Solid Lipid Nanoparticles for Drug Delivery: A Comprehensive Review.

Baburao Mohite*, Manisha Mane, Sarika Suryavanshi, Shrirang Kharmate,

 Pranali Patil, Anand Gadad.

Ashokrao Mane College of Pharmacy, Peth Vadgaon;416112, (M.S.) India

*Correspondence:  baburaomohite4243@gmail.com 

INTRODUCTION

Over the past two decades, technology has made significant strides, leading to the development of materials ranging from micro to nano sizes. Reducing particle sizes to the nanoscale increases the total surface area of materials by several orders of magnitude. Nanoparticles are defined as particles ranging in size from one to a thousand nanometers. While the term "nano" has various applications, nanomaterials possessing superior biodegradability and biocompatibility are considered optimal carriers for drug delivery systems in biomedical applications. Presently, scientists and researchers are primarily focused on devising novel approaches or pathways to regulate the pharmacodynamics, immunogenicity, biorecognition, pharmacokinetics (ADME), and non-specific toxicity of pharmaceuticals. When it comes to treating chronic human diseases, nanoparticular drug delivery systems are a successful strategy that effectively meets pharmacological and biopharmaceutical needs¹. Below are a number of nano-based systems made of various materials that can be used as nanocarriers.

1.      Biodegradable

a.       Liposomes

b.      Solid lipid Nanoparticle

c.       Nanostructured lipid Carrier

d.      Niosomes

e.       Nanoemulsion

f.        Nanocrystals

2.      Biodegradable/ Non-Biodegradable

a.       Silica Nanoparticle

b.      Magnetic Nanoparticle

c.       Carbon Nanotube

3.      Biodegradable/ Non-Biodegradable

a.       Polymeric Nanoparticle

b.      Polymerosomes

Solid-Lipid Nanoparticles

Introduced in 1991, solid lipid nanoparticles (SLN) present a viable alternative to conventional colloidal carriers like polymeric micro- and nanoparticles, liposomes, and emulsions. These solid lipid-based nanoparticles have gained considerable attention as innovative colloidal drug carriers for intravenous applications. SLNs, or sub-micron colloidal carriers, consist of physiological lipids dispersed in water or an aqueous surfactant solution, with sizes ranging from 50 to 1000 nm. Small-sized nanoparticles (SLN) exhibit distinctive characteristics such as a large surface area, high drug loading capacity, and phase interaction at the interface, rendering them appealing for enhancing medicinal efficacy².

SLN are frequently utilised to improve a drug's solubility and bioavailability^3,4. Because of their small size (between 50 and 1000 nm), these delivery methods have improved permeability, which enables them to successfully pass through physiological barriers. Reducing particle size is associated with a notable increase in the surface area of insoluble drug particles upon oral administration. Better absorption via the gastrointestinal tract's monolayer cells results from this. SLNs have been shown to enhance lymphatic transport through microfold cells (M cells) and are also more readily absorbed by cells. A decrease in early medication metabolism brought upon by improved lymphatic conveyance increases drug bioavailability. The stratum corneum's impermeability to a wide range of medications at sufficient concentrations is the main barrier to topical delivery in the dermal system. Additionally, because of the small size of the particles, SLN can increase the bioavailability of medications that penetrate healthy skin. The amount of the encapsulated medicine that reaches the desired site of action is enhanced because of their close proximity to the stratum corneum⁵.

The reasons for the growing interest in lipid-based systems are:

Ø  Lipids improve oral bioavailability and minimize variability in plasma profiles.

Ø  Improved characterization of lipid excipients.

Ø  Enhanced capability to tackle technology transfer and scale-up manufacturing issues⁶.

