A Review on Solid Lipid Nanoparticles for Topical Delivery of Anti-Inflammatory Drugs

Skin disorders like eczema, psoriasis, acne and contact dermatitis are chronic and significantly affect a patient's quality of life. These conditions are commonly associated with redness, swelling, pain and itching which reflects inflammation in the body ^[1]. Corticosteroids, NSAIDs and biologics are anti-inflammatory medications that can be used topically and are frequently prescribed for such conditions. Even while these treatments work well for their particular ailments, they have disadvantages, such as poor skin absorption, low bioavailability, and a higher chance of systemic side effects if taken for an extended length of time ^[2]. The use of sophisticated drug delivery systems has grown in popularity over the past few decades in an effort to increase the efficacy and safety of topical treatments. One of the most promising among them is Solid Lipid Nanoparticles (SLNs). SLNs are submicron carriers comprised of solid lipids and stabilizers comprising few solid lipid nanoparticles and have many benefits as drug carriers such as biocompatibility, bioavailability as well as the potential for controlled and sustained drug release. Owing to their distinctive characteristics, SLNs have gained attention as a means of addressing the drawbacks of conventional topical dosage forms, by improving the overall permeability of drugs through the skin and more accurate localization of the active agent over the affected area ^[3]. Over the last few decades, there has been growing interest in the use of SLNs for the delivery of anti-inflammatory drugs. In addition, other studies have reported the use of SLNs to encapsulate both hydrophilic and lipophilic drugs and also highlighted their ability to be surface modified to enable targeting of specific receptors, making them effective vectors for a variety of pharmaceutical uses ^[4]. In this regard, this review will highlight the recent works done in the formulation and use of SLN as a means of delivery of anti-inflammatory medication through topical route. It will discuss the history of SLNs, biological mechanisms that account for their success in drug delivery, formulation techniques, their application in the management of patients with common inflammatory skin diseases and their principal barriers to use. As a result of reviewing existing scientific literature alongside future work plans, this article articulates the great promise of SLNs in the treatment of inflammatory skin diseases.

Fundamentals Of Solid Lipid Nanoparticles (SLNs)

Solid Lipid Nanoparticles (SLNs) are less than one micron sized transdermal drug delivery systems that have a stabilizing surfactant or polymer on the surface of a solid lipid core mentioned in Figure No: 1 and 2. Use of SLNs has been of great value in the pharmaceutical and biomedical fields because of their biocompatible properties as well as several other advantages like controlled release, and enhanced stability compared to other nanocarriers like liposomes and emulsions ^[5]_.

Composition and Structure of SLNs:

Figure No: 1: Structure of SLNs

Figure No: 2: Composition of SLNs

1. Lipid Core

The lipid or lipids that make up the majority of solid lipid nanocarriers have an impact on the regulated release pattern of the lipid dispersion, stability, and drug encapsulation. SLNs dispersion can be made from biocompatible and biodegradable lipid components, such as fatty acids, glycerides, and waxes ^[6]. Applications of SLNs have been documented in the domains of pharmaceutical nanotechnology, cosmetics, and food sectors. The lipids employed in solid lipid dispersion are physiologically well-tolerated, reasonably priced, and generally recognized as safe (GRAS) ^[7].

2. Surfactants/Stabilizers

Hydrophilic (ethylene oxide) and lipophilic (hydrocarbon chain) moiety combine to generate the head and tail of surfactants, which are amphipathic in nature. The surfactant deposited on the colloidal system's interface at low concentration lowers the interfacial tension by lowering the interfacial free energy ^[8]. To create a stable lipid colloidal system, surfactants are utilized.
During the production of colloidal systems, the surfactants spread the oily phase across the aqueous phase, and following refrigeration, they stabilize colloidal nanoparticles. The widespread consensus is that ionic and non-ionic surfactants exhibit steric repulsion stability and electrostatic stability, respectively. Small amounts of non-ionic surfactants are employed to simulate true steric stability; however, the Gibbs-Marangoni effect causes instability as a result. Both positively and negatively charged functional groups are present in zwitterionic or amphoteric surfactants. When creating colloidal lipid nanoparticles, amphoteric surfactants such phospholipids and phosphatidylcholines are employed. In both high and low pH states, they demonstrated the characteristics of cationic and anionic surfactants shown in Figure No: 3 ^[9].

Examples of Surfactants ^[10]:

Figure No: 3: Examples of Surfactants

3. Encapsulated drug

SLNs can be used to encapsulate both lipophilic and hydrophilic drugs. Lipophilic drugs are dissolved in the lipid core, while hydrophilic drugs are either dispersed in the aqueous phase during the preparation process or incorporated at the interface of the lipid core and surfactant layer. The encapsulation of anti-inflammatory drugs, such as corticosteroids, NSAIDs, or plant-derived compounds, in SLNs can enhance their solubility, stability, and controlled release ^[11].         

Properties of SLNS ^[12]:

1. Size and Morphology

SLNs have been reported to have a size range between 50 to 1000 nm, however most formulations are expected to be in the submicron range (100-500 nm) to help in the penetration of the skin more easily. The particle size can have an important effect on the rate of drug release as well as penetration of the skin and distribution ^[13]. The spherical shape SLNs or oval SLNs however their morphology is to be affected by preparation method and type of lipid used to form SLNs. Surface roughness and charge can be adjusted to aid in drug targeting and aid in skin engagement.

2. Surface Charge

The surface charge of SLNs is considered to be one of the most important factors determining the stability, permeation of skin and the interactions of cells occurring. A SLN can be positively, negatively or neutral charged depending upon the concentration and charge of the surfactant or adding increasing agents. In most cases applying a negative charge on the skin is more favourable since it aids in penetration and reduces chances of irritation. However, this can differ in certain instances whereby a neutral or lightly positive charged SLNs are employed for targeting specific skin receptors ^[14].

3. Controlled and Sustained Release

One of the most significant advantages of SLNs is their ability to provide controlled and sustained drug release. This is achieved through the slow diffusion of the encapsulated drug from the solid lipid matrix into the surrounding environment (e.g., the skin). The release rate of the drug can be manipulated by altering the composition of the lipid matrix, the drug-to-lipid ratio, and the presence of surfactants. SLNs can offer a prolonged therapeutic effect, reducing the need for frequent dosing ^[15].

4. Stability

SLNs are more stable than traditional liquid emulsions or liposomes, as the solid lipid core is less prone to hydrolysis and oxidation, which can degrade the encapsulated drug.  The solid nature of SLNs also provides a protective barrier for sensitive drugs, particularly those that are prone to chemical degradation (e.g., anti-inflammatory compounds). This stability is crucial for ensuring the consistency of the therapeutic effect over time ^[16].

Advantages of SLNS ^[17]:

Figure No: 4: Advantages of SLNs

Figure No: 5: Disadvantages of SLNs

When administering SLNs loaded with any anti-inflammatory topical medication, the mechanisms underlying the efficient skin penetration and preservation of therapeutic concentrations at the site are essential to the therapeutic outcome. For example, in this situation, longer-lasting therapeutic action, altered drug pharmacokinetics, and improved skin penetration. In this study, we examine the fundamental ideas that govern how SLNs function in topical medication administration ^[19].

Figure No: 6: Mechanism of action of Anti-inflammatory drugs using SLNs

General Methods of Preparation of Solid Lipid Nanoparticles:

Water, emulsifier, and solid lipid (matrix material) are the three main excipients of SLNs. Here, the term "lipid" is used more broadly to refer to ^[20]:

• saturated monoacid triglycerides (e.g. tristearin, tripalmitin, trilaurin, and trimyristin);
• partial glycerides such as glyceryl monostearate, glyceryl behenate and glyceryl palmitostearate;
• fatty acids (e.g. stearic acid, behenic acid, palmitic acid and decanoic acid);
• steroids like cholesterol and;
• waxes such as cetyl palmitate.

Here some preparation techniques of SLN’s are given:

1. High Pressure Homogenization Technique
2. Microemulsion Technique
3. Solvent Emulsification Evaporation Technique
4. Solvent Emulsification Diffusion Technique
5. Melting Dispersion Technique (Hot Melt Encapsulation Method)
6. Ultrasonication Technique
7. Double Emulsion Technique
8. Membrane Contactor Technique
9. Solvent Injection Technique
10. Supercritical Fluid Technique
11. Microchannel/Microfluidic Technique

1.High Pressure Homogenization Technique:

The high-pressure homogenization method involves pushing melted lipid solution at high velocity and high pressure (100–200 bars) through a small opening of a few micron ranges. Sudden drop in pressure that results in cavitation. After further disruption from the combination's impact on the solid surface, the mixture is eventually released as a homogenized product. Thus, cavitation and shear stress are the forces that cause particles to break down into submicron ranges ^[21].  High pressure homogenization includes two types of techniques i.e. Hot Homogenization technique and Cold Homogenization technique. The drug loaded in melted lipid is dispersed in an aqueous surfactant solution of the same temperature using a high shear device (such as Ultra Turrax) in the Hot Homogenization Technique (HHT)^[22] and in the Cold Homogenization Technique (CHT) was created to stop temperature-induced drug degradation, the hydrophilic drug's partitioning from the lipid phase to the aqueous phase, and the intricacy of the nanoemulsion's crystallization step, which can result in multiple modifications and/or supercooled melts^[23].

2. Microemulsion Technique:

By using a traditional microemulsion technique, SLNs were created. The temperature of a mixture of water and surfactant was raised to 85°C, the same temperature as the lipid phase that contained solid lipid. The hot aqueous phase was then added to the molten lipid phase at 85°C while being constantly stirred to create a hot o/w microemulsion. At a ratio of 1:50 (microemulsion: water, v/v), the hot o/w microemulsion was subsequently dissolved in cold water (2-4°C) to create a dispersion of SLN. To dissolve the drug in the lipid, the solid lipid and the drug were heated together for drug-loaded SLNs ^[24].

3. Solvent Emulsification Evaporation Technique:

An aqueous phase is created by emulsifying a water-immiscible organic solvent (such as chloroform) with the lipid matrix. A dispersion of nanoparