Solid Lipid Nanoparticles vs. Nanostructured Lipid Carriers: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Cláudia Viegas
,
Ana B. Patrício
,
João M. Prata
,
Akhtar Nadhman
,
Pavan Kumar Chintamaneni
,
Pedro Fonte

Solid–lipid nanoparticles and nanostructured lipid carriers are delivery systems for the delivery of drugs and other bioactives used in diagnosis, therapy, and treatment procedures. These nanocarriers may enhance the solubility and permeability of drugs, increase their bioavailability, and extend the residence time in the body, combining low toxicity with a targeted delivery. Nanostructured lipid carriers are the second generation of lipid nanoparticles differing from solid lipid nanoparticles in their composition matrix. The use of a liquid lipid together with a solid lipid in nanostructured lipid carrier allows it to load a higher amount of drug, enhance drug release properties, and increase its stability. Therefore, a direct comparison between solid lipid nanoparticles and nanostructured lipid carriers is needed. 

  • lipid nanoparticle
  • NLC
  • nanocarrier
  • nanoparticle characterization

1. Introduction

Nanomedicine aims to provide accurate diagnoses and treatments for diseases more effectively, with minimal adverse effects. Nanomedicine has gained popularity because of its efficiency in delivering drugs and other bioactives to target tissues more accurately in a controlled manner by encapsulating or attaching them to nanostructures [1][2]. These drug delivery systems involve nanocarriers that are colloidal drug carrier systems having submicron particle sizes, typically below 1000 nm. Due to their high surface area to volume ratio, nanocarriers can modify the basic properties and bioactivity of drugs. They also allow drug protection (e.g., from humidity, pH changes, and enzymes); improved pharmacokinetics and biodistribution of the drugs; either by passive or active targeting, resulting in reduced toxicities and improved therapeutic benefits [3][4][5]; enhanced bioavailability; controlled drug releasing profiles; prolonged blood circulation times; enhanced intracellular penetration; and site- and organ-specific targeted delivery.
Different types of materials have been used to produce nanoparticles, mainly polymeric, lipid, and inorganic materials. Among these, lipid nanocarriers have considerable advantages due to their biocompatibility, biodegradability, low toxicity, scale-up capacity, and delivery of both hydrophilic and lipophilic drugs in a controlled or targeted manner [6][7]. These carriers may also permeate physiological barriers, such as the blood–brain barrier and the intestinal epithelium [8]. Further, to combine the advantages of different materials, hybrid nanoparticles may also be obtained to improve the features of lipid-based nanoparticles. For example, a new approach can be developed based on the physical modification of the lipid matrix with polymers, producing a lipid–polymeric matrix to entrap the drugs [9][10][11].
Intralipid® was the first safe lipid parental emulsion developed in the 60s [12]. In the same decade, liposomes were first described by Bangham et al., and since then, liposomes have become the traditional models for lipid-based formulations [13][14]. A spherical vesicle with an aqueous nucleus enclosed by a lipidic bilayer membrane is what defines a liposome. Since then, liposomes have been extensively studied from pharmaceutical to cosmetic applications, due to their advantages as a carrier system with the additional benefit of protection from enzymatic activity. However, further development of liposomal formulations has been hindered by its major obstacles. Some of those are the limited physical stability of the liposomal suspension, drug leakage, low targeting ability, non-specific clearance by monocytes and macrophages, and up-scaling difficulties [3][15][16][17]. Several other carrier systems of a lipidic nature were developed, such as nanopellets for perioral administration, described by Speiser and colleagues (lipidic microparticles), nanosuspensions produced by ball milling or high-pressure homogenization (HPH), lipospheres [18][19][20], and many others.

2. Structural Features of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

Lipid particles with sizes on a nanoscale possess unique physical, mechanical, chemical, and biological features, which may differ greatly from their core components in SLNs and NLCs (Figure 1). These nanostructures are essentially composed of lipids and surfactants and can be used to deliver therapeutic agents (by encapsulation, incorporation, or/and surface attachment) and deliver them to target tissues [2][21]. Table 1 describes the compounds mostly used in their production. The structural key feature differences between SLNs and NLCs are represented in the following sections.
Figure 1. Structural matrix of SLN and NLC. Adapted with permission from [22].
Table 1. Chemical classification, source, and function of the compounds used to produce SLNs and NLCs.
Compound Classification Source Function
1-Tetradecanol (myristyl alcohol) Straight chain saturated fatty alcohol Myristica fragrans Solid lipid
Beeswax Wax ester Honey bees (Apis mellifera) Solid lipid
Caprylic/capric triglyceride Triglyceride Coconut oil Liquid lipid
Castor oil Fatty acid composed Castor beans Liquid lipid
Cetyl palmitate Wax ester Stony corals, Psidium guajava Solid lipid
Cholesteryl myristate Cholesterol ester Trachyrhamphus serratus Solid lipid
Cholesterol Modified steroid Animal, vegetable fat Solid lipid
Compritol® 888 ATO Mixture of mono-, di- and triglycerides of behenic acid (C22) - Surfactant
1,2-dioleoyl-3-dimethylammonium propane (DODAP) Ionizable cationic lipid - Solid lipid
Dipalmitoylphosphatidylcholine (DPPC) Phospholipid Pulmonary surfactant Solid lipid
1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) Amine phospholipid Escherichia coli Solid lipid
Gelucire® 50/13 Mixture of fatty acids (C16 and C18), esters of glycerol, PEG esters and free PEG - Surfactant
Glyceryl monostearate Glycerol ester of a saturated fatty acid Aristolochia cucurbitifolia, Lobelia longisepala Surfactant
Labrafac™ CC Mixture of medium chain triglycerides, mainly from caprylic (C8) and capric (C10) acids - Liquid lipid
Lecithin Mixture of phospholipids in oil Soybean, egg Surfactant
Miglyol® 812 N Glycerol triester of caprylic and capric acid (triglyceride esters) Coconut, palm kernel oil Liquid lipid
Myristylmyristate Tetradecanoate ester Coconut, palm kernel oil Solid lipid
Oleic acid Middle chain triglyceride Olive oil Liquid lipid
Palmitic acid Saturated fatty acid Palm oil Solid lipid
Phosphatidylcholine Phospholipid Soybeans, eggs Solid lipid
Poloxamer 407/Pluronic® F-127 Triblock copolymer - Surfactant
Precirol® ATO-5 Mixtures of diesters of glycerin and stearic acid - Solid lipid
Polyvinylalcohol (PVA) Synthetic polymer of vinyl alcohol - Surfactant
Sodium lauryl sulfate (SLS) Ethoxylated lauryl alcohol Coconut, palm kernel oil Surfactant
Squalene Triterpenoid Olive, wheat germ, and rice bran oils Liquid lipid
Steric acid Saturated fatty acid Animal, vegetable fat Solid lipid
Tricaprin Triglyceride Milkfat, palm kernel oil, and coconut oil Solid lipid
Tripalmitin Triglyceride Lysiphlebia japonica, Tagetes erecta Solid lipid
Tristearin Triglyceride Lysiphlebia japonica, Sciadopitys verticillata Solid lipid
Tween® Mixture of sorbitol, ethylene oxide, and oleic acid - Surfactant

2.1. Solid Lipid Nanoparticles

SLNs were first described by Müller and Lucks in the early 90s, alongside the description of the method used for production in a patent application [23]. However, the term SLN was only used a few years later by the same group, when describing a method for loading magnetite into nanoparticles [18]. SLNs are composed of a physiological lipid that is solid at room and body temperature, a surfactant, and water [15][17][24]. The SLN lipidic phase is usually produced from steroids, di- or triglycerides, glyceride mixtures, or even waxes, typically used at 0.1 and 30% (w/v) and remaining in the solid state at room and body temperature. On the other hand, the surfactant concentration is in a range of 0.5 to 5% (w/v), in the generally recognized as a safe (GRAS) category [17][24][25][26]. A combination of surfactants can be also used to improve the stability of the SLN [27].
The structure of SLNs depends on various factors, such as the components of the formulation, the solubility of the compounds including the drug, and the production method. Three different structures of SLN are reported [15][28]. In the SLN homogeneous matrix model (Type I) (Figure 2), the particles are produced by a cold or hot homogenization technique for very lipophilic drugs. In the first method, the drug is dissolved in a lipid matrix, and, due to high-pressure homogenization, mechanical breakings cause nanoparticle formation. In the second method, the lipid is dissolved in a lipid matrix while increasing the temperature and the nanoparticles are formed similarly. In the SLN drug-enriched shell model (Type II) (Figure 2), the particles may be produced by the hot homogenization technique. During the cooling of the system, the lipid molecules precipitate first, forming a lipid core. Meanwhile, the concentration of the drug increases in the rest of the melted lipid until its solubility limit is reached. When this point is reached, the mix of drug and melted lipid crystalizes, forming an outer shell. This model is not the best for prolonged release of the drug but can be very interesting to increase drug penetration with topical application, especially when associated with the occlusive effect of SLNs. Lastly, the SLN drug-enriched core model (Type III) (Figure 2) forms nanoparticles when the drug concentration is close to its solubility limit in the melted lipid. This type is the opposite of type II since the first compound to precipitate is the drug, which forms the core, and the shell is composed of the lipid and a low concentration of the drug [15][26][28][29][30][31]. Table 2 describes several examples of studies about the development, applications, and characterization of SLNs.
Figure 2. Structure of the 3 different types of SLN: homogenous matrix model (Type I), drug-enriched shell model (Type II), and drug-enriched core model (Type III). The drug is represented in white color. Reprinted with permission from [32].
Table 2. Examples of studies performed using SLN. The nanoparticles components and features, loaded drug, production method, and therapeutic purpose are debriefed.
Solid–Lipid Surfactant Drug Production Method Therapeutic Purpose Delivery Route Characteristics Ref
Gelucire® 50/13 Tween® 85 Grapeseed-derived proanthocyanidins Melt Emulsification Technique Chronic Respiratory Diseases Spray Instillation Size: 243 ± 24 nm
PdI: 0.41
Zeta: −14.5 ± 1.0 mV
EE: NA		 [33]
Palmitic Acid/Cholesteryl Myristate (68,5/31,5%) (w/w) Sodium Lauryl Sulfate (SLS) Rifampicin Melt Emulsification Technique Tuberculosis NA Size: 400 ± 20 nm
PdI: 0.43 ± 0.09
Zeta: −35.3 ± 0.29 mV
EE: 56.48% (w/w)		 [34]
Compritol 888 ATO, cholesterol, and Tf-PEG-OA 1% Polyvinylalcohol (PVA) Paclitaxel (PTX) Solvent Evaporation Method Leukemia NA Size: 176 nm
PdI: NA
Zeta: −22.5 ± 1.56 mV
EE: 92.5 ± 1.35%		 [35]
Tripalmitin/Hydrogenated soybean phosphatidylcholine (HSPC) (80/20%) (w/w) Polyethylene glycol monostearate (PGM) Apomorphine NA Parkinson’s Disease Oral Size: 63.20 ± 0.98 nm
PdI: 0.31 ± 0.02
Zeta: 7.3 ± 0.25 mV
EE: NA		 [36]
Compritol® 888 ATO Tween® 80 Quercetin NA Alzheimer’s Disease Oral Size: 0.42 to 4.62 µm
PdI: NA
Zeta: −23.6 to −5.13 mV
EE: 85.7%		 [37]
Beeswax Tween® 80
Poloxamer 407		 NA Hot melt microemulsion Skin Hydration Topical Size: 95.72 ± 9.63 nm
PdI: 0.323 ± 0.03
Zeta: −9.85 ± 0.57 mV
EE: NA		 [38]
Stearic Acid Poloxamer 407
Soybean Phosphatidylcholine		 Resveratrol Sonication Anti-tumoral Topical Size:155.50 ± 0.26 nm
PdI: 0.140 ± 0.02
Zeta: −2.60 ± 1.27 mV
EE: NA		 [39]
Poly Lactic-co-Glycolic Acid (PLGA) 1% polyoxyethylenepolyoxypropylene Apigenin Nanoprecipitation Cosmetic Topical Size: 102.19 ± 0.002 nm
PdI: 0.258
Zeta: 12.1 ± 0.0 mV
EE: 87.2 ± 0.005		 [40]
Tricaprin Cetyl Palmitate, Tween® 60 Tego Care 450 Amphisol K, 1-Tetradecanol Resveratrol Hot melt homogenization Cosmetic Topical Size: 102.190 ± 0.002 nm
PdI: 0.258
Zeta: 12.1 ± 0.0 mV
EE: 52.45%		 [41]
In addition to the advantages, SLNs also have relevant disadvantages such as possible aggregation, instability during storage, and low drug loading for some drugs [7]. For these reasons, and to overcome them, NLCs have been developed.