STRUCTURAL FEATURES AND GENERAL COMPONENTS OF SLNS:

SLNs are spherical particles comprising a solid lipid matrix encapsulating drug molecules, with a surfactant layer to stabilize them in an aqueous phase. SLNs differ from NLCs in their lipid composition; SLNs are made from solid lipids, whereas NLCs consist of a blend of solid and liquid lipids⁷. After preparation, SLN matrices exist in α and β’ forms, which are high-energy modifications. These matrices primarily comprise similar lipid molecules that tend to rearrange into the more stable β form. Consequently, during storage, drugs encapsulated within SLNs may be expelled due to this rearrangement. Additionally, matrices composed of similar lipid molecules have limited space for accommodating drugs⁸. Conversely, NLC matrices are composed of dissimilar lipid molecules, resulting in imperfect or amorphous structures⁹. The basic components required for producing SLNs include solid lipids, liquid lipids (oils), and emulsifiers. Often, the selection of lipids is based on their ability to solubilize drugs, with preference given to those capable of solubilizing larger amounts for SLN preparation¹⁰. Emulsifiers play a vital role in stabilizing nanoparticles (NPs). In SLNs, the majority of emulsifiers are hydrophilic, such as polysorbate 80 (Tween 80), lecithin, poloxamer 407 (Pluronic F127), poloxamer 188 (Pluronic F68), phosphatidylcholine, PEG-40 castor oil (Cremophor® RH40), sodium deoxycholate, and sodium dodecyl sulfate. Emulsifiers undergo screening to determine the optimal concentration, typically falling within a range of 0.1–5% (w/v)¹¹.

Figure 1: Structure of Solid Lipid Nanoparticles

THE PURPOSE OF DEVELOPING SLN:

Nanoscale drug delivery methodologies have been devised to address the following concerns:

Ø  Drug concentrations that are low or fluctuate as a result of oral drug delivery are linked to restricted absorption, fast metabolism, and excretion.

Ø  Drugs' insufficient solubility presents a problem when it comes to injecting aqueous drug solutions intravenously.

Ø  The significant degree of toxicity demonstrated by specific medicinal medications. Drugs can be converted into SLN to improve targeted delivery and reduce the risk of toxicity or negative consequences¹².

ADVANTAGES OF SLNS:

SLNs amalgamate the benefits of various colloidal systems, including liposomes, nano-emulsions, and polymeric nanoparticles. The primary advantages of SLNs are summed up as follows:

Ø  SLNs exhibit no bio-toxicity due to the biocompatible and biodegradable nature of the lipids used.

Ø  SLNs can be manufactured without the need for organic solvents.

Ø  SLNs demonstrate high physical stability.

Ø  SLNs can facilitate both drug targeting and controlled drug release.

Ø  Incorporating active compounds into SLNs can enhance their stability.

Ø  Both lipophilic and hydrophilic medications can be encapsulated within SLNs.

Ø  Producing SLNs on a large scale is straightforward.

Ø  SLNs can be sterilized^13,14.

DISADVANTAGES OF SOLID LIPID NANOPARTICLES:

There are a number of disadvantages to SLNs' perfect crystalline structure, including as their limited drug loading efficiency and the possibility of drug expulsion as a result of crystallisation during storage.

Ø  Lipid dispersions have a high-water content.

Ø  Transdermal drug delivery is limited.

Ø  The loading capacity for hydrophilic drugs is limited.

Ø  Polymorphic transformation.

Ø  Particle size enlargement during storage.

Ø  Lipid dispersion undergoing gelation.

Ø  The toxicity of lipid nanoparticles on retinal cells remains inadequately explored^15,16.

THE PRINCIPLE OF DRUG RELEASE FROM SLNS:

The typical criteria for drug release from lipid nanoparticles are as follows:

Ø  Higher drug discharge is achieved by a larger surface area due to the small molecule size measured in nanometers.

Ø  Slow drug release is possible when the medication is evenly distributed across the lipid system. It is determined by the SLN sort and drug entanglement model.

Ø  The rapid drug release is attributed to the crystallization behavior of the lipid carrier and the high mobility of the drug.

Ø  Due to the larger surface area of the outer layer of the particle allowing for drug deposition, the drug-enriched shell model exhibits rapid initial drug release within the first five minutes.

Ø  Prolonged release became possible when the particles reached a sufficient size, such as lipid macromolecules, as the burst release diminished with larger particle sizes.

Ø  The type and concentration of the surfactant, which interact with the outer shell and affect its structure, should be emphasized as a critical external component. Low surfactant concentrations result in limited bursts and prolonged drug release.

Ø  Particle size has a variable effect on drug release rate depending on several factors such as drug composition, lipid structural properties, and surfactant in the SLN formulation, as well as manufacturing conditions and time, equipment, and sterilisation and lyophilization^17,18.

THE EFFECT OF FORMULATION VARIABLES ON THE PROPERTIES OF SLNS:

Excipients are essential for building any drug delivery system and play a key role in determining the efficacy and quality of the final product.

The effect of lipid

Using the hot homogenization approach, it was possible to observe how the kind of lipid affected the characteristics of SLNs. It has been reported that a lipid with a high melting point forms bigger SLNs because the dispersed phase has a higher viscosity. The characteristics of SLNs are also influenced by lipid hydrophobicity, lipid crystal formation, and lipid crystallisation. Because lipids are mixtures of several substances, the way they are made can vary from batch to batch. Furthermore, the quality of SLNs might be affected by the providers as well as minute changes in lipid composition. The characteristics affected by the type of lipid include particle size, zeta potential, and in vitro drug release. Chakraborty et al. indicated that an increase in lipid content beyond 5-10% results in larger SLN particle size¹⁹.

Effect of surfactant

The kind of emulsifier used has a big impact on the characteristics of SLNs. When the amount of emulsifier is increased during preparation, any decrease in surface tension and particle size will be realised. A big surface area will result from any reduction in the particle size. In order to cover the surfaces of the produced nanoparticles through High-Pressure Homogenization, an excess of surfactant should be applied during the creation of the main dispersion of SLNs. The diffusion time between the surfaces of the produced particles and micelles varies depending on the type of surfactant. Prior research has shown that surfactants with low molecular weight require less time for redistribution, whereas those with high molecular weight take longer to redistribute. The addition of sodium glycocholate, a co-emulsifying agent, further reduces the size of the prepared nanoparticles^20,21.

STORAGE STABILITY OF SLN:

When SLNs are stored for an extended period of time, their physical characteristics can be ascertained by tracking variations in their viscosity, zeta potential, drug content, and particle size over time. External factors such as light and temperature appear to be crucial for long-term stability. Generally, a dispersion must maintain a zeta potential greater than -60 mV to ensure physical stability²².

4^oC - Optimal storage temperature.

20^oC - Extended storage did not lead to aggregation of drug-loaded SLNs or drug loss..

50^oC - A rapid increase in particle size was noted..

TECHNIQUES FOR SLNS PREPARATION:

High Pressure Homogenization

High-pressure homogenization (HPH) is a dependable and appropriate technique for preparing SLNs, NLCs, and LDCs, which can be conducted at elevated temperatures (hot HPH technique) or at or below room temperature (cold HPH technique). SLNs, formed from solid lipids or lipid blends, are produced by high-pressure homogenization of melted lipids and disperse in an aqueous outer phase stabilized by surfactants such as Tween 80, SDS, lecithin, etc²³.

a.                  Hot homogenization

Typically, hot homogenization involves temperatures surpassing the lipid's melting point. Using a high shear mixing device, a pre-emulsion of the drug-loaded lipid melt and the aqueous emulsifier phase (at the same temperature) is created. This yields a heated oil/water emulsion, which, upon cooling, induces lipid crystallization and forms solid-liquid nanoparticles (SLNs). Higher processing temperatures lead to smaller particle sizes due to reduced viscosity of the lipid phase. However, elevated temperatures also accelerate degradation of the medicine and carrier. With high kinetic energy, particles tend to increase in size with higher homogenization temperatures or increased cycles. Typically, 3-5 homogenization cycles at pressures ranging from 500 to 1500 bar are employed²⁴.

b.                  Cold homogenization

In order to address the issues with drug loss into the aqueous phase, partitioning linked to the hot homogenization approach, and temperature-related degradation, cold homogenization was created. Unpredictable lipid polymeric transitions brought on by the intricate nanoemulsion crystallisation process, which can lead to many modifications or supercooled melts. Here, the medication is mixed with melted fat and quickly cooled with liquid nitrogen or dry iceSolid material is ground using a mortar mill. Subsequently, lipid microparticles produced are dispersed in a cold emulsifier solution at room temperature or below. Precise temperature control is essential to ensure lipid homogenization in a solid state. However, cold homogenization typically results in larger particle sizes and a wider size distribution compared to hot homogenization samples²⁴.

Ultrasonication/high speed homogenization

Moreover, high-speed homogenization and ultrasonication techniques can be used to create SLNs. For smaller particle sizes, high-speed homogenization and ultrasonication must be combined. It has a number of disadvantages, including the potential for metal contamination and physical instability such particle growth during storage, even if it reduces shear stress. It makes use of a probe Sonicator or a bath Sonicator²⁵.

Solvent evaporation method

SLNs can also be produced using an emulsion precursor, where the organic phase consists of a solvent that may be volatile or only partially water miscible. Both O/W and W/O/W emulsions can be created: lipophilic drugs that dissolve in the system's inner organic phase alongside the lipid are administered as O/W emulsions. W/O/W emulsions are suitable for hydrophilic drugs, which dissolve in the multiple system's intermediate organic phase while the lipid dissolves in the inner aqueous phase. Nanoparticles are formed by removing the solvent either through evaporation (solvent evaporation technique for volatile solvents) or through water dilution (solvent diffusion technique for partially water miscible solvents): as a result of solvent removal, lipid precipitates as nanoparticles encapsulating the drug²⁶.

Solvent emulsification-evaporation method

In this process, lipids are first dissolved in an organic solvent (like cyclohexane). Subsequently, the drug-containing aqueous phase, along with the lipid phase, is homogenized under high pressure. The organic solvent is then extracted from the emulsion by evaporating it under low pressure (40–60 mbar). The precipitation of lipid in the aqueous media due to solvent evaporation leads to the formation of drug-loaded nanoparticles²⁷.

Supercritical fluid method

This technique, comparatively novel for SLN preparation, utilizes carbon dioxide (a supercritical fluid) to remove the solvent from o/w emulsions. While CO2 is a preferable choice, it may not dissolve many drugs. Therefore, supercritical anti-solvent precipitation (SAS) can serve as an alternative to SFEE²⁸.

Microemulsion based method

This method entails heating an aqueous phase containing surfactants to the same temperature as the lipids, which are melted at the appropriate temperature. Subsequently, the melted lipids are stirred at the same temperature while the hot aqueous phase is added. The dispersion of hot oil in water microemulsion in cold water at a 1:50 ratio solidifies the lipid nanoparticles²⁹.

Spray drying method

This method differs from lyophilization in converting an aqueous SLN dispersion into a pharmaceutical product. It is recommended to utilize lipids with a melting point exceeding 70°C for this process, which is more cost-effective compared to lyophilization. However, partial melting of the particles and high-temperature shear stresses in this method can lead to particle aggregation. According to Freitas and Mullera (1998), the best results were achieved with a 1% SLN concentration in a trehalose in water solution or a 20% SLN concentration in ethanol-water combinations (10/90 v/v)³⁰.

Double emulsion method

Two distinct methods are required to prepare warm w/o/w double microemulsions. First, melted lipid, surfactant, and co-surfactant are combined with an aqueous solution containing the drug at a temperature slightly above the lipid's melting point to form a transparent system. In the second step, the produced w/o microemulsion is mixed with water, surfactant, and co-surfactant to create a transparent w/o/w system. SLNs can be produced by combining heated micro double emulsions with cold water and then washing the dispersion media using an ultrafiltration system. Multiple emulsions are inherently unstable due to layer rupture on the surface of the internal droplets, internal oil droplet coalescence, and internal aqueous droplet coalescence inside the oil phase³¹.

Precipitation technique

Another approach to produce solid lipid nanoparticles involves precipitation, requiring the use of solvents. Following the dissolution of glycerides in an organic solvent like chloroform, the resulting mixture is emulsified in an aqueous phase.

Film ultrasound dispersion

            The aqueous mixture containing the emulsions was introduced subsequent to the addition of lipid and drug to appropriate organic solutions. These solutions were then subjected to spinning, decompression, and evaporation to create a thin lipid film. Finally, ultrasound and a diffuser probe were utilized to construct compact and uniformly sized solid lipid nanoparticles (SLN).

CHARACTERIZATION OF SLNS:

Particle Size and Zeta Potential

Various techniques, including photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM), as well as SEM combined with energy-dispersive X-ray spectroscopy, can be employed to ascertain the size of nanoparticles. Among these, PCS and electron microscopy methods are the most commonly utilized. SEM and TEM are particularly valuable for assessing the morphology and shape of lipid nanoparticles, providing insight into particle size and distribution. Additionally, atomic force microscopy (AFM) serves as an advanced tool for nanoparticle characterization, offering a means to visualize the particles in their initial, undisturbed state and to analyze surface characteristics. By measuring the interaction between the surface and the probing tip, AFM achieves spatial resolution down to 0.01 meters. This technique can detect particle sizes ranging from 3 nanometers to 3 microns, leveraging variations in the intensity of scattered light generated by particle interactions^32,33.

X-ray diffraction and differential scanning calorimeter (DSC)

The geometric scattering of radiation from crystal planes within a solid enables the identification of their presence or absence, facilitating the measurement of crystallinity levels. Differential scanning calorimetry (DSC) can be utilized to assess the properties and crystallinity degree of drugs encapsulated within nanoparticles³⁴.

Atomic force microscopy (AFM)

Through this method, a probe tip featuring atomic-scale sharpness is meticulously scanned across a sample to generate a topographical map, derived from the interactions between the tip and the surface. Atomic force microscopy serves as a valuable instrument for achieving ultra-high resolution of particles³⁴.

Entrapment efficiency

The entrapment efficiency of the drug is assessed by quantifying the concentration of free drug in the dispersion medium. Ultracentrifugation was performed using Centrisart, equipped with a filter membrane (with a molecular weight cutoff of 20,000 Da) at the base of the sample recovery chamber. During this process, solid lipid nanoparticles (SLNs) containing the encapsulated drug remain in the outer chamber, while the aqueous phase migrates into the sample recovery chamber. The quantity of drug present in the aqueous phase is determined using either high-performance liquid chromatography (HPLC) or a UV spectrophotometer³⁵.

CURRENT CHALLENGES AND LIMITATIONS OF SOLID LIPID NANOPARTICLES:

Numerous reports on solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC) formulations feature pharmaceutical ingredients already available in formulations with effective therapeutic outcomes at low costs, including famotidine, carvedilol, metformin, ibuprofen, dexamethasone, aliconazole, and various others. However, a notable portion of these reports focuses on experimental drugs lacking approved therapeutic indications, such as curcumin, rhein, or quercetin. Nevertheless, it's not all discouraging news. Given that "naked" nucleic acids administered parenterally cannot achieve therapeutic levels within target cells, the utilization of nanocarriers becomes imperative, particularly in RNA or DNA therapy. In bodily fluids, they break down quickly and are eliminated by the kidneys. Even if they get to reach the intended area, they cannot enter the cells. Therefore, whatever the associated cost, it is compensated by the possibility of having this type of therapies in the market.

When considered as a whole, the existing findings regarding the pharmaceutical use of SLN/NLC offer positive outlooks. As was covered in the earlier sections, these nanocarriers have shown to be effective and safe drug delivery systems that can enhance the pharmacokinetic profile and efficacy of the encapsulated pharmaceuticals. There are also a wide range of therapeutic applications that can benefit from their use. Before lipid nanoparticles can be made into commercially viable medicines with approved medicinal indications, there are a number of obstacles that must be solved, including large-scale manufacturing procedures, sterilisation, tailoring tactics, and stability difficulties^36,37.

CONCLUSION:

SLNs are regarded as an appealing drug carrier and a substitute for conventional colloidal dispersion systems. Because the utilised solid lipid is biocompatible, the SLNs serve as a secure and efficient drug delivery system. This article discussed the various ways to prepare solid-liquid nanoparticles (SLNs), how formulation variables affect SLN characteristics, benefits and drawbacks of SLNs, SLN structural features and general components, the idea behind drug release from SLNs, the goal of developing SLNs, and SLN characterization.

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