INTRODUCTION
In the past few years, there has been a fascinating development in nanoscale drug delivery technologies. Majorly biocompatible polymers and lipid excipients have been on the rise, which efficiently incorporated in the lipid nanosystems. These lipids are usually physiological lipids possessing little acute and chronic toxicities (Hadis et al., 2019; Harde et al., 2011). Solid lipid nanoparticles (SLNs) offer an amalgamating effect of several carrier systems such as liposomes and niosomes. Similar to other carrier systems, SLNs are also constituted by biocompatible excipients that are physiologically accepted and homology to polymeric nanoparticles. The solid matrix in SLNs also proposes to protect the loaded therapeutic molecules against the rough biological environment and also shield the other chemical degradations with maximum feasibility to alter the release profiles of the therapeutic molecule. Altogether, these proficiencies make the SLNs an exceptional carrier system (Das and Chaudhury, 2011).
SLNs are morphologically spherical with a smooth surface possessing mean diameter ranging between 50 and 1,000 nm. Both in vivo and in vitro behaviors are dependent on the physicochemical characterization of SLNs. Solid lipid (at 25°C–28°C), emulsifiers for certain times simultaneously, and along with appropriate solvent for solubilizing lipid and non-lipid components, together constitute the typical SLNs (Fig. 1).
While formulating SLNs, lipids listed in Generally Regarded as Safe are commonly employed (Weber et al., 2014). These comprise of fatty acids/esters, cholesterol, triglycerides (e.g., compritol® 888 and caprylic), and waxes (bees, carnauba, etc.). Pluronic F68/F127, poloxamers, and sodium cholate are considered for emulsification. Organic salts, surface modifiers, and ionic polymers are served for PEGylation, specific targeting, surface charge modifications. SLNs are classified into (a) drug-loaded shell, (b) drug-loaded core, and (c) homogeneous matrix, based on entrenched site of the therapeutic molecule within the SLN structure. Advantages and applications are shown in Figure 2.
The process of cooling hot liquid droplets followed by phase separation yields a drug-loaded shell. This rapid cooling results in liquid precipitation that forms SLNs on complete cooling. This category of SLNs fits well for topical conditions. Unlike the shell model, drug-loaded core, the drug ought to crystallize much before liquid precipitate. The drug-loaded core model facilitates the sustained release of therapeutic agents and obeys Fick’s law of diffusion. Highly lipophilic drugs are dispersed homogeneously within the lipid matrix employing cold homogenization. Hence, SLNs benefit in smooth production, employing simple homogenization techniques (Aleksandra et al., 2018; Jenning et al., 2000). A comprehensive understanding of various production techniques is further discussed in the following section.
PREPARATION OF SLN
High-pressure homogenization
High-pressure homogenization (HPH) has been used as a reliable technique for the preparation of SLN. Several manufacturers produce homogenizers of diverse sizes at a reasonable cost. The particles of the submicron range are obtained at elevated shear stress and cavitation compulsion. Nanoemulsions for parenteral nutrition are produced by HPH. HPH pushes the liquid at high pressures (100–2,000 bar) through a narrow space (range of few microns). The fluid moves faster over a short distance with high velocity. With homogenization, even the high lipid concentration could be transformed into nanodispersions (Wolfgang and Karsten, 2001).
Figure 1. Structure of SLNs. [Click here to view] |
Figure 2. Representation of advantages and applications SLNs formulations. [Click here to view] |
Hot and cold homogenization techniques are the means for the manufacturing of SLN. A preparatory step involves in both the cases. Lipid matrix used in this process is extracted from the physiological lipids which reduce the risk of acute and chronic toxicity.
Hot homogenization
Temperatures higher than the melting point of the lipid are selected for this process and can subsequently be considered as the homogenization of an emulsion. An aqueous surfactant is used for the combination of lipid and drug at the same temperature. A device for high shear mixing is used to prepare a hot pre-emulsion, resulting in an emulsion of oil in water type. Then, the product is left for cooling, and this leads to the initiation of crystals of lipid and then the formation of SLNs. For the production of perfect SLNs, 3–5 cycles of homogenization at a pressure of 500–1,500 bar are necessary (Akanksha et al., 2012). One should always be aware that there is a rise in temperature with HPH. With the rise in the number of cycles or the pressure, there is a growth in the particle size. This is due to attractive forces between the particles which are due to the energy of moving the particles (Siekmann and Westesen, 1994). Finally, cooling of the nanoemulsion to room temperature is done, where the recrystallization of lipids occurs and this leads to the formation of nanoparticles (Fig. 3).
Cold homogenization
This technique has been developed to combat the problems of hot homogenization such as faster deterioration due to high temperatures, loss of drug during homogenization into the aqueous phase, and undetermined polymorphic transformations of the lipid due to the complexity of crystallization.
The first elementary step is indistinguishable as in the hot homogenization technique which includes the solubilization of drug in the lipid melt. The successive steps are altered; the drug-containing melt is refrigerated speedily with the aid of solid carbon dioxide or liquid nitrogen for attaining a homogenous drug distribution lipid matrix. The solid is then levigated into a fine dust by using a ball mill. Typical dust size attained is in the range of 50–100 μm. In the chilled aqueous surfactant, the fine dust particles are dispersed. Now, the dispersion is subjected to HPH to initiate the SLN production (Fig. 4). However, compared to a hot homogenization technique, greater particle sizes and wider size distribution are typical of the cold homogenized product (Mehnert and Mäder, 2001)
Cold homogenization lessens the heat vulnerability, but it is not completely avoided due to the softening of lipid mixture in the opening step.
Figure 3. Hot homogenization technique. [Click here to view] |
Figure 4. Cold homogenization technique. [Click here to view] |
Ultrasonication
SLN was also produced by high-speed stirring or sonication (Eldem et al., 1991). The impedimenta used for this method is prevalent in every single laboratory. The main drawback of this technique is wider particle size distribution ranging into micrometer range which is the main cause for physical instability (Svilenov and Tzachev, 2009). Particle gain on storage and potential metal decay are acute problems in this method. After many studies and intense research, it was proved that high-speed stirring and ultrasonication, when operated combinedly at high temperatures, yield a steady formulation (Eldem et al., 1991) (Fig. 5).
Solvent emulsification–evaporation
In this method, the lipophilic material and hydrophobic drug are dissolved in water-immiscible organic solvents such as cyclohexane, toluene, and chloroform. Now, by using a high-speed homogenization, the mixture is emulsified in an aqueous phase. The coarse emulsion is instantly allowed to flow through a microfluidizer. A rotary evaporator with mechanical agitation at room temperature and decreased pressure is used to evaporate the organic solvent (Ramteke et al., 2012). The main mastery of this technique is bypassing the thermal stress. Therefore, now, there is a possibility for the incorporation of highly thermolabile drugs (Fig. 6). The clear-cut disadvantage is the use of an organic solvent which may react with drug molecules (Sjostrom and Bergenstahl, 1992)
Figure 5. High shear homogenization or ultrasonication technique. [Click here to view] |
Figure 6. Solvent emulsification-evaporation technique. [Click here to view] |
Supercritical fluid (ScF)
This is a comparatively advanced technique for the manufacturing of SLNs. The supercritical fluid has distinct thermophysical properties which can be finely adjusted by minute modifications in the pressure. It is solvent-free processing (Chen et al., 2006; Kaiser et al., 2001). With the elevation in pressure, the density and capability of fluid to liquefy compounds enhance, whereas the velocity remains the same. ScF is a substance above its pressure and critical temperature. The fluid has special properties at these conditions: liquid-like density, gas-like viscosity, and larger diffusivities than those of typical liquid (intermediate to that of a liquid and a gas), giving rise to its higher mass-transfer rate. Various techniques such as rapid expansion of supercritical solutions (RESS), supercritical antisolvent process and precipitation with a compressed antisolvent process (PCA), particles from gas-saturated solutions/suspensions, and supercritical extraction from emulsions can be used.
The high solubility of the drug in ScCO2 (solvent) is required for carrying out RESS technology. In this process, the supercritical fluid is quickly enlarged via a nozzle to convert the solute as micro- or nanoparticles. There are three major factors which regulate the particle, and the particle growth is a short residence time, not much time available for particle growth and maximum dilution of the particles in the expansion chamber (Garces et al., 2018). Pure powder griseofulvin has been acquired using a cosolvent such as methanol which improves the drug solubility in ScCO2 for about 28 folds. The usage of a simple capillary nozzle, griseofulvin NPs in the range of 50−250 nm has been derived (Thakur and Gupta, 2005).
In the PCA technique, an atomized drug solution along with compressed carbon dioxide is introduced into the chamber. After the solution gets supersaturated, fine crystals precipitate out. A supercritical fluid with poor drug solubility is selected and used. The drug is dissolved in the solvent. This solvent should be miscible with the supercritical fluid. The supercritical fluids pull out all the solvent, and then, the drug solution becomes supersaturated after introducing the drug solution into the supersaturated solution. The drug precipitates as fine crystals (Alessi et al., 2012). The key advantage of this method is the particles which are acquired as a dry powder, instead of suspension (Fig. 7).
Microemulsion
SLN preparations were developed by Gasco and coworkers on the basis of reducing the concentration of microemulsions (Akanksha et al., 2012). These microemulsions are biphasic units consisting of external and internal mediums. Combination consists of a low melting fatty acid (e.g., stearic acid), an emulsifier (e.g., polysorbate 20, polysorbate 60, and soy phosphatidylcholine), coemulsifiers (e.g., butanol and sodium mono cetyl phosphate), and water. In the cold water (2°C–3°C), the hot microemulsion is diffused. Based on the combination of microemulsion, the dilution process can be fixed. In this method, there is no extra energy consumed for attaining the submicron size (Gasco, 1997; Ramteke et al., 2012) The main criteria for the production of nanoparticles are that they can be produced only with certain solvents which rapidly distribute into the aqueous phase (Fig. 8), whereas more lipophilic solvents are utilized for obtaining the large particle sizes. The main advantage of this method is low mechanical energy input which is sufficient.
Spray drying
It is another procedure to lyophilization for the modification of an aqueous dispersion into a drug. It is an economical method when compared to lyophilization. There is a chance of particle gathering due to the elevated temperature, shear forces, and incomplete melting of the particle (Jawahar et al., 2012). Freitas et al. (1998) recommended that the lipids with a boiling point higher than 70°C should be selected for spray drying. The best result was procured by spray drying with SLN concentration of 1% in a solution of trehalose in water or 20% trehalose in ethanol–water mixtures (10/90 v/v).
Figure 7. Supercritical fluid technique. [Click here to view] |
Double emulsion
This method is used for the preparation of hydrophilic-loaded SLNs based on solvent emulsification–evaporation (Svilenov and Tzachev, 2014). First, the drug is dissolved in aqueous-based solutions and then dissolved in a liquid melt. A stabilizer is used for the stabilization of the primary emulsion (He et al., 2015). This primary emulsifier is dispersed in the aqueous phase composed of hydrophilic emulsifier. Now, the double emulsion is blended and then separated by sifting (Fig. 9). Poly (lactic-co-glycolic acid) (PLGA) is vital for the primary w/o emulsion emulsification process. It is observed that with the increase in the concentration of PLGA, there is an enhancement in loading capacity, w/o emulsion stability, and the encapsulation efficiency. PLGA has no impact on the SLN particle size, and with the increase in the concentration of PLGA, there is a significant decline in the zeta potential.
Figure 8. Microemulsion technique. [Click here to view] |
Figure 9. Double emulsion technique. [Click here to view] |
Characterization of SLNs
Several techniques and instruments employed for the characterization of SLNs are discussed as follows (Paurnima et al., 2018; Poovi and Damodharan, 2017).
Visual size and distribution
Photon correlation spectroscopy (PCS)
PCS measures the variations of scattered light by means of particle movement. It measures a size range of about a few nanometers to 3 microns. It depends on the diffraction angle on the particle radius (Jerome et al., 2004).
Laser diffraction (LD)
LD has a merit that it has a wide range from nanometer to lower millimeter. Polarization intensity differential scattering increased the sensitivity of LD to small particles (Mukherjee et al., 2009).
Dynamic light scattering
It records the difference in the intensity of the scattered light in the time gap of microseconds. Light is scattered under Brownian motion and quantified by the compilation of an autocorrelation function. Few presumptions such as size, low concentration, and viscosity are measured by this coefficient (Van de Ven et al., 2009).
Static light scattering (SLS)
It is also known as Fraunhofer diffraction. It is a method where the pattern of the scattered light is collected from a solution of particles and placed in an electromagnetic equation. It is a rough and quick method (Akanksha et al., 2012).
Electrical surface potential and pH
Zeta potential
Its measurement can be analyzed using zeta potential analyzer or zetameter. Zeta potential gives information about the magnitude of the electrostatic repulsion or attraction between particles in the aqueous suspension of SLN (Mishra et al., 2012).
pH-sensitive probes
A pH probe is a scientific device that determines the H+ ion activity in hydrophilic liquids. On the basis of pH, they give information about the acidity and alkalinity of the substances. The magnitude of electrochemical potential is estimated by the Nernst equation (Karmen et al., 2011).
Shape and surface morphology
Transmission electron microscopy
A high energy beam of electrons are exceled across the analyte (very fine), and thus, interactions among these electrons and the atoms can be used to perceive the features such as the crystal structure and features in the structure such as dislocations and grain boundaries (Jores et al., 2004).
Scanning electron microscopy
It produces sample images by scanning the surface with a focused beam of electrons. These electrons interact with samples and produce various signals that contain information about the surface topography and composition of the sample.
Atomic force microscopy
This involves colloidal or resistance across the sample. This movement between tip and surface is tracked by the topological map based on the forces that play. This approach helps us to obtain ultrahigh resolution by mapping the sample (Carrillo et al., 2013).
Optical microscopy
Optical microscopy also referred to as light microscopy is a type of microscope, which utilizes the light of visible range along with an arrangement of magnifying lenses to observe the small objects. This type of microscope captures the image by normal, photosensitive cameras to obtain a micrograph (Majid et al., 2019).
Crystallinity
X-ray diffraction
This process is used to measure the degree of crystallinity, and this is determined by the scattering of radiation from the crystal plane within a solid substance. X-ray diffraction method can be used to determine the crystallinity with a nanoparticle. This method is useful to test the bulk material (Andreas et al., 2012)
Surface hydrophobicity
Two-phase partition
This method splits the compounds in two different immiscible fluids usually polar and nonpolar, on the basis of their relative solubilities. The chemical potential aids in the separation process. The two major types are polymer/polymer and polymer/salt systems. Some of the factors affecting the phase separation are pH, biomolecule concentration, polymer concentration, and biomolecule’s surface properties. They impart sensitive conditions that do not damage liable biomolecules (Johanna et al., 2018).
Contact angle measurement
The contact angle is the angle between soli–liquid interaction at interface or two vapors or two liquids. It is based on Young’s equation. The device used to measure is goniometer. A scale of maximum contact angle to minimum contact is seen in a dynamic phenomenon of contact angle hysteresis. Contact angle has been crucial in parameter to estimate the wetting capacity of the polymer membrane surface. There are a few factors affecting the contact angle such as heterogeneity, surface roughness, and size and shape of the particle (Kai et al., 2017).
Examples of alternative instrument are radiolabel probe and synchrotron radiation X-ray (Poumellec et al., 2016).
Density
Gas pycnometer
The gas pycnometer is an apparatus used to calculate the true density of a solid material by using Archimedes principle and Boyle’s law. In this instead of a fluid an inert gas is used, mostly helium is used. There are a few advantages as it gives quick with accurate results.