2.2. Nanostructured Lipid Carriers

NLCs are the second generation of lipid nanocarriers and were created in the late 90s to solve the disadvantages of SLN [15][28]. NLCs are composed of a mixture of solid and liquid lipids, in a ratio of up to 70:30, respectively, and an aqueous phase composed of a surfactant [42][43]. The lipids used in these formulations are biologically compatible, which is important to reduce toxicity [44].
Incorporating both liquid lipids and solid lipids results in a more imperfect matrix in the NLC structure, thus resulting in more efficient drug loading and incorporation [45]. NLCs can be classified, according to their structure, into three different types (Figure 3), which differ mainly in their lipid composition.
Figure 3. Structures of different types of NLC: imperfect crystal (Type I), amorphous (Type II), and multiple type (Type III). The drug is represented in white. Reprinted with permission from [32].
The imperfect crystal type (Type I) results from mixing lipids with different chain lengths or by using either mono-, di- or triglycerides. By doing so, a matrix comprising several voids and imperfections provides a more suitable environment for drug incorporation. The amorphous type (Type II) is obtained by using medium chain length triglycerides along with solid lipids. The solid lipids do not undergo recrystallization after NLC cooling, thus resulting in solid particles with an amorphous structure. By not recrystallizing during the cooling phase, and even during storage, the unwanted release of the drug is reduced, thus improving its shelf life. Multiple type NLCs (Type III) are obtained by mixing solid lipids with an oil such as an oleic acid and/or medium and long-chain triacylglycerols. To achieve a multiple type NLC, the oil must be mixed in a ratio above its solubility in the solid lipid, resulting in the formation of very small oil compartments (nanocompartments) in the NLC matrix during the cooling phase of the nanoemulsion [28][29][45]. Table 3 summarizes several examples of studies about the development and application as well nanoparticle characterization of NLC.
Table 3. Examples of studies performed with NLC. The nanoparticles’ components and features, drug loading, production method and therapeutic purpose are debriefed.
Solid Lipid Liquid Lipid Surfactant Drug Production Method Therapeutic Purpose Delivery Route Characteristics Ref
Stearic acid Oleic acid Soya Lecithin Glyceryl Monostearate Docetaxel (DTX) Modified film ultrasonication–dispersion method Murine Malignant Melanoma Parenteral Size: 203.67 ± 4.15 nm
PdI: NA
Zeta: −31.17 ± 2.20 mV
EE: 89.39 ± 0.99%		 [46]
Precirol® ATO-5 Squalene Myverol Lovastatin Hot melt homogenization Cholesterol Oral Size: 278.8 ± 0.6 nm
PdI: ≤0.25
Zeta: −32.4 ± 0.4 mV
EE: 83.8 ± 2.5		 [47]
Comprito® 888 ATO Miglyol 812N Lecithin Vinpocetin (VIN) High-pressure homogenization Brain Disorders Oral Size: 177 ± 5.4 nm
PdI: NA
Zeta: −24.7 ± 1.4 mV
EE: 95.3 ± 1.4		 [48]
Precirol® ATO-5 Oleic Acid Tween® 80 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2) Ultrasonication Melanoma Topical Size: 219.67 ± 5.26 nm
PdI: ≤0.3
Zeta: −24.88 ± 1.78 mV
EE: 72%		 [49]
Cetyl Palmitate Miglyol 812N Tween® 60 Curcumin Modified hot homogenization Brain Disorders Oral/Intravenous Size: 183 ± 12 nm
PdI: 0.13 ± 0.01
Zeta: −21 ± 2 mV
EE: 82 ± 15%		 [50]
Glyceryl Tribehenate Oleic acid P 407 Raloxifene hydrochloride (RLX) Hot homogenization Osteoporosis Oral Size: 120 ± 3 nm
PdI: 0.293
Zeta: 14.4 ± 0.5 mV
EE: 91.71		 [51]
Precirol ATO-5 Miglyol 812N Tween® 80 Rifapentine (RPT) Hot ultra-sonication Tuberculosis Oral/Pulmonary Size: 242 ± 9 nm
PdI: 0.17 ± 0.01
Zeta: −22 ± 2 mV
EE:		 [52]
Glycerol monostearate (GMS) Medium chain triglyceride (MCT) Poloxamer 188
Soybean lecithin		 Amoitone B Emulsion-evaporation and low temperature-solidification Tumor Therapy NA Size: 241.2 ±  4.4 nm
PDI: NA
Zeta: 18.4 ± 0.2 mV
EE: 71.5 ± 1.1%		 [53]
Myristyl
Myristate		 Crodamolt GTCC-LQ Pluronic F128 Metvan Sonication Bone Cancer NA Size: 230.8 ± 3.1 nm
PdI: 0.235 ± 0.010
Zeta: −7.9 ± 0.8 mV
EE: 77.6 ± 4.8%		 [54]
Stearic acid or beeswax Carvacrol Kolliphor188® Carvacrol Warm microemulsion oil in water (o/w) Leishmaniasis Parenteral Size: 98 ± 0.80 nm
PdI: 0.166 ± 0.04
Zeta: −25 ± 5 mV		 [55]

2.3. Comparison between Solid Lipid Nanoparticles and Nanostructured Lipid Carrier

SLNs have been widely studied as systems for drug delivery for several delivery routes, such as oral, parenteral, and topical delivery. Due to their structure, which can be finely tuned depending on the chemical profile of its active ingredients and excipients, one expects several advantages. However, the modified release property is dependent on the solid state of the particle, e.g., crystallization and physicochemical transitions. Retarded or suppressed crystallization had been reported, resulting in a poor drug payload. Lipidic materials typically undergo physicochemical transitions, e.g., matrix molecule rearrangement. This phenomenon results in not only a more densely packed and arranged matrix, but also an altered shape, which presents an unfavorable localization for many drug molecules. The payload depends not only on the physicochemical properties of the drugs to be incorporated but also on the type of matrix material. Drugs that could not be incorporated inside the SLN matrix may adsorb on the nanoparticle surface or even lead to the separation of the particle matrix [3][7][9][29][56]. To overcome unwanted drug release during storage, a more imperfect matrix is desirable. To accomplish that, the use of spatially different molecules is needed.
NLCs are formed by mixing different combinations of solid and liquid lipids, in a ratio from 70:30 to 99:1, which remain in the solid state at both body and room temperature, and by controlling the content of liquid lipids in the formulation, improved incorporation and immobilization of drug molecules is achieved. Whereas in SLNs, the drug molecules are dispersed in their molecular form, in NLCs the imperfections in the matrix formed by the differences between solid and liquid lipids leads to more spaces available for drugs, which improves the incorporation of drug molecules in both molecular form and amorphous clusters, also avoiding the potential expulsion of the active compound during storage [3][9][29][56][57][58]. In Table 4 their classification by properties is shown, which highlights the comparison between SLNs and NLCs.
Table 4. Comparison between SLN and NLC. Advantages and disadvantages.
SLN NLC
Lipids Use of physiological lipids; however, there is a lower stability comparatively with other materials
Solvents Absence of organic solvents
Application Application in different industries (food, cosmetic, pharmaceutical)
Bioavailability Improved bioavailability of drugs
Drugs loaded Loads both lipophilic and hydrophilic drugs; however, has difficulty in loading therapeutic proteins
Drug delivery Targeted drug delivery and enhanced drug permeation
Scale-up Cheaper and easier to scale up than polymeric nanoparticles
Protection Protection of drug molecules from enzymatic activity, harsh pH, and moisture
Cytotoxicity Cytotoxicity concerns due to the nature and concentration of matrix lipids
Drug loading capacity Limited drug loading capacity Improved drug loading capacity
Controlled drug release profile Difficulty in adjusting the drug release profile Better controlled drug release profile
Polymorphic transitions Prone to polymorphic transitions No polymorphic transition takes place
Release during storage Unwanted drug release during storage Minimal drug release during storage
Physical stability Possible particle aggregation or fusion during storage Better physical stability during storage
Water content High water content Low water content

3. Production Methods of Solid–lipid Nanoparticles and Nanostructured Lipid Carriers

There are several methodologies to produce lipid nanoparticles such as SLNs and NLCs. The most common methods are high-pressure homogenization (hot and cold), microemulsification, solvent emulsification (evaporation or diffusion), solvent injection, double emulsion, ultra-sonication or high-speed homogenization, spray drying, and microfluidics. These methods are schematized in Figure 4 and Figure 5 and are briefly described in the following sections.
Figure 4. Production methods to obtain SLNs and NLCs. Adapted from [32].
Figure 5. Spray drying (A) and microfluidics (B) methods to obtain SLN and NLC.

3.1. High-Pressure Homogenization

HPH is the most common method and consists of a potent and trustworthy technique for the preparation of SLNs and NLCs [59]. There are two types of high-pressure homogenization, hot HPH, and cold HPH. In both, the first step is to dissolve the drug in a solid lipid melted at approximately 5–10 °C above its melting point [24][60].
Hot HPH consists of adding an aqueous surfactant solution at the same temperature as the melted lipid to the drug–lipid melt. After this step, the substances are homogeneously dispersed by high-shear mixing, forming the pre-emulsion. The hot pre-emulsion is then submitted, at the same temperature, to high-pressure homogenization to reduce particle size to the nanoscale. Generally, three cycles at 500 bars are appropriate. The last step is cooling down the oil-in-water (o/w) nanoemulsion to room temperature, which leads to lipid re-crystallization, thus forming the solid matrix of the lipid nanoparticle [24][61].
The cold HPH method consists of rapidly cooling the drug–lipid melt, using either dry ice or liquid nitrogen. The rapid cooling forces the drug to be homogenously mixed within the lipid matrix. Afterward, the obtained solid is pulverized into particles within the micron range (with either a ball mill or mortar), followed by its dispersion in an aqueous surfactant solution which is already cooled down (pre-emulsion). The pre-emulsion is then subjected to high-pressure homogenization at room or below room temperature, breaking the microparticles into nanoparticles [24][59][61].

3.2. Ultra-Sonication or High-Speed Homogenization

Ultra-sonication and high-speed homogenization are used to mix the lipid phase and the containing surfactant aqueous phase [62][63]. Nanoparticles obtained by this method usually have high polydispersity, which can be dealt with by using probe-based sonicators. Despite obtaining a less dispersed distribution, there is a risk of cross-contamination from the probe metal [64]. Even if this method has its drawbacks, high-speed homogenization, for example, becomes much more efficient, simpler, cheaper, and easier to reproduce if multiple cycles of homogenization at high velocities and high pressure (100–200 MPa) conditions are implemented.

3.3. Double Emulsion

The double emulsion method involves the preparation of a primary emulsion (w/o), which consists of dissolving a drug molecule (usually hydrophilic) in an aqueous solvent (inner aqueous phase) that is dispersed in a lipid phase containing an emulsifier, known as the oil phase. Afterward, an aqueous solution containing a hydrophilic emulsifier is added to the primary emulsion, which forms a double emulsion (w/o/w) after stirring. Since this method generates nanoparticles with high polydispersity, it is not recommended for delivery in some administration routes [24][65][66].

3.4. Microemulsion Method

The microemulsion method was developed by Gasco et al., and similarly to HPH, it starts by melting the solid lipid(s) at a temperature higher than its/their melting points (by 5 to 10 °C) and dissolving the drug in melted lipid(s) [67]. In the following step, an aqueous surfactant solution with a temperature above the temperature of the melted lipid is added to the drug–lipid melt with continuous stirring until a transparent microemulsion is obtained. The microemulsion formed is dispersed in cold water by gentle stirring and the microparticles are broken into nanoparticles which crystallize to form the SLN or NLC. Nanoparticles produced by this method are diluted, so at the end of the process, the preparation needs to be concentrated by ultrafiltration or lyophilization. The main disadvantage is the need for a high concentration of surfactants [61][68].

3.5. Solvent Injection

This novel approach consists of lipids being dissolved in water-miscible organic solvents pharmacologically accepted, such as ethanol, acetone, or isopropanol, followed by injection in an aqueous phase with constant mixing, causing the lipid precipitation. The dispersion is then filtered to remove excess lipid content. By adding an emulsifier to the aqueous phase, lipid droplets form at the injection site and stabilize the particle until solvent diffusion occurs [69].

3.6. Solvent Emulsification-Evaporation

In this method, the solid lipid is dissolved in an organic solvent and afterward emulsified in an aqueous solution while stirring. The organic solvent evaporates during stirring, forming nanoparticles by precipitation of the lipid in the aqueous phase. The concentration of the lipid will directly impact the size of the particles. This method is suitable for thermolabile drugs due to the absence of thermal stress. However, this method is not suitable for drugs capable of interacting with the organic solvent [61][70].

3.7. Solvent Emulsification-Diffusion

The solvent emulsification-diffusion technique uses a partially water-miscible organic solvent containing saturated water to achieve thermodynamic equilibrium, avoiding the diffusion of the solvent from the droplets into the aqueous phase. The lipid and the drug are dispersed in the solvent and then added to an aqueous solution containing a surfactant, forming an o/w emulsion. The particles are formed by adding more water, which facilitates solvent diffusion into the continuous phase and incites precipitation of the nanoparticles [71][72].

3.8. Spray Drying

Spray drying is a common method for high melting point lipids. It is also used as an alternative method to lyophilization in SLN and NLC formulations [73]. The principle behind spray drying consists of inducing particle agglomeration through elevated temperatures and shear stress, resulting in partial melting and increased kinetic energy. This leads to multiple particle collisions. Despite being more efficient than other methods, it is rarely used due to the risk of inducing particle aggregation and structural changes in the lipid core and surfactant films or even particle degradation by high temperatures [74][75][76][77][78].

3.9. Microfluidics

Microfluidics is a more recent method, which has been introduced as a novel methodology to produce nanoparticles with optimized uniformity [79][80]. By forcing liquids into a microfluidic chip at steady flow rates, the nanoliter amount of these reagents collides and rapidly mixes under precise pressure [81]. Submitting a pre-emulsion to high-pressure microfluidics and cooling it down to room temperature can minimize the particles’ polydispersity, reduce production times, and avoid organic solvents. Overall, it could be a promising approach for the large-scale production of drug-loaded SLNs and NLCs [82][83].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15061593

