of natural-based biological hydrogels combined with growth factors on skin wound healing
- Nanozymes – A route to overcome microbial resistance: A viewpoint
- Recent developments and applications of smart nanoparticles in biomedicine
- Contemporary review on carbon nanotube (CNT) composites and their impact on multifarious applications
- Interfacial interactions and reinforcing mechanisms of cellulose and chitin nanomaterials and starch derivatives for cement and concrete strength and durability enhancement: A review
- Diamond-like carbon films for tribological modification of rubber
- Layered double hydroxides (LDHs) modified cement-based materials: A systematic review
- Recent research progress and advanced applications of silica/polymer nanocomposites
- Modeling of supramolecular biopolymers: Leading the in silico revolution of tissue engineering and nanomedicine
- Recent advances in perovskites-based optoelectronics
- Biogenic synthesis of palladium nanoparticles: New production methods and applications
- A comprehensive review of nanofluids with fractional derivatives: Modeling and application
- Electrospinning of marine polysaccharides: Processing and chemical aspects, challenges, and future prospects
- Electrohydrodynamic printing for demanding devices: A review of processing and applications
- Rapid Communications
- Structural material with designed thermal twist for a simple actuation
- Recent advances in photothermal materials for solar-driven crude oil adsorption
Articles in the same Issue
- Research Articles
- Theoretical and experimental investigation of MWCNT dispersion effect on the elastic modulus of flexible PDMS/MWCNT nanocomposites
- Mechanical, morphological, and fracture-deformation behavior of MWCNTs-reinforced (Al–Cu–Mg–T351) alloy cast nanocomposites fabricated by optimized mechanical milling and powder metallurgy techniques
- Flammability and physical stability of sugar palm crystalline nanocellulose reinforced thermoplastic sugar palm starch/poly(lactic acid) blend bionanocomposites
- Glutathione-loaded non-ionic surfactant niosomes: A new approach to improve oral bioavailability and hepatoprotective efficacy of glutathione
- Relationship between mechano-bactericidal activity and nanoblades density on chemically strengthened glass
- In situ regulation of microstructure and microwave-absorbing properties of FeSiAl through HNO3 oxidation
- Research on a mechanical model of magnetorheological fluid different diameter particles
- Nanomechanical and dynamic mechanical properties of rubber–wood–plastic composites
- Investigative properties of CeO2 doped with niobium: A combined characterization and DFT studies
- Miniaturized peptidomimetics and nano-vesiculation in endothelin types through probable nano-disk formation and structure property relationships of endothelins’ fragments
- N/S co-doped CoSe/C nanocubes as anode materials for Li-ion batteries
- Synergistic effects of halloysite nanotubes with metal and phosphorus additives on the optimal design of eco-friendly sandwich panels with maximum flame resistance and minimum weight
- Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model
- Controllable morphology of Bi2S3 nanostructures formed via hydrothermal vulcanization of Bi2O3 thin-film layer and their photoelectrocatalytic performances
- Development of (−)-epigallocatechin-3-gallate-loaded folate receptor-targeted nanoparticles for prostate cancer treatment
- Enhancement of the mechanical properties of HDPE mineral nanocomposites by filler particles modulation of the matrix plastic/elastic behavior
- Effect of plasticizers on the properties of sugar palm nanocellulose/cinnamon essential oil reinforced starch bionanocomposite films
- Optimization of nano coating to reduce the thermal deformation of ball screws
- Preparation of efficient piezoelectric PVDF–HFP/Ni composite films by high electric field poling
- MHD dissipative Casson nanofluid liquid film flow due to an unsteady stretching sheet with radiation influence and slip velocity phenomenon
- Effects of nano-SiO2 modification on rubberised mortar and concrete with recycled coarse aggregates
- Mechanical and microscopic properties of fiber-reinforced coal gangue-based geopolymer concrete
- Effect of morphology and size on the thermodynamic stability of cerium oxide nanoparticles: Experiment and molecular dynamics calculation
- Mechanical performance of a CFRP composite reinforced via gelatin-CNTs: A study on fiber interfacial enhancement and matrix enhancement
- A practical review over surface modification, nanopatterns, emerging materials, drug delivery systems, and their biophysiochemical properties for dental implants: Recent progresses and advances
- HTR: An ultra-high speed algorithm for cage recognition of clathrate hydrates
- Effects of microalloying elements added by in situ synthesis on the microstructure of WCu composites
- A highly sensitive nanobiosensor based on aptamer-conjugated graphene-decorated rhodium nanoparticles for detection of HER2-positive circulating tumor cells
- Progressive collapse performance of shear strengthened RC frames by nano CFRP
- Core–shell heterostructured composites of carbon nanotubes and imine-linked hyperbranched polymers as metal-free Li-ion anodes
- A Galerkin strategy for tri-hybridized mixture in ethylene glycol comprising variable diffusion and thermal conductivity using non-Fourier’s theory
- Simple models for tensile modulus of shape memory polymer nanocomposites at ambient temperature
- Preparation and morphological studies of tin sulfide nanoparticles and use as efficient photocatalysts for the degradation of rhodamine B and phenol
- Polyethyleneimine-impregnated activated carbon nanofiber composited graphene-derived rice husk char for efficient post-combustion CO2 capture
- Electrospun nanofibers of Co3O4 nanocrystals encapsulated in cyclized-polyacrylonitrile for lithium storage
- Pitting corrosion induced on high-strength high carbon steel wire in high alkaline deaerated chloride electrolyte
- Formulation of polymeric nanoparticles loaded sorafenib; evaluation of cytotoxicity, molecular evaluation, and gene expression studies in lung and breast cancer cell lines
- Engineered nanocomposites in asphalt binders
- Influence of loading voltage, domain ratio, and additional load on the actuation of dielectric elastomer
- Thermally induced hex-graphene transitions in 2D carbon crystals
- The surface modification effect on the interfacial properties of glass fiber-reinforced epoxy: A molecular dynamics study
- Molecular dynamics study of deformation mechanism of interfacial microzone of Cu/Al2Cu/Al composites under tension
- Nanocolloid simulators of luminescent solar concentrator photovoltaic windows
- Compressive strength and anti-chloride ion penetration assessment of geopolymer mortar merging PVA fiber and nano-SiO2 using RBF–BP composite neural network
- Effect of 3-mercapto-1-propane sulfonate sulfonic acid and polyvinylpyrrolidone on the growth of cobalt pillar by electrodeposition
- Dynamics of convective slippery constraints on hybrid radiative Sutterby nanofluid flow by Galerkin finite element simulation
- Preparation of vanadium by the magnesiothermic self-propagating reduction and process control
- Microstructure-dependent photoelectrocatalytic activity of heterogeneous ZnO–ZnS nanosheets
- Cytotoxic and pro-inflammatory effects of molybdenum and tungsten disulphide on human bronchial cells
- Improving recycled aggregate concrete by compression casting and nano-silica
- Chemically reactive Maxwell nanoliquid flow by a stretching surface in the frames of Newtonian heating, nonlinear convection and radiative flux: Nanopolymer flow processing simulation
- Nonlinear dynamic and crack behaviors of carbon nanotubes-reinforced composites with various geometries
- Biosynthesis of copper oxide nanoparticles and its therapeutic efficacy against colon cancer
- Synthesis and characterization of smart stimuli-responsive herbal drug-encapsulated nanoniosome particles for efficient treatment of breast cancer
- Homotopic simulation for heat transport phenomenon of the Burgers nanofluids flow over a stretching cylinder with thermal convective and zero mass flux conditions
- Incorporation of copper and strontium ions in TiO2 nanotubes via dopamine to enhance hemocompatibility and cytocompatibility
- Mechanical, thermal, and barrier properties of starch films incorporated with chitosan nanoparticles
- Mechanical properties and microstructure of nano-strengthened recycled aggregate concrete
- Glucose-responsive nanogels efficiently maintain the stability and activity of therapeutic enzymes
- Tunning matrix rheology and mechanical performance of ultra-high performance concrete using cellulose nanofibers
- Flexible MXene/copper/cellulose nanofiber heat spreader films with enhanced thermal conductivity
- Promoted charge separation and specific surface area via interlacing of N-doped titanium dioxide nanotubes on carbon nitride nanosheets for photocatalytic degradation of Rhodamine B
- Elucidating the role of silicon dioxide and titanium dioxide nanoparticles in mitigating the disease of the eggplant caused by Phomopsis vexans, Ralstonia solanacearum, and root-knot nematode Meloidogyne incognita
- An implication of magnetic dipole in Carreau Yasuda liquid influenced by engine oil using ternary hybrid nanomaterial
- Robust synthesis of a composite phase of copper vanadium oxide with enhanced performance for durable aqueous Zn-ion batteries
- Tunning self-assembled phases of bovine serum albumin via hydrothermal process to synthesize novel functional hydrogel for skin protection against UVB
- A comparative experimental study on damping properties of epoxy nanocomposite beams reinforced with carbon nanotubes and graphene nanoplatelets
- Lightweight and hydrophobic Ni/GO/PVA composite aerogels for ultrahigh performance electromagnetic interference shielding
- Research on the auxetic behavior and mechanical properties of periodically rotating graphene nanostructures
- Repairing performances of novel cement mortar modified with graphene oxide and polyacrylate polymer
- Closed-loop recycling and fabrication of hydrophilic CNT films with high performance
- Design of thin-film configuration of SnO2–Ag2O composites for NO2 gas-sensing applications
- Study on stress distribution of SiC/Al composites based on microstructure models with microns and nanoparticles
- PVDF green nanofibers as potential carriers for improving self-healing and mechanical properties of carbon fiber/epoxy prepregs
- Osteogenesis capability of three-dimensionally printed poly(lactic acid)-halloysite nanotube scaffolds containing strontium ranelate
- Silver nanoparticles induce mitochondria-dependent apoptosis and late non-canonical autophagy in HT-29 colon cancer cells
- Preparation and bonding mechanisms of polymer/metal hybrid composite by nano molding technology
- Damage self-sensing and strain monitoring of glass-reinforced epoxy composite impregnated with graphene nanoplatelet and multiwalled carbon nanotubes
- Thermal analysis characterisation of solar-powered ship using Oldroyd hybrid nanofluids in parabolic trough solar collector: An optimal thermal application
- Pyrene-functionalized halloysite nanotubes for simultaneously detecting and separating Hg(ii) in aqueous media: A comprehensive comparison on interparticle and intraparticle excimers
- Fabrication of self-assembly CNT flexible film and its piezoresistive sensing behaviors
- Thermal valuation and entropy inspection of second-grade nanoscale fluid flow over a stretching surface by applying Koo–Kleinstreuer–Li relation
- Mechanical properties and microstructure of nano-SiO2 and basalt-fiber-reinforced recycled aggregate concrete
- Characterization and tribology performance of polyaniline-coated nanodiamond lubricant additives
- Combined impact of Marangoni convection and thermophoretic particle deposition on chemically reactive transport of nanofluid flow over a stretching surface
- Spark plasma extrusion of binder free hydroxyapatite powder
- An investigation on thermo-mechanical performance of graphene-oxide-reinforced shape memory polymer
- Effect of nanoadditives on the novel leather fiber/recycled poly(ethylene-vinyl-acetate) polymer composites for multifunctional applications: Fabrication, characterizations, and multiobjective optimization using central composite design
- Design selection for a hemispherical dimple core sandwich panel using hybrid multi-criteria decision-making methods
- Improving tensile strength and impact toughness of plasticized poly(lactic acid) biocomposites by incorporating nanofibrillated cellulose
- Green synthesis of spinel copper ferrite (CuFe2O4) nanoparticles and their toxicity
- The effect of TaC and NbC hybrid and mono-nanoparticles on AA2024 nanocomposites: Microstructure, strengthening, and artificial aging
- Excited-state geometry relaxation of pyrene-modified cellulose nanocrystals under UV-light excitation for detecting Fe3+
- Effect of CNTs and MEA on the creep of face-slab concrete at an early age
- Effect of deformation conditions on compression phase transformation of AZ31
- Application of MXene as a new generation of highly conductive coating materials for electromembrane-surrounded solid-phase microextraction
- A comparative study of the elasto-plastic properties for ceramic nanocomposites filled by graphene or graphene oxide nanoplates
- Encapsulation strategies for improving the biological behavior of CdS@ZIF-8 nanocomposites
- Biosynthesis of ZnO NPs from pumpkin seeds’ extract and elucidation of its anticancer potential against breast cancer
- Preliminary trials of the gold nanoparticles conjugated chrysin: An assessment of anti-oxidant, anti-microbial, and in vitro cytotoxic activities of a nanoformulated flavonoid
- Effect of micron-scale pores increased by nano-SiO2 sol modification on the strength of cement mortar
- Fractional simulations for thermal flow of hybrid nanofluid with aluminum oxide and titanium oxide nanoparticles with water and blood base fluids
- The effect of graphene nano-powder on the viscosity of water: An experimental study and artificial neural network modeling
- Development of a novel heat- and shear-resistant nano-silica gelling agent
- Characterization, biocompatibility and in vivo of nominal MnO2-containing wollastonite glass-ceramic
- Entropy production simulation of second-grade magnetic nanomaterials flowing across an expanding surface with viscidness dissipative flux
- Enhancement in structural, morphological, and optical properties of copper oxide for optoelectronic device applications
- Aptamer-functionalized chitosan-coated gold nanoparticle complex as a suitable targeted drug carrier for improved breast cancer treatment
- Performance and overall evaluation of nano-alumina-modified asphalt mixture
- Analysis of pure nanofluid (GO/engine oil) and hybrid nanofluid (GO–Fe3O4/engine oil): Novel thermal and magnetic features
- Synthesis of Ag@AgCl modified anatase/rutile/brookite mixed phase TiO2 and their photocatalytic property
- Mechanisms and influential variables on the abrasion resistance hydraulic concrete
- Synergistic reinforcement mechanism of basalt fiber/cellulose nanocrystals/polypropylene composites
- Achieving excellent oxidation resistance and mechanical properties of TiB2–B4C/carbon aerogel composites by quick-gelation and mechanical mixing
- Microwave-assisted sol–gel template-free synthesis and characterization of silica nanoparticles obtained from South African coal fly ash
- Pulsed laser-assisted synthesis of nano nickel(ii) oxide-anchored graphitic carbon nitride: Characterizations and their potential antibacterial/anti-biofilm applications
- Effects of nano-ZrSi2 on thermal stability of phenolic resin and thermal reusability of quartz–phenolic composites
- Benzaldehyde derivatives on tin electroplating as corrosion resistance for fabricating copper circuit
- Mechanical and heat transfer properties of 4D-printed shape memory graphene oxide/epoxy acrylate composites
- Coupling the vanadium-induced amorphous/crystalline NiFe2O4 with phosphide heterojunction toward active oxygen evolution reaction catalysts
- Graphene-oxide-reinforced cement composites mechanical and microstructural characteristics at elevated temperatures
- Gray correlation analysis of factors influencing compressive strength and durability of nano-SiO2 and PVA fiber reinforced geopolymer mortar
- Preparation of layered gradient Cu–Cr–Ti alloy with excellent mechanical properties, thermal stability, and electrical conductivity
- Recovery of Cr from chrome-containing leather wastes to develop aluminum-based composite material along with Al2O3 ceramic particles: An ingenious approach
- Mechanisms of the improved stiffness of flexible polymers under impact loading
- Anticancer potential of gold nanoparticles (AuNPs) using a battery of in vitro tests
- Review Articles
- Proposed approaches for coronaviruses elimination from wastewater: Membrane techniques and nanotechnology solutions
- Application of Pickering emulsion in oil drilling and production
- The contribution of microfluidics to the fight against tuberculosis
- Graphene-based biosensors for disease theranostics: Development, applications, and recent advancements
- Synthesis and encapsulation of iron oxide nanorods for application in magnetic hyperthermia and photothermal therapy
- Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect
- State-of-the-art review of fabrication, application, and mechanical properties of functionally graded porous nanocomposite materials
- Insights on magnetic spinel ferrites for targeted drug delivery and hyperthermia applications
- A review on heterogeneous oxidation of acetaminophen based on micro and nanoparticles catalyzed by different activators
- Early diagnosis of lung cancer using magnetic nanoparticles-integrated systems
- Advances in ZnO: Manipulation of defects for enhancing their technological potentials
- Efficacious nanomedicine track toward combating COVID-19
- A review of the design, processes, and properties of Mg-based composites
- Green synthesis of nanoparticles for varied applications: Green renewable resources and energy-efficient synthetic routes
- Two-dimensional nanomaterial-based polymer composites: Fundamentals and applications
- Recent progress and challenges in plasmonic nanomaterials
- Apoptotic cell-derived micro/nanosized extracellular vesicles in tissue regeneration
- Electronic noses based on metal oxide nanowires: A review
- Framework materials for supercapacitors
- An overview on the reproductive toxicity of graphene derivatives: Highlighting the importance
- Antibacterial nanomaterials: Upcoming hope to overcome antibiotic resistance crisis
- Research progress of carbon materials in the field of three-dimensional printing polymer nanocomposites
- A review of atomic layer deposition modelling and simulation methodologies: Density functional theory and molecular dynamics
- Recent advances in the preparation of PVDF-based piezoelectric materials
- Recent developments in tensile properties of friction welding of carbon fiber-reinforced composite: A review
- Comprehensive review of the properties of fly ash-based geopolymer with additive of nano-SiO2
- Perspectives in biopolymer/graphene-based composite application: Advances, challenges, and recommendations
- Graphene-based nanocomposite using new modeling molecular dynamic simulations for proposed neutralizing mechanism and real-time sensing of COVID-19
- Nanotechnology application on bamboo materials: A review
- Recent developments and future perspectives of biorenewable nanocomposites for advanced applications
- Nanostructured lipid carrier system: A compendium of their formulation development approaches, optimization strategies by quality by design, and recent applications in drug delivery
- 3D printing customized design of human bone tissue implant and its application
- Design, preparation, and functionalization of nanobiomaterials for enhanced efficacy in current and future biomedical applications
- A brief review of nanoparticles-doped PEDOT:PSS nanocomposite for OLED and OPV
- Nanotechnology interventions as a putative tool for the treatment of dental afflictions
- Recent advancements in metal–organic frameworks integrating quantum dots (QDs@MOF) and their potential applications
- A focused review of short electrospun nanofiber preparation techniques for composite reinforcement
- Microstructural characteristics and nano-modification of interfacial transition zone in concrete: A review
- Latest developments in the upconversion nanotechnology for the rapid detection of food safety: A review
- Strategic applications of nano-fertilizers for sustainable agriculture: Benefits and bottlenecks
- Molecular dynamics application of cocrystal energetic materials: A review
- Synthesis and application of nanometer hydroxyapatite in biomedicine
- Cutting-edge development in waste-recycled nanomaterials for energy storage and conversion applications
- Biological applications of ternary quantum dots: A review
- Nanotherapeutics for hydrogen sulfide-involved treatment: An emerging approach for cancer therapy
- Application of antibacterial nanoparticles in orthodontic materials
- Effect of natural-based biological hydrogels combined with growth factors on skin wound healing
- Nanozymes – A route to overcome microbial resistance: A viewpoint
- Recent developments and applications of smart nanoparticles in biomedicine
- Contemporary review on carbon nanotube (CNT) composites and their impact on multifarious applications
- Interfacial interactions and reinforcing mechanisms of cellulose and chitin nanomaterials and starch derivatives for cement and concrete strength and durability enhancement: A review
- Diamond-like carbon films for tribological modification of rubber
- Layered double hydroxides (LDHs) modified cement-based materials: A systematic review
- Recent research progress and advanced applications of silica/polymer nanocomposites
- Modeling of supramolecular biopolymers: Leading the in silico revolution of tissue engineering and nanomedicine
- Recent advances in perovskites-based optoelectronics
- Biogenic synthesis of palladium nanoparticles: New production methods and applications
- A comprehensive review of nanofluids with fractional derivatives: Modeling and application
- Electrospinning of marine polysaccharides: Processing and chemical aspects, challenges, and future prospects
- Electrohydrodynamic printing for demanding devices: A review of processing and applications
- Rapid Communications
- Structural material with designed thermal twist for a simple actuation
- Recent advances in photothermal materials for solar-driven crude oil adsorption