Viscosity
Viscometer
A viscometer is a device used to calculate the viscosity of a fluid. For fluids with changes in flow conditions, another device named rheometer is used. Viscometer can only determine under a single flow condition. Usually, either the object passes through the fluid or the liquid stays without movement or vice versa. For the condition of flow, there need to have a slight value of Reynolds’ number for laminar flow. There are different types of viscometers: u-tube viscometer, falling sphere viscometer, Krebs’ viscometer, quartz viscometer, etc. (Vandana and Amit, 2019).
Molecular weight
Gel permeation chromatography
It is otherwise known as size exclusive chromatography that enables separation on the basis of analyte size.
In vitro release
Membrane diffusion method is broadly used to investigate in vitro drug dissolution. The methods including dialysis sac method, reverse dialysis sac method, and side-by-side dialysis method are used, in many devices (Ghada and Rania, 2009).
Sample and separation methods are used to separate the dispersed nanoparticles from the continuous phase. Amount of drug is examined. Because of the little size of nanoparticulate systems, it is very hard to segregate them from the media (Ramteke et al., 2012)
Continuous flow methods were developed initially to alter the oral dosage release. The use of United States Pharmacopeia apparatus four method has a lot of advantages in restoring the in vitro surrounding (Junxian et al., 2009).
Summarizing Studies on Lipid Nanoparticles for Their Therapeutic Benefits
Enhanced bioavailability
Nanomedicine is a credible approach in improving the therapeutic benefit of anticancer drugs (Fan et al., 2014). Intravenous administration has raised difficulties for patients undergoing chemotherapy as it requires professional supervision. The major advantage of oral chemotherapy is patient compliance and flexibility in timing and ease of administration. Unfortunately, due to the rough biological conditions and poor diffusion across gastrointestinal (GI) tract, many anticancer drugs are poorly bioavailable through oral administration (Mei et al., 2013). Paclitaxel shows successful activity against breast, lung, and ovarian cancers. Cytochrome P450 activity and P-glycoprotein (P-gp) present in the stomach lining and liver limit the bioavailability of drug through oral route (Hendrikx et al., 2013). These difficulties in oral delivery of anticancer drugs, namely, drug-resistant tumors, toxicity, and low stability, are resolved by SLNs (Yadav et al., 2014).
Some materials may be entrapped in the external layer of SLNs to enhance the therapeutic activity of the oral delivery systems. Wheat germ agglutinin (WGA) was coated by Pooja et al. (2016) to enhance the oral paclitaxel delivery. The incorporation of paclitaxel into WGA-covered SLNs led to a fold increase in mean residence time. Baek et al. improved the surface of paclitaxel with the aid of hydroxypropyl-beta-cyclodextrin (Baek et al., 2012). The dextrin has a property to enhance the solubility and prevent the oxidation of lipids (Zafar et al., 2014).
Docetaxel is a second-generation taxane enormously used for the cure of prostate, lung, breast, and neck/head cancers. Due to poor bioavailability, the designing of oral docetaxel is hindered. Tween 80 or D-alpha-tocopherol polyethylene glycol succinate-coated SLNs were developed to boost the oral delivery of the drug (Cho et al., 2014). SLNs showed a sustained docetaxel release when set side by side with taxotere. Vorinostat is an inhibitor of histone deacetylase (HDAC) that effectively promotes apoptosis and cell cycle arrest for the cure of T-cell lymphoma (Ozaki et al., 2008). Combination of HDAC and a variety of DNA destroying agents is a favorable chemotherapeutic plan for the death of tumor cells. Hashem et al. assessed the bioavailability through oral route and cytotoxicity of SLNs enveloping tamoxifen, the drug for dealing with breast cancer (Hashem et al., 2014). The profiles for in vitro release testing gave out an instant preliminary release followed by sustained release. About a 1.6-fold increase in bioavailability was observed with SLNs administration.
Nowadays, oral SLNs are used in antitubercular therapy. Antitubercular drugs such as pyrazinamide, rifampicin, and isoniazid loaded in SLN were able to drop the dosage frequency and boost the patient compliance (Pandey et al., 2005). The mechanism for the preparation of antitubercular drug-loaded SLNs is emulsion solvent diffusion technique. These drugs enhanced bioavailability. Paclimer is a standard formulation developed to assist in maintaining progressive and systematic levels of paclitaxel (PTX) for a long duration of time. The composition constitutes of polilactofate polymer-loaded PTX, which was developed by Harper in 1999 who later tested its efficiency in the treatment of non-small-cell lung carcinoma (Jain et al., 2012). Expansile is another standard nanoparticle formulation used for lung cancer cells. This drug has a special feature of responding to the high acidic pH present around the cancer cells. These nanoparticles act on the acidic-hydrophobic group that causes swelling of polymeric nanoparticle and release of the payload (Zubris et al., 2012).
Disorders such as depression and anxiety which are treated by oral dose are constrained by aqueous solubility, first-pass effect, and short half-life (Jain et al., 2012). Treatment for psychotic disorders needs regular dose administration, which can lead to less patient compliance and high cost (Zubris et al., 2012). By mixing dopamine agonist, apomorphine is formed which is used in the treatment of Parkinson’s disease. The quick breakdown of apomorphine in the GI tract has shown the results of 1.7% in a bioavailability (Subramony, 2006). SLNs gave the results of 13-fold higher in bioavailability than the reference solution. There are a few headache disorders such as migraines which carry symptoms of nausea, photophobia, etc. The first drug accepted by the US Food and Drug Administration was sumatriptan. Encapsulated sumatriptan chitosan-coated SLNs were used (Hansraj et al., 2015). Rizatriptan-loaded SLNs exhibited an 18-fold increase in brain uptake in rats according to an in vivo study. The first-line antidepressant venlafaxine is used for the treatment of depressive disorders and anxiety. Since venlafaxine substrate at P-gp, its penetration is reduced across GI and blood–brain barrier (Minassi et al., 2013). However, a marked increase in area under the curve (AUC) of about 1.5-fold was observed from SLNs in the brain venlafaxine solution.
For treating cardiovascular (CV)-related diseases, SLNs have been used orally, to enhance drug plasma concentration and prolong circulation duration. These features are important for attaining better therapeutic benefits. Under refrigeration at room temperature, the optimized SLNs were stable for 3 months (Hernandez et al., 2002). A 2.2-fold increase in the oral bioavailability of SLNs was given by the pharmacokinetic study as compared with nisoldipine suspension. For hypertension and heart failure remission, a prodrug of candesartan called candesartan cilexetil and an angiotensin-2 type-I receptor antagonist is employed. Using dynasan as the solid–lipid, oral bioavailability was increased more than 2.8-fold by SLNs after inclusion of candesartan cilexetil (Dudhipala and Veerabrahma, 2016). An antihypertensive drug called carvedilol has a low oral bioavailability of 20% because of the first-pass effect. SLNs were developed with N-carboxymethyl chitosan coating which improved oral delivery while protecting carvedilol in an acidic environment (Venishetty et al., 2012). In simulated gastric fluid, 5.2% of the drug was released by polymer-coated SLNs for 24 hours. The AUC of polymer-coated SLNs was higher than non-coated SLNs and free control. Anemia could be treated using iron supplements. However, in the GI system, these iron supplements that are commercially available can cause undesirable effects (Murioz et al., 2011). Hence, a biphasic release behavior with a burst release followed by sustained release iron-loaded SLNs is exerted. There was about a 4-fold gain in oral iron bioavailability.
Oral raloxifene has been accepted in the treatment of postmenopausal osteoporosis. Due to its poor aqueous solubility and glucuronide conjugation, thus only 2% raloxifene is orally bioavailable (Gluck and Maricic, 2003). Using compritol 888 ATO as the lipid and poloxamer 188 as emulsifier SLNs for raloxifene delivery was prepared (Hu et al., 2008). SLNs yielded a prolonged drug release for 24 hours, whereas control gave complete release within 4 hours. For the treatment of postmenopausal osteoporosis, a calcium-regulating peptide hormone called salmon calcitonin secreted from the ultimobranchial gland of salmon is employed (Cheng et al., 2009). In a study, prepared SLNs exhibited effective in vivo hypercalcemic effect in rats than free calcitonin. The examination of the protective efficacy of SLNs on calcitonin opposed to pancreatin was studied. A major part of free calcitonin was broken down within 15 minutes, whereas in SLNs the rate of degradation was much slower.
SLNs were extensively used in treating infections, and they were utilized for loading antimicrobial agents to cure bacterial, parasitic, viral, and fungal infections. For example, antitubercular drug isoniazid proposed by the World Health Organization for treating all sorts of tuberculosis. A drug with a short half-life suggests the requirement for repeated dosing which leads to toxicity in the liver (Preziosi, 2007). SLNs loaded with isoniazid enhanced the bioavailability and extended circulation retention (Bhandari et al., 2013). A three-phase design was observed from the in vitro release comprising a primary rapid release, followed by a hump and eventually subsided. Miconazole is a broad-spectrum antifungal drug with poor water solubility. A loading of miconazole in SLNs exhibited a two-phase drug release with a primary outburst followed by a delayed release (Aljaeid et al., 2016). In the diffusion disk, the SLNs showed a better mortality.
Lopinavir was used in the antiretroviral treatment, a human immunodeficiency virus (HIV) protease inhibitor. Since the first-pass metabolism and P-gp efflux it, SLNs behave as a viable porter for lopinavir. Due to its particle size and release rate, the lopinavir-loaded SLNs were stable for 4 months at 4°C (Negi et al., 2013). When compared with the solution form of lopinavir, the SLNs gave a higher oral bioavailability because of improved lymphatic delivery. Compritol 888 was utilized as the solid–lipid for formulating lopinavir-loaded SLNs (Negi et al., 2014). Primaquine is exclusively used to prevent the relapsing form of malaria. Higher doses of primaquine conventionally lead to hematological- and GI-related toxicity (Baird, 2012). A good controllable release of the drug over 72 hours was observed by the entrapment of primaquine in SLNs (Omwoyo et al., 2014). In these days, praziquantel is used for the treatment of parasitic disease, schistosomiasis. Due to the minimal effect on schistosomiasis, De souza et al. added praziquantel into SLNs to study the improvement of therapeutic efficiency (De Souza et al., 2014). After a detailed study, it was noticed that SLNs were more efficient causing parasitic mortality in less duration when differentiated to free drug.
Enhanced permeation
The current research suggests the availability of abundant compounds obtained from natural resources for the treatment of cancer (Aljuffali et al., 2016). The anti-inflammatory, antioxidant, anti-apoptotic, vasodilating, and antimicrobial potentials of these products are responsible for their anticancer effects (Iriti et al., 2009). An innate form of Vitamin E tocotrienol has a promising anticancer activity in breast malignancy. However, oral delivery of gamma-tocotrienol is less effective (9%) (Yap et al., 2003). To improve the permeation in the intestine, SLNs were employed as the design for gamma-tocotrienol (Abuasal et al., 2012). SLNs are used as targeted drug carriers for the cure of neoplasms. SLNs packed with drugs such as camptothecin and methotrexate have been used for targeting tumors (Ruckman et al., 2006). An anticancer drug tamoxifen has been loaded in SLNs to improve the penetrability and retentivity and also for the sustained release of the drug following IV administration in breast cancer therapy (Murthy, 2005).
Enhanced cellular uptake
Hyperglycemia, a result of diabetes, is a serious pathological condition leading to nervous system-related and CV destruction. Through the oral route, the absorption of insulin is tough because of gastric pH (acidic), epithelial cells of the GI tract, and various digestive enzymes (Gundogdu and Yurdasiper, 2014). After many research experiments, SLNs were found as the conveyors to guard the proteins and peptides which are known for the sensitivity toward the environmental considerations (Almeida and Souto, 2007). SLNs enveloped with stearic acid-octaarginine as a conveyor for insulin was outlined by Zhang et al. (2012). Octaarginine is a cell-permeating protein chain, which induces cellular uptake of certain drugs (Golan et al., 2016). This design expressed a remarkably enhanced hypoglycemic effect (3-fold) in rats when differentiated with nonenveloped SLNs. SLNs were designed consisting of Dynasan 114 as the lipid solid matrix for the case of insulin delivery through the oral route (Ansari et al., 2016). SLNs also expressed a greater protection of insulin from the GI environment when discerned from the solution form. SLNs enclosed with polyethylene glycol (PEG) were designed to enhance the stability of glibenclamide in gastric solution. Oral SLNs showed a rapid decrease in glucose levels and further sustained for 8 hours after administration, whereas the administration of free glibenclamide through oral route (5 mg/kg) decreased glucose levels after 4 hours, and it retained to primary high levels in diabetic rats (Goncalves et al., 2016).
Reduced toxicity
Metal nanoparticle has a cytotoxic impact on lung cells, and this is caused by the presence of metal nanoparticle in water, medicine, food, and cosmetic creams and lotions which we use on a daily basis. The size, concentration, and duration of exposure affect the level of cytotoxicity. These factors play a role in lung cancer and need to be controlled. The studies have been conducted for lung cancer therapy and diagnoses using nanoparticle. However, there has been a more extensive study with gold (Au) nanoparticle. Annihilation of A549 lung cancer cells could be achieved using hallow Au/silver (Ag) nanostructures with dendritic morphology (Hu et al., 2008). Similarly, Au-based nanomaterials conjugated with an antibody for photothermal therapy of tumor cells have been developed. It was observed that Gold nanoparticles (Au-NPs) in conjugation with methotrexate, an analog of folic acid, produced a cytotoxic effect. It was observed that conventional treatment for lung cancer is costly and failed to deliver the accurate results, and hence, a need for novel technique for the diagnosis of lung cancer from Au-NP-based diagnosis from breath sample was studied (Chen et al., 2007). Principally volatile organic compound is altered in exhaled breath of person suffering from lung cancer compared to healthy individuals. Enzyme-linked immune solvent assay is less effective than hallow Au nanospheres in detecting lung cancer (Chon et al., 2009). Neodymium used in treatment of cancer cell belongs to group of rare earth metals. Neodymium is observed to be cytotoxic against cancer cell neodymium oxide (nano Nd2O3), which was observed to induce vacuolization and extensive autophagy in cells by disturbing mitochondrial membrane and also arrest cycle in S phase (Chen et al., 2005).
Diamonds measuring less than 1 μm are called nanodiamonds. These are carbon materials generated by events such as an explosion and meteoritic impacts. As it is not cytotoxic in lung cells, it remains harmless and biocompatible. It has numerous implementations such as tracing and tagging of cancer cells (Liu et al., 2007). These nanoparticles associate with different molecules such as DNA, proteins, chemicals, and various anticancer drugs through covalent and noncovalent bonds. Superficially reorganized carboxylated nanometer-sized diamond was evaluated and detected. There was no reduction in cell viability and change in the protein expression profile in lung cells, but they stimulated cytotoxicity. In the case of lung cancer therapy, nanodiamonds are associated covalently with PTX. During experimentation, this combination when injected into xenograft of immunodeficiency mice restricted the growth of tumor and formation of cancer cells in the lungs by instigating apoptosis and mitotic arrest (Liu et al., 2010).
Metals and their combinations have been used in the field of medicine from thousands of years. Arsenic, antimony, bismuth, gold, vanadium, iron, rhodium, titanium, gallium, and platinum are the ten most vital metals which show many anticancer activities. Transition metals can associate with many negatively charged atoms by presenting a varied number of oxidation states. For instance, a transition metal complex named cisplatin contains an ion of platinum metal in its center (Desoize, 2004). Cis-diamminedichloroplatinum (DDP, cis-platin), which is an anticancer drug, is useful for the treatment of varied types of tumors, but because of its poor cancer-specific targeting and its dangerous side effects, its use nowadays is limited. Then, in 2011, Peng et al. reported the production of biocompatible epidermal growth factor receptor (EGFR)-targeted heparin DDP nanoparticles by associating one chain variable fragment anti-EGFR antibody to it as the ligand of targeting for cancer in the lungs (Peng et al., 2011). Newly, a new class of metal-established anticancer drugs of ruthenium has come out its efficiency in activity when compared to platinum and its less toxicity. Some of these drugs passed phase-1 trials (Vajpayee et al., 2011).