References

  1. Soares, S.; Sousa, J.; Pais, A.; Vitorino, C. Nanomedicine: Principles, Properties, and Regulatory Issues. Front. Chem. 2018, 6, 360.
  2. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; del Pilar Rodriguez-Torres, M.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71.
  3. Jaiswal, P.; Gidwani, B.; Vyas, A. Nanostructured lipid carriers and their current application in targeted drug delivery. Artif. Cells Nanomed. Biotechnol. 2016, 44, 27–40.
  4. Alexis, F.; Rhee, J.-W.; Richie, J.P.; Radovic-Moreno, A.F.; Langer, R.; Farokhzad, O.C. New frontiers in nanotechnology for cancer treatment. Urol. Oncol. 2008, 26, 74–85.
  5. ud Din, F.; Aman, W.; Ullah, I.; Qureshi, O.S.; Mustapha, O.; Shafique, S.; Zeb, A. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int. J. Nanomed. 2017, 12, 7291–7309.
  6. Akel, H.; Ismail, R.; Katona, G.; Sabir, F.; Ambrus, R.; Csóka, I. A comparison study of lipid and polymeric nanoparticles in the nasal delivery of meloxicam: Formulation, characterization, and in vitro evaluation. Int. J. Pharm. 2021, 604, 120724.
  7. Ghasemiyeh, P.; Mohammadi-Samani, S.J.R.i.p.s. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: Applications, advantages and disadvantages. Res. Pharm. Sci. 2018, 13, 288.
  8. Khosa, A.; Reddi, S.; Saha, R.N. Nanostructured lipid carriers for site-specific drug delivery. Biomed. Pharmacother. 2018, 103, 598–613.
  9. Sgorla, D.; Bunhak, É.J.; Cavalcanti, O.A.; Fonte, P.; Sarmento, B. Exploitation of lipid-polymeric matrices at nanoscale for drug delivery applications. Expert Opin. Drug Deliv. 2016, 13, 1301–1309.
  10. Liu, Y.; Jiang, Z.; Hou, X.; Xie, X.; Shi, J.; Shen, J.; He, Y.; Wang, Z.; Feng, N. Functional lipid polymeric nanoparticles for oral drug delivery: Rapid mucus penetration and improved cell entry and cellular transport. Nanomed. Nanotechnol. Biol. Med. 2019, 21, 102075.
  11. Sgorla, D.; Lechanteur, A.; Almeida, A.; Sousa, F.; Melo, E.; Bunhak, É.; Mainardes, R.; Khalil, N.; Cavalcanti, O.; Sarmento, B. Development and characterization of lipid-polymeric nanoparticles for oral insulin delivery. Expert Opin. Drug Deliv. 2018, 15, 213–222.
  12. Hallberg, D.; Holm, I.; Obel, A.L.; Schuberth, O.; Wretlind, A. Fat emulsions for complete intravenous nutrition. Postgrad. Med. J. 1967, 43, 307–316.
  13. Bangham, A.D.; Standish, M.M.; Watkins, J.C. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965, 13, 238–252, IN26–IN27.
  14. Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal formulations in clinical use: An updated review. Pharmaceutics 2017, 9, 12.
  15. Muller, R.H.; Radtke, M.; Wissing, S.A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev. 2002, 54 (Suppl. S1), S131–S155.
  16. Dudhipala, N.; Janga, K.Y.; Gorre, T. Comparative study of nisoldipine-loaded nanostructured lipid carriers and solid lipid nanoparticles for oral delivery: Preparation, characterization, permeation and pharmacokinetic evaluation. Artif. Cells Nanomed. Biotechnol. 2018, 46, 616–625.
  17. Fonte, P.; Andrade, F.; Araújo, F.; Andrade, C.; das Neves, J.; Sarmento, B. Chitosan-coated solid lipid nanoparticles for insulin delivery. Methods Enzymol. 2012, 508, 295–314.
  18. Müller, R.H.; Maaβen, S.; Weyhers, H.; Specht, F.; Lucks, J.S. Cytotoxicity of magnetite-loaded polylactide, polylactide/glycolide particles and solid lipid nanoparticles. Int. J. Pharm. 1996, 138, 85–94.
  19. Eldem, T.; Speiser, P.; Hincal, A. Optimization of spray-dried and -congealed lipid micropellets and characterization of their surface morphology by scanning electron microscopy. Pharm. Res. 1991, 8, 47–54.
  20. Domb, A.J. Long acting injectable oxytetracycline-liposphere formulations. Int. J. Pharm. 1995, 124, 271–278.
  21. Jahangirian, H.; Lemraski, E.G.; Webster, T.J.; Rafiee-Moghaddam, R.; Abdollahi, Y. A review of drug delivery systems based on nanotechnology and green chemistry: Green nanomedicine. Int. J. Nanomed. 2017, 12, 2957–2978.
  22. Barroso, L.; Viegas, C.; Vieira, J.; Ferreira-Pêgo, C.; Costa, J.; Fonte, P. Lipid-based carriers for food ingredients delivery. J. Food Eng. 2021, 295, 110451.
  23. Mueller Rainer Prof, D.R.; Lucks, J.-S. Arzneistofftraeger Aus Festen Lipidteilchen-Feste Lipidnanosphaeren (SLN). DE4131562A1, 18 September 1991.
  24. Parhi, R.; Suresh, P. Preparation and characterization of solid lipid nanoparticles-a review. Curr. Drug Discov. Technol. 2012, 9, 2–16.
  25. Morales, J.O.; Valdés, K.; Morales, J.; Oyarzun-Ampuero, F. Lipid nanoparticles for the topical delivery of retinoids and derivatives. Nanomedicine 2015, 10, 253–269.
  26. Naseri, N.; Valizadeh, H.; Zakeri-Milani, P. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application. Adv. Pharm. Bull. 2015, 5, 305–313.
  27. Kumar, S.; Randhawa, J.K. High melting lipid based approach for drug delivery: Solid lipid nanoparticles. Mater. Sci. Eng. C Mater. Biol. Appl. 2013, 33, 1842–1852.
  28. Souto, E.B.; Almeida, A.J.; Müller, R.H. Lipid Nanoparticles (SLN®, NLC®) for Cutaneous Drug Delivery:Structure, Protection and Skin Effects. J. Biomed. Nanotechnol. 2007, 3, 317–331.
  29. Viegas, C.; Seck, F.; Fonte, P. An insight on lipid nanoparticles for therapeutic proteins delivery. J. Drug Deliv. Sci. Technol. 2022, 77, 103839.
  30. zur Mühlen, A.; Schwarz, C.; Mehnert, W. Solid lipid nanoparticles (SLN) for controlled drug delivery—Drug release and release mechanism. Eur. J. Pharm. Biopharm. 1998, 45, 149–155.
  31. Üner, M.; Yener, G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J. Nanomed. 2007, 2, 289–300.
  32. Borges, A.; De Freitas, V.; Mateus, N.; Fernandes, I.; Oliveira, J. Solid lipid nanoparticles as carriers of natural phenolic compounds. Antioxidants 2020, 9, 998.
  33. Castellani, S.; Trapani, A.; Spagnoletta, A.; Di Toma, L.; Magrone, T.; Di Gioia, S.; Mandracchia, D.; Trapani, G.; Jirillo, E.; Conese, M. Nanoparticle delivery of grape seed-derived proanthocyanidins to airway epithelial cells dampens oxidative stress and inflammation. J. Transl. Med. 2018, 16, 140.
  34. Maretti, E.; Costantino, L.; Buttini, F.; Rustichelli, C.; Leo, E.; Truzzi, E.; Iannuccelli, V. Newly synthesized surfactants for surface mannosylation of respirable SLN assemblies to target macrophages in tuberculosis therapy. Drug Deliv. Transl. Res. 2019, 9, 298–310.
  35. Dai, Y.; Huang, J.; Xiang, B.; Zhu, H.; He, C. Antiproliferative and apoptosis triggering potential of paclitaxel-based targeted-lipid nanoparticles with enhanced cellular internalization by transferrin receptors—A study in leukemia cells. Nanoscale Res. Lett. 2018, 13, 271.
  36. Tsai, M.-J.; Huang, Y.-B.; Wu, P.-C.; Fu, Y.-S.; Kao, Y.-R.; Fang, J.-Y.; Tsai, Y.-H. Oral Apomorphine Delivery from Solid Lipid Nanoparticles with Different Monostearate Emulsifiers: Pharmacokinetic and Behavioral Evaluations. J. Pharm. Sci. 2011, 100, 547–557.
  37. Dhawan, S.; Kapil, R.; Singh, B. Formulation development and systematic optimization of solid lipid nanoparticles of quercetin for improved brain delivery. J. Pharm. Pharmacol. 2011, 63, 342–351.
  38. Souza, C.; de Freitas, L.A.P.; Maia Campos, P.M.B.G. Topical formulation containing beeswax-based nanoparticles improved In Vivo skin barrier function. AAPS PharmSciTech 2017, 18, 2505–2516.
  39. Rigon, R.; Fachinetti, N.; Severino, P.; Santana, M.; Chorilli, M. Skin Delivery and In Vitro biological evaluation of trans-resveratrol-loaded solid lipid nanoparticles for skin disorder therapies. Molecules 2016, 21, 116.
  40. Das, S.; Das, J.; Samadder, A.; Paul, A.; Khuda-Bukhsh, A.R. Efficacy of PLGA-loaded apigenin nanoparticles in Benzopyrene and ultraviolet-B induced skin cancer of mice: Mitochondria mediated apoptotic signalling cascades. Food Chem. Toxicol. 2013, 62, 670–680.
  41. Carlotti, M.E.; Sapino, S.; Ugazio, E.; Gallarate, M.; Morel, S. Resveratrol in solid lipid nanoparticles. J. Dispers. Sci. Technol. 2012, 33, 465–471.
  42. Beloqui, A.; Solinís, M.Á.; Rodríguez-Gascón, A.; Almeida, A.J.; Préat, V. Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomed. Nanotechnol. Biol. Med. 2016, 12, 143–161.
  43. Doktorovova, S.; Souto, E.B. Nanostructured lipid carrier-based hydrogel formulations for drug delivery: A comprehensive review. Expert Opin. Drug Deliv. 2009, 6, 165–176.
  44. Gaba, B.; Fazil, M.; Ali, A.; Baboota, S.; Sahni, J.K.; Ali, J. Nanostructured lipid (NLCs) carriers as a bioavailability enhancement tool for oral administration. Drug Deliv. 2015, 22, 691–700.
  45. Pathak, K.; Keshri, L.; Shah, M. Lipid nanocarriers: Influence of lipids on product development and pharmacokinetics. Crit. Rev. Ther. Drug Carr. Syst. 2011, 28, 357–393.
  46. Liu, D.; Liu, Z.; Wang, L.; Zhang, C.; Zhang, N. Nanostructured lipid carriers as novel carrier for parenteral delivery of docetaxel. Colloids Surf. B 2011, 85, 262–269.
  47. Chen, C.-C.; Tsai, T.-H.; Huang, Z.-R.; Fang, J.-Y. Effects of lipophilic emulsifiers on the oral administration of lovastatin from nanostructured lipid carriers: Physicochemical characterization and pharmacokinetics. Eur. J. Pharm. Biopharm. 2010, 74, 474–482.
  48. Zhuang, C.-Y.; Li, N.; Wang, M.; Zhang, X.-N.; Pan, W.-S.; Peng, J.-J.; Pan, Y.-S.; Tang, X. Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability. Int. J. Pharm. 2010, 394, 179–185.
  49. Malta, R.; Loureiro, J.B.; Costa, P.; Sousa, E.; Pinto, M.; Saraiva, L.; Amaral, M.H. Development of lipid nanoparticles containing the xanthone LEM2 for topical treatment of melanoma. J. Drug Deliv. Sci. Technol. 2021, 61, 102226.
  50. Neves, A.R.; van der Putten, L.; Queiroz, J.F.; Pinheiro, M.; Reis, S. Transferrin-functionalized lipid nanoparticles for curcumin brain delivery. J. Biotechnol. 2021, 331, 108–117.
  51. Murthy, A.; Rao Ravi, P.; Kathuria, H.; Malekar, S. Oral Bioavailability Enhancement of Raloxifene with Nanostructured Lipid Carriers. Nanomaterials 2020, 10, 1085.
  52. Magalhães, J.; Chaves, L.L.; Vieira, A.C.; Santos, S.G.; Pinheiro, M.; Reis, S. Optimization of rifapentine-loaded lipid nanoparticles using a quality-by-design strategy. Pharmaceutics 2020, 12, 75.
  53. Luan, J.; Zhang, D.; Hao, L.; Li, C.; Qi, L.; Guo, H.; Liu, X.; Zhang, Q. Design and characterization of Amoitone B-loaded nanostructured lipid carriers for controlled drug release. Drug Deliv. 2013, 20, 324–330.
  54. Cacicedo, M.L.; Ruiz, M.C.; Scioli-Montoto, S.; Ruiz, M.E.; Fernández, M.A.; Torres-Sanchez, R.M.; Baran, E.J.; Castro, G.R.; León, I.E. Lipid nanoparticles—Metvan: Revealing a novel way to deliver a vanadium compound to bone cancer cells. New J. Chem. 2019, 43, 17726–17734.
  55. Galvão, J.G.; Santos, R.L.; Silva, A.R.S.T.; Santos, J.S.; Costa, A.M.B.; Chandasana, H.; Andrade-Neto, V.V.; Torres-Santos, E.C.; Lira, A.A.M.; Dolabella, S.; et al. Carvacrol loaded nanostructured lipid carriers as a promising parenteral formulation for leishmaniasis treatment. Eur. J. Pharm. Sci. 2020, 150, 105335.