Enhanced biocompatibility
Engineered nanomaterials have a distinctive size, shape, charge on the surface, crystallinity, solubility, and surface coating. These features can trigger chemical state in cells to actuate a pro-oxidant condition within the cells, giving rise to disproportionate energy in the cells, causing the induct of inflammation path to the death of cells. For example, silver nanoparticles, which are round in shape, are mostly harmless to human alveolar epithelial cells, whereas wire-shaped nanoparticles exhibit vigorous cell toxicity (Stoehr et al., 2011). The cell toxicity to varied cell lines has catalyzed necrosis and apoptosis techniques, which are one after the other stimulated by modifying the structure of the membrane (Carlson, 2008). The sole limitation that holds back the substantial implementation of Ag–NP is its deprived biocompatibility to the living conditions. Altering organically by covering the Ag-NP with latex from stems of Euphorbia nivulia, a medicinal plant showed a remarkable enhancement in the biocompatibility of silver nanoparticles. These nanoparticles are cytotoxic against human lung carcinoma cell (A549) condition on dose (Valodkar et al., 2011). Latex-covered nanoparticles are produced from the terpenoid and peptide portions of the latex, which cross the membrane of the cell and can be employed as a biocompatible transporter for the NP.
Polymeric micelles are immensely confederated nanoplatforms for targeting cancer, distribution of the drug, and cancer imaging. Supermagnetic iron oxide is extensively used as a contrasting agent, which enhances the visibility of blood vessels. A multifunctional micelle (MFM) system is converted into code along with a lung cancer-targeting peptide and enfolded with superparamagnetic iron oxide and doxorubicin for MR imaging and therapeutic delivery. When compared to a scrambled peptide-coded MFM, LCP-coded MFM exhibited remarkably upgraded alpha, beta-based cell targeting in H2009 lung cancer cells (Guthi et al., 2010). An aqueous soluble and biocompatible theranostic anticancer drug transporter has been developed by conjoining fluorescent polymer chain and folic acid along with magnetic iron oxide or silica. Folic acid that is added helps for targeted drug delivery, and the fluorescent agent helps in imaging the target (Chen et al., 2010).
Bionanoparticle approaches are the major research in metal-based nanotherapeutics, but in the case of in-vivo studies, their biocompatibility and toxicity are major concerns to be noted. Hence, to control the above-mentioned problems, the present researchers have diverted their concentration on the bionanotechnology-based therapeutic component. In this development, an already existing biological system is selected and is incorporated with therapeutic nanoparticles. This incorporation with biological components improved the stability and biocompatibility of the overall system. The examples for this type of systems are models with carrier molecules such as albumin nanoparticles or ABI-007 or hematoporphyrin-linked albumin nanoparticles with therapeutic components such as paclitaxel or gamma-emitting nuclides or carboplatin (Green et al., 2006; Ibrahim et al., 2002). Table 1 shows further research findings of SLN formulations reported by researchers. Tables 2 and 3 show the patents and clinical trials of various lipid systems in recent times, respectively.
Table 1. Research findings of SLNs formulations reported by researchers. [Click here to view] |
Table 2. List of patents published for various lipid systems. [Click here to view] |
Table 3. List of clinical trials being carried in for lipid systems for various disease types. [Click here to view] |
CONCLUSION
SLNs have radically gained the attention of several researchers with its exceptional properties and benefits over other conventional dosage forms, and other colloidal counterparts of SLN have proved to be a significant discovery in nanotechnology because of their effective performance and as a safe vehicle in pharmaceutical drug delivery. SLN as a colloidal drug carrier puts together the advantages of polymeric nanoparticles and fat-based emulsions. These systems abet various benefits such as easy incorporation of lipid- and water-soluble drugs, adequate physical stability, and available at low cost and easy to manufacture. Their inherent characteristics qualify SLNs as competent nanocarriers in the expansion of targeted delivery systems for the clinical trial investigations. Similarly, SLNs also favor sustained release besides effective drug targeting.
AUTHORS’ CONTRIBUTION
All the authors were equally contributed to the data collection, information, writing, and critical review helped design for a framework of the document.
CONFLICT OF INTEREST
The authors report no conflict of interest.
FUNDING
None.
REFERENCES
Abuasal BS, Lucas C, Peyton B, Alayoubi A, Nazzal S, Sylvester PW, Kaddoumi A. Enhancement of intestinal permeability utilizing solid lipid nanoparticles increases gamma-tocotrienol oral bioavailability. Lipids, 2012; 47:461–9. CrossRef
Adriana T, Giuseppe T, Delia M, Nicola C, Nicoletta D, Vincenzo DL, Hector C, Maria AE. Glutathione-loaded solid lipid nanoparticles based on Gelucire® 50/13: spectroscopic characterization and interactions with fish cells. J Drug Delivery Sci Technol, 2018; 47:359–66. CrossRef
Aji AMR, Chacuko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles for intestinal lymphatic targeting. Eur J Pharm Sci, 2011; 1:11–8. CrossRef
Akanksha G, Deepti S, Navneet G. Solid lipid nanoparticles method, characterization and applications. Int Curr Pharm J, 2012; 1:384–93. CrossRef
Aleksandra Z, Carlos M, Nuno R, Silva AM, Nowak I, Souto EB. Anti-inflammatory and anti-cancer activity of citral: optimization of citral-loaded solid lipid nanoparticles (SLN) using experimental factorial design and LUMiSizer®. Int J Pharm, 2018; 553:428–40. CrossRef
Alessi P, Cortesi A, De Zordi N, Gamse T, Kikic I, Moneghini M. Supercritical antisolvent precipitation of quercetin systems: preliminary experiments. Chem Biochem Eng Q, 2012; 26:391–8.
Aljaeid BM, Hosny KM. Miconazole-loaded solid lipid nanoparticles: formulation and evaluation of a novel formula with high bioavailability and antifungal activity. Int J Nanomed, 2016; 11:7–441. CrossRef
Aljuffali IA, Fang CL, Chen CH, Fang JY. Nanomedicine as a strategy for natural compound delivery to prevent and treat cancers. Curr Pharm Design, 2016; 22:4219–31. CrossRef
Almeida AJ, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev, 2007; 59:90–478. CrossRef
Alper OA, Abdurrahman A, Behiye S. Influence of glyceryl behenate, tripalmitin and stearic acid on the properties of clarithromycin incorporated solid lipid nanoparticles: formulation, characterization, antibacterial activity and cytotoxicity. J Drug Delivery Sci Technol, 2019; 54:101–240. CrossRef
Andjelka BK, Rainer HM, Snezana DS, Gordana MV, Cornelia MK. Solid lipid nanoparticle stabilized with polyhydroxy surfactants: preparation, characterization and physical stability investigation. Colloids Surf A, 2014; 5:15–25. CrossRef
Andreas N, Hauseb G, Mäder K. Physicochemical characterization of curcuminoid-loaded solid lipid nanoparticles. Int J Pharm, 2012; 423:440–51. CrossRef
Ansari MJ, Anwar MK, Jamil S, Al-Shdefat R, Ali BE, Ahmad MM, Ansari MN. Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats. Drug Deliv, 2016; 23:9–1972. CrossRef
Arjun N, Kishan V. Preparation, characterization and evaluation of quetiapine fumarate solid lipid nanoparticles to improve the oral bioavailability. J Pharm, 2013; 2013:1–7. CrossRef
Aynur G, Christina K, Candace L, Hannah M, Jenney R, Farah H. Seabuckthorn as a novel prebiotic source improves probiotic viability in yogurt. LWT- Food Sci Technol, 2016; 66:490–5. CrossRef
Baek JS, So JW, Shin SC, Cho CW. Solid lipid nanoparticles of paclitaxel strengthened by hydroxypropyl-beta-cyclodextrin as an oral delivery system. Int J Mol Med, 2012; 30:953–9. CrossRef
Baird JK. Primaquine toxicity forestalls effective therapeutic management of the endemic malarias. Int J Parasitol, 2012; 42:54–1049. CrossRef
Bhandari R, Kaur IP. Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles. Int J Pharm, 2013; 441:12–202. CrossRef
Brijesh S, Dignesh K, Himanshu B, Manju M, Harish P. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: effect on formulation and characterization parameters. Eur J Pharm Sci, 2015; 78:54–66. CrossRef
Carlson C, Hussain SM, Schrand AM, Braydich SLK, Hess KL, Jones RL, Schlager JJ. Unique cellular interaction of silver nanoparticles: size-dependent generation of reactive oxygen species. J Phys Chem B, 2008; 112:13608–19. CrossRef
Carrillo C, Sanchez HN, Garcia ME, Perez LP, Sune NJM, Tico JR, Suñé C, Miñarro M. DNA delivery via cationic solid lipid nanoparticles (SLNs). Eur J Pharm Sci, 2013; 2:65–157. CrossRef
Chen D, Jiang M, Li N, Gu H, Xu Q, Ge J, Xia X, Lu J. Modification of magnetic silica/iron oxide nanocomposites with fluorescent polymethacrylic acid for cancer targeting and drug delivery. J Mater Chem, 2010; 20:6422–9. CrossRef
Chen Y, Yang L, Feng C, Wen LP. Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells. Biochem Biophys Res Commun, 2005; 337:52–60. CrossRef
Chen YJ, Jin RX, Zhou YQ, Zeng J, Zhang H, Feng QR. Preparation of solid lipid nanoparticles loaded with Xionggui powder-supercritical carbon dioxide fluid extraction and their evaluation in vitro release. Zhongguo Zhong Yao Za Zhi, 2006; 31:376–9.
Chen, Y, Tsai, C, Huang, P, Chang, MY, Cheng, PC, Chou, CH, Chen, H, Wang, CR, Shiau, AL, Wu, CL. Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. Mol Pharmacol, 2007; 4:713–22. CrossRef
Cheng, FY, Chen, CT, Yeh. CS. Comparative efficiencies of photothermal destruction of malignant cells using antibody-coated silica@Au nanoshells, hollow Au/Ag nanospheres and Au nanorods. Nanotechnology, 2009; 20:425104. CrossRef
Cho HJ, Park JW, Yoon IS, Kim DD. Surface-modified solid lipid nanoparticle for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake. Int J Nanomed, 2014; 9:495–504. CrossRef
Chon, H, Lee, S, Son, SW, Oh, CH, Choo, J. Highly sensitive immunoassay of lung cancer marker carcinoembryonic antigen using surface-enhanced Raman scattering of hollow gold nanospheres. Anal Chem, 2009; 81:3029–34. CrossRef
Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech, 2011; 12:62–76. CrossRef
Desoize B. Metals and metal compounds in cancer treatment. Anticancer Res, 2004; 24:1529–44.
De Souza AL, Andreani T, deOliveira RN, Kiill CP, dosSantos FK, Allegretti SM, Chaud MV, Souto EB, Silva AM, Gremião MP. In vitro evaluation of permeation, toxicity and effect of praziquantel-loaded solid lipid nanoparticles against Schistosoma mansoni as a strategy to improve efficacy of the schistosomiasis treatment. Int J Pharm, 2014; 463:7–31. CrossRef
Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid liquid nanoparticle for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation. Drug Deliv, 2016; 23:395–4045. CrossRef
Eldem T, Speiser P, Hincal A. Optimization of spray-dried and congealed lipid microparticles and characterization of their surface morphology by scanning electron microscopy. Pharm Res, 1991; 8:47–54. CrossRef
Elena U, Emilio M, Cinizia P, Danila C, Elena P, Maria GD, Maria RG. The effect of formulation and concentration of cholesteryl butyrate solid lipid nanoparticle on NIH-H460 cell proliferation. Eur J Pharm Biopharm, 2001; 2:197–202. CrossRef
Fabiano Y, Christian S, Joachim S, Mont KV, Daniel C, Ben K, Daniel C, Friedrich W, Margareth KKDF. Effects of doxorubicin on the structural and morphological characterization of solid lipid nanoparticles (SLN) using small angle neutron scattering (SANS) and small angle X-ray scattering (SAXS). Phys B, 2018; 551:191–6. CrossRef
Fan Z, Fu PP, Yu H, Ray PC. Theranostic nanomedicine for cancer detection and treatment. J Food Drug Anal, 2014; 22:3–17. CrossRef
Freitas C, Muller RH. Spray-drying of solid lipid nanoparticles. Eur J Pharma Biopharm, 1998; 46:145–51. CrossRef
Gamze G, Mehatap K, Lutifi G. Preparation and characterization of ascorbic acid loaded solid lipid nanoparticles and investigation of their apoptotic effects. Colloids Surf B, 2014; 121:270–80. CrossRef
Garces A, Amaral M, Silva A. Formulations based on solid lipid nanoparticles and nanostructured lipid carriers for cutaneous use. Eur J Pharm Sci, 2018; 112:157–67. CrossRef
Gasco MR. Solid lipid nanospheres from warm microemulsions. Pharm Tech Eur, 1997; 9:52–8.
Ghada A, Rania HF. Diazepam-loaded solid lipid nanoparticles: design and characterization. AAPS PharmSciTech, 2009; 1:211–9. CrossRef
Gluck O, Maricic M. Skeletal and nonskeletal effects of raloxifene. Curr Osteoporos Rep, 2003; 1:123–8. CrossRef
Golan M, Feinshtein V, David A. Conjugates of HA2 with octaarginine-grafted HPMA copolymer offer effective siRNA delivery and gene silencing in cancer cells. Eur J Pharm Biopharm, 2016; 109:103–12. CrossRef
Goncalves LM, Maestrelli F, Di Cesare Mannelli L, Ghelardini C, Almeida AJ, Mura P. Development of solid lipid nanoparticles as carriers for improving oral bioavailability of glibenclamide. Eur J Pharm Biopharm, 2016; 102:41–50. CrossRef
Green MR, Manikhas GM, Orlov S, Afanasyev B, Makhson AM, Bhar P, Hawkins MJ. Abraxane, a novel cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol, 2006; 17:1263–8. CrossRef
Gundogdu E, Yurdasiper A. Drug transport mechanism of oral antidiabetic nanomedicines. Int J Endocrinol Metab, 2014; 12:e2847. CrossRef
Guthi JS, Yang SG, Huang G, Li S, Khemtong C, Kessinger CW, Peyton M, Minna JD, Brown KC, Gao J. MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. Mol Pharm, 2010; 7:32–40. CrossRef
Hadis R, Seid RF, Seid MJ. Nanoencapsulation of carotenoids within lipid-based nanocarriers. J Control Release, 2019; 298:38–67. CrossRef
Hansraj GP, Singh SK, Kumar P. Sumatriptan succinate loaded chitosan solid liquid nanoparticles for enhanced anti-migraine potential. Int J Biol Macromal, 2015; 81:467–76. CrossRef
Harde H, Das M, Jain S. Solid lipid nanoparticles: an oral bioavailability enhancer vehicle. Expert Opin Drug Deliv, 2011; 8:1407–24. CrossRef
Hashem FM, Nasr M, Khairy A. In vitro cytotoxicity and bioavailability of solid lipid nanoparticles containing tamoxifen citrate. Pharm Dev Technol, 2014; 19:824–32. CrossRef
Hassan HA, Florentin M, Aya NK, Jordane J, Michel L. Chitosan - Shea butter solid nanoparticles assemblies for the preparation of a novel nanoparticles in microparticles system containing curcumin. Colloids Surf A, 2018; 553:359–67. CrossRef
He H, Wang P, Cai C, Yang R, Tang X. VB12-coated Gel-Core-SLN containing insulin: another way to improve oral absorption. Int J Pharm, 2015; 493:451–9. CrossRef
Hendrikx JJ, Lagas JS, Rosing H, Schellens JH, Bejinen JH, Schinkel AH. P-glycoprotein and cytochrome P450 3A act together in restricting the oral bioavailability of paclitaxel. Int J Cancer, 2013; 132:2439–47. CrossRef
Hernandez HR, Coll T, Rachitzky P, Arrnas HM, Armas PMC, Velasco M, Rizzo A. Comparison of two nimodipine formulations in healthy volunteers. J Hum Hypertens, 2002; 16:142–4. CrossRef
Home - ClinicalTrials.Gov. Available via https://clinicaltrials.gov/ (Accessed 15 April 2020).
Hu KW, Huang CC, Hwu JR, Su WC, Shieh DB, Yeh CS. A new photothermal therapeutic agent: core-free nanostructured Au x Ag1-x dendrites. Chemistry, 2008; 14:2956–64. CrossRef
Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring SE, Bedikian A, Hortobagyi GN, Ellerhorst JA. Phase I and pharmacokinetic study of ABI-007, a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res, 2002; 8:1038–44.
Iriti M, Faoro F. Bioactivity of grape chemicals for human health. Nat Prod Commun, 2009; 4:611–34. CrossRef
Jain, S, Kumar, D, Swarnakar, NK, Thanki, K. Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel. Biomaterials, 2012; 33:6758–68. CrossRef
Jawahar N, Gowtham MSNR, Sumeet S. Solid lipid nanoparticles for oral delivery of poorly soluble drugs. J Pharm Sci Res, 2012; 4:1848–55.
Jenning V, Schafer-Korting M, Gohla S. Vitamin A-loaded solid lipid nanoparticles for topical use: drug release properties. J Control Release, 2000; 66:115–26. CrossRef
Jerome G, Patrick S, Adina L, Anthony WC. Solid Lipid Nanoparticles (SLNs): preparation and properties of Calix[4]resorcinarene derived systems. J Inclusion Phenom Macrocyclic Chem, 2004; 48:3744.
Jin KK, Jeong SP, Chong KK. Development of a binary lipid nanoparticles formulation of itraconazole for parenteral administration and controlled release. Int J Pharm, 2010; 383:209–15. CrossRef
Johanna M, Kathleen O, Ralf G, Anja SH. Fate of edible solid lipid nanoparticles (SLN) in surfactant stabilized o/w emulsions. Part 2: release and partitioning behavior of lipophilic probes from SLN into different phases of o/w emulsions. Colloids Surf A, 2018; 558:623–31. CrossRef
Jores K, Mehnert W, Drechsler M, Bunjes H, Johann C, Mäder K. Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J Control Release, 2004; 2:27–217. CrossRef
Junxian Y, Songhong Z, Shaochuan S, Zhuo C, Kejian Y, Jizhong C. Continuous production of solid lipid nanoparticles by liquid flow-focusing and gas displacing method in microchannels. Chem Eng Sci, 2009; 64:4115–22. CrossRef
Kai T, Xuewei LV, Shanshan WU, Senwei X, Xiaobo H, Chenguang B. Measurement for contact angle of iron ore particles and water. ISIJ Int, 2017; 58:379–400. CrossRef
Kaiser CS, Rompp H, Schmidt PC. Pharmaceutical applications of supercritical carbon dioxide. Pharmazie, 2001; 56:907–26.
Karmen TP, Stane P, Bilijana J, Slavko P, Stane S, Julijana K. A novel fluorescent probe for more effective monitoring of nanosized drug delivery systems within the cells. Int J Pharm, 2011; 1:93–384. CrossRef
Shah KA, Date AA, Joshi MD, Patravale VB. Solid lipid nanoparticles of tretinoin: potential in topical delivery. Int J Pharm, 2007; 1:163–71. CrossRef
Liu KK, Cheng CL, Chang CC, Chao JI. Biocompatible and detectable carboxylated nanodiamond on human cell. Nanotechnology, 2007; 18:325102. CrossRef
Liu KK, Zheng WW, Wang CC, Chiu YC, Cheng CL, Lo YS, Chen C, Chao JI. Covalent linkage of nanodiamond paclitaxel for drug delivery and cancer therapy. Nanotechnology, 2010; 21:315106. CrossRef
Long C, Zhang L, Qian Y. Preparation and crystal modification of ibuprofen-loaded solid lipid microparticles. Chin J Chem Eng, 2006; 14:518–25. CrossRef
Majid S, Farnoosh A, Ali AS, Keivan A, Nasrin H, Anwarun H, Mostafa AES Mojtaba F. Plasmonic gold nanoparticles: optical manipulation, imaging, drug delivery and therapy. J Control Release, 2019; 311–312:170–89. CrossRef
Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev, 2001; 47:165–96. CrossRef
Mei L, Zhang Z, Zhao I, Huang L, Yang XL, Tang J, Feng SS. Pharmaceutical nanotechnology for oral delivery of anticancer drugs. Adv Drug Deliv Rev, 2013; 65:880–90. CrossRef
Minassi A, Sanchez-Duffhues G, Collado JA, Munoz E, Appendino G. Dissecting the pharmacophore of curcumin. Which structural element is critical for which action. J Nat Prod, 2013; 76:1105–12. CrossRef
Mishra DK, Dhote V, Bhatnagar P, Mishra PK. Engineering solid lipid nanoparticles for improved drug delivery: promises and challenges of translational research. Drug Deliv Transl Res, 2012; 2:238–53. CrossRef
Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci, 2009; 4:349–58. CrossRef
Murioz M, Garcia-Erce JA, Remacha AF. Disorders of iron metabolism: part 2. Iron deficiency and iron overloaded. J Clin Pathol, 2011; 64:287–96. CrossRef
Murthy RS. Solid lipid nanoparticles as carriers for anti-cancer drugs to solid tumours. Drug Deliv, 2005; 12:385–92.
Negi JS, Chattopadhyay P, Sharma AK, Ram V. Development and evaluation of glycerate behenate based on solid lipid nanoparticles (SLNs) using hot self-nanoemulsification (SNE) technique. Arch Pharm Res, 2014; 37:70–361. CrossRef
Negi JS, Chattopadhyay P, Sharma AK, Ram V. Development of solid lipid nanoparticles (SLNs) of lopinavir using hot self nano-emulsification (SEN) technique. Eur J Pharm Sci, 2013; 48:9–231. CrossRef
Omwoyo WN, Ogutu B, Oloo F, Swai H, Kalombo L, Melariri P, Mahanga GM, Gathirwa JW Preparation, characterisation, and optimization of primaquine-loaded solid lipid nanoparticles. Int J Nanomed, 2014; 9:74–3865. CrossRef
Outuki PM, Kleinubing SA, Hoscheid J, Montanha MC, da Silva EA, DoCouto RO, Kimura E, Cardoso MLC. The incorporation of Pterodon pubescens fruit oil into optimized nanostructured lipid carriers improves its effectiveness in colorectal cancer. Ind Crops Prod, 2018; 123:719–30. CrossRef
Ozaki K, Kishikawa F, Tanaka M, Sakamoto T, Tanimura S, Kohno M, Histone deacetylase inhibitors enhance the chemosensitivity of tumour cells with cross-resistance to a wide range of DNA-damaging drugs. Cancer Sci, 2008; 99:376–84. CrossRef
Pandey R, Sharma S, Khuller GK. Oral SLN based antitubercular chemotherapy. Tuberculosis, 2005; 85:415–20. CrossRef
Paurnima T, Saugata S, Ashok M. Physicochemical characterization of solid lipid nanoparticles comprised of glycerol monostearate and bile salts. Colloids Surf B, 2018; 172:517–25. CrossRef
Peng XH, Wang Y, Huang D, Wang Y, Shin HJ, Chen Z, Spewak MB, Mao H, Wang X, Wang Y, Chen ZG, Nie S, Shin DM. Targeted delivery of cisplatin to lung cancer using ScFvEGFR-heparin-cisplatin. ACS Nano, 2011; 5:9480–9493. CrossRef
Pooja D, Kulhari H, Kuncha M, Rachamalla SS, Adams DJ, Bansal V, Sistla R. Improving efficacy, oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles. Mol Pharm, 2016; 13:3903–12. CrossRef
Poovi G, Damodharan N. Lipid nanoparticles: different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustainable Chem Pharm, 2017; 6:37–56. CrossRef
Poumellec MA, Dejode M, Figl A, Darcourt J, Haudebourg J, Sabah Y, Voury A, Martaens A, Barranger E. [Sentinel node detection using optonuclear probe (gamma and fluorescence) after green indocyanine and radio-isotope injections]. Gynecol Obstet Fertil, 2016; 4:10–207. CrossRef
Preziosi P. Isoniazid: metabolic aspects and toxicological correlates. Curr Drug Metab, 2007; 8:51–839. CrossRef
Wang Q, Yang Q, Cao X, Wei Q, Firempong CK, Guo M, Shi F, Xu X, Deng W, Yu J. Enhanced oral bioavailability and anti-gout activity of [6]-shogaol-loaded solid lipid nanoparticles. Int J Pharm, 2018; 550:24–34. CrossRef
Raj K, Ashtosh S, Kajal S, Divya D, Neha G, Prem FS. Preparation, characterization and in vitro cytotoxicity of Fenofibrate and Nabumetone loaded solid lipid nanoparticles. Mater Sci Eng, 2020; 106:110184. CrossRef
Ramteke KH, Joshi SA, Dhole SN Solid lipid nanoparticle: a review. IOSR J Pharm, 2012; 2:34–44. CrossRef
Ruckman K, Sivakumar M, Ganeshkumar PA. Methotrexate loaded solid lipid nanoparticles: for effective treatment of carcinoma. J Nanosci Nanotechnol, 2006; 6:2991–5. CrossRef
Sethuraman S, Balakrishnan S, Ganesh M, Kandasamy R, Kasi PD. α-Bisabolol loaded solid lipid nanoparticles attenuates Aβ aggregation and protects Neuro-2a cells from Aβ induced neurotoxicity. J Mol Liq, 2018; 264:431–41. CrossRef
Siekmann B, Westesen K. Melt-homogenized solid lipid nanoparticles stabilized by the nonionic surfactant tyloxapol. I. Preparation and particle size determination. Pharm Pharmacol Lett, 1994; 3:194–7.
Sjostrom B, Bergenstahl B. Preparation of submicron drug particles in lecithin-stabilized o/w emulsions: model studies of the precipitation of cholesteryl acetate. Int J Pharm, 1992; 88:53–62. CrossRef
Soliman M-S, Shirin Z, Elaheh E-A. Piroxicam loaded solid lipid nanoparticles for topical delivery: preparation, characterization and in vitro permeation assessment. J Drug Delivery Sci Technol, 2018; 47:427–33. CrossRef
Sonia T, Rossella R, Silvia M, Giuseppe PV, Annarita SL, Fabio M, Roberta C. Solid lipid nanoparticles made of trehalose monooleate for cyclosporin-A topic release. J Drug Delivery Sci Technol, 2019; 49:563–9. CrossRef
Souto EB, Wising SA, Barbosa CM, Millar RH. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. Int J Pharm, 2004; 1:71–7. CrossRef
Stoehr LC, Gonzalez E, Stampfl A, Casals E, Duschl A, Puntes V, Oostingh GJ, Shape matters: effects of silver nanospheres and wires on human alveolar epithelial cells. Part Fibre Toxicol, 2011; 8:1–15. CrossRef
Subramony JA. Apomorphine in dopaminergic therapy. Mol pharm, 2006; 3:380-5. CrossRef
Rizvi SZH, Shah FA, Khan N, Muhammad I, Ali KH, Ansari MM, Din FU, Qureshi OS, Kim KW, Choe YH, Kim JK, Zeb A. Simvastatin-loaded solid lipid nanoparticles for enhanced anti-hyperlipidemic activity in hyperlipidemia animal model. Int J Pharm, 2019; 560:136–43. CrossRef
Thakur R, Gupta RB. Rapid Expansion of Supercritical Solution with Solid Cosolvent (RESS−SC) process: formation of griseofulvin nanoparticles. Ind Eng Chem Res, 2005; 44:7380–7. CrossRef
Vajpayee V, Yang YJ, Kang SC, Kim H, Kim IS, Wang M, Stang PJ, Chi K-W. Hexanuclear self-assembled arene-ruthenium nano-prismatic cages: potential anticancer agents. Chem Commun, 2011; 47:5184–6. CrossRef
Valodkar, M, Jadeja, RN, Thounaojam, MC, Ranjitsinh VD, Sonal T. In vitro toxicity study of plant latex capped silver nanoparticles in human lung carcinoma cells. Mater Sci Eng C, 2011; 31:1723–8. CrossRef
Van de Ven H, Vermeersch M, Shunmugaperumal T, Vandervoort J, Maes L, Ludwig A. Solid lipid nanoparticle (SLN) formulations as a potential tool for the reduction of cytotoxicity of saponins. Pharmazie, 2009; 3:6–172.
Vandana BP, Amit GM. Preparation and characterization of solid lipid nanoparticles-based gel for topical delivery. Pharm Nanotechnol, 2019; 2000:293–302. CrossRef
Venishetty VK, Chede R, Komuravelli R, Adepu L, Sistla R, Diwan PV. Design and evaluation of polymer coated carvedilol loaded solid liquid nanoparticles to improve the oral bioavailability: a novel strategy to avoid intraduodenal administration. Colloids Surf B, 2012; 95:1–9. CrossRef
Weber S, Zimmer A, Pardeike J. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for pulmonary application: a review of the state of the art. Eur J Pharm Biopharm, 2014; 86:7–22. CrossRef
WIPO – Search International and National Patent Collections. Available via https://patentscope.wipo.int/search/en/search.jsf (Accessed 12 April 2020).
Wolfgang M, Karsten M. Solid lipid nanoparticles production, characterization and applications. Adv Drug Deliv Rev, 2001; 47:165–96. CrossRef
Kang X, Chen H, Li S, Jie L, Hu J, Wang X, Qi J, Ying X, Du Y. Magnesium lithospermate B loaded PEGylated solid lipid nanoparticles for improved oral bioavailability. Colloids Surf B Biointerfaces, 2018; 161:597–605. CrossRef
Yadav P, Soni G, Mahor A, Alok S, Singh PP, Verma A. Solid lipid nanoparticles; an effective and promising drug delivery system a review. Int J Pharm Sci Res, 2014; 5:1152–62.
Yap SP, Yuen KH, Lim AB. Influence of route of administration on the absorption and disposition of alpha- gamma- and delta-tocotrienols in rats. J Pharm Pharmacol, 2003; 55:53–8. CrossRef
Zhang Y, Li Z, Zhang K, Yang G, Wang Z, Zhao J, Hu R, Feng N. Ethyl oleate-containing nanostructured lipid carriers improve oral bioavailability of trans-ferulic acid as compared with conventional solid lipid nanoparticles. Int J Pharm, 2016; 1:57–64. CrossRef
Zafar N, Fessi H, Elaissari A. Cyclodextrin containing biodegradable particles: from preparation to drug delivery applications. Int J Pharm, 2014; 461:351–66. CrossRef
Zhang ZH, Zhang YL, Zhou JP, Lv HX. Solid lipid nanoparticles modified with stearic acid-octaarginine for oral administration of insulin. Int J Nanomed, 2012; 7:9–3333. CrossRef
Zubris, KAV, Colson, YL, Grinstaff, MW. Hydrogels as intracellular depots for drug delivery. Mol Pharmaceul, 2012; 9:196–200. CrossRef