  56. Shidhaye, S.S.; Vaidya, R.; Sutar, S.; Patwardhan, A.; Kadam, V.J. Solid lipid nanoparticles and nanostructured lipid carriers—Innovative generations of solid lipid carriers. Curr. Drug Deliv. 2008, 5, 324–331.
  57. Domingo, C.; Saurina, J. An overview of the analytical characterization of nanostructured drug delivery systems: Towards green and sustainable pharmaceuticals: A review. Anal. Chim. Acta 2012, 744, 8–22.
  58. Pardeike, J.; Hommoss, A.; Müller, R.H. Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. Int. J. Pharm. 2009, 366, 170–184.
  59. Mehnert, W.; Mäder, K. Solid lipid nanoparticles Production, characterization and applications. Adv. Drug Deliv. Rev. 2001, 47, 165–196.
  60. Li, Q.; Cai, T.; Huang, Y.; Xia, X.; Cole, S.P.C.; Cai, Y. A review of the structure, preparation, and application of NLCs, PNPs, and PLNs. Nanomaterials 2017, 7, 122.
  61. Das, S.; Ng, W.K.; Tan, R.B.H. Are nanostructured lipid carriers (NLCs) better than solid lipid nanoparticles (SLNs): Development, characterizations and comparative evaluations of clotrimazole-loaded SLNs and NLCs? Eur. J. Pharm. Sci. 2012, 47, 139–151.
  62. Abdelbary, G.; Haider, M. In vitro characterization and growth inhibition effect of nanostructured lipid carriers for controlled delivery of methotrexate. Pharm. Dev. Technol. 2013, 18, 1159–1168.
  63. Esposito, E.; Drechsler, M.; Cortesi, R.; Nastruzzi, C. Encapsulation of cannabinoid drugs in nanostructured lipid carriers. Eur. J. Pharm. Biopharm. 2016, 102, 87–91.
  64. Fang, C.L.; Al-Suwayeh, S.A.; Fang, J.Y. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat. Nanotechnol. 2013, 7, 41–55.
  65. Jaganathan, K.S.; Rao, Y.U.; Singh, P.; Prabakaran, D.; Gupta, S.; Jain, A.; Vyas, S.P. Development of a single dose tetanus toxoid formulation based on polymeric microspheres: A comparative study of poly(D,L-lactic-co-glycolic acid) versus chitosan microspheres. Int. J. Pharm. 2005, 294, 23–32.
  66. Utada, A.S.; Lorenceau, E.; Link, D.R.; Kaplan, P.D.; Stone, H.A.; Weitz, D.A. Monodisperse double emulsions generated from a microcapillary device. Science 2005, 308, 537–541.
  67. Gasco Maria, R. Method for Producing Solid Lipid Microspheres Having a Narrow Size Distribution. U.S. Patent 5,250,236A, 2 August 1991.
  68. Igartua, M.; Saulnier, P.; Heurtault, B.; Pech, B.; Proust, J.E.; Pedraz, J.L.; Benoit, J.P. Development and characterization of solid lipid nanoparticles loaded with magnetite. Int. J. Pharm. 2002, 233, 149–157.
  69. Schubert, M.A.; Muller-Goymann, C.C. Solvent injection as a new approach for manufacturing lipid nanoparticles-evaluation of the method and process parameters. Eur. J. Pharm. Biopharm. 2003, 55, 125–131.
  70. Shahgaldian, P.; Da Silva, E.; Coleman, A.W.; Rather, B.; Zaworotko, M.J. Para-acyl-calix-arene based solid lipid nanoparticles (SLNs): A detailed study of preparation and stability parameters. Int. J. Pharm. 2003, 253, 23–38.
  71. Hu, F.Q.; Hong, Y.; Yuan, H. Preparation and characterization of solid lipid nanoparticles containing peptide. Int. J. Pharm. 2004, 273, 29–35.
  72. Trotta, M.; Chirio, D.; Cavalli, R.; Peira, E. Hydrophilic microspheres from water-in-oil emulsions by the water diffusion technique. Pharm. Res. 2004, 21, 1445–1449.
  73. Kaur, P.; Mishra, V.; Shunmugaperumal, T.; Goyal, A.K.; Ghosh, G.; Rath, G. Inhalable spray dried lipidnanoparticles for the co-delivery of paclitaxel and doxorubicin in lung cancer. J. Drug Deliv. Sci. Technol. 2020, 56, 101502.
  74. Freitas, C.; Müller, R.H. Spray-drying of solid lipid nanoparticles (SLNTM). Eur. J. Pharm. Biopharm. 1998, 46, 145–151.
  75. Zhang, X.; Pan, W.; Gan, L.; Zhu, C.; Gan, Y.; Nie, S. Preparation of a Dispersible PEGylate Nanostructured Lipid Carriers (NLC) Loaded with 10-Hydroxycamptothecin by Spray-Drying. Chem. Pharm. Bull. 2008, 56, 1645–1650.
  76. Xia, D.; Shrestha, N.; van de Streek, J.; Mu, H.; Yang, M. Spray drying of fenofibrate loaded nanostructured lipid carriers. Asian J. Pharm. Sci. 2016, 11, 507–515.
  77. Zhong, Q.; Zhang, L. Nanoparticles fabricated from bulk solid lipids: Preparation, properties, and potential food applications. Adv. Colloid Interface Sci. 2019, 273, 102033.
  78. Marante, T.; Viegas, C.; Duarte, I.; Macedo, A.S.; Fonte, P. An Overview on Spray-Drying of Protein-Loaded Polymeric Nanoparticles for Dry Powder Inhalation. Pharmaceutics 2020, 12, 1032.
  79. Lababidi, N.; Sigal, V.; Koenneke, A.; Schwarzkopf, K.; Manz, A.; Schneider, M. Microfluidics as tool to prepare size-tunable PLGA nanoparticles with high curcumin encapsulation for efficient mucus penetration. Beilstein J. Nanotechnol. 2019, 10, 2280–2293.
  80. Lopes, C.; Cristóvão, J.; Silvério, V.; Lino, P.R.; Fonte, P. Microfluidic production of mRNA-loaded lipid nanoparticles for vaccine applications. Expert Opin. Drug Deliv. 2022, 19, 1381–1395.
  81. Garg, S.; Heuck, G.; Ip, S.; Ramsay, E. Microfluidics: A transformational tool for nanomedicine development and production. J. Drug Target. 2016, 24, 821–835.
  82. Haider, M.; Abdin, S.M.; Kamal, L.; Orive, G. Nanostructured lipid carriers for delivery of chemotherapeutics: A review. Pharmaceutics 2020, 12, 288.
  83. Chen, S.; Liu, W.; Wan, J.; Cheng, X.; Gu, C.; Zhou, H.; Chen, S.; Zhao, X.; Tang, Y.; Yang, X. Preparation of Coenzyme Q10 nanostructured lipid carriers for epidermal targeting with high-pressure microfluidics technique. Drug Dev. Ind. Pharm. 2013, 39, 20–28.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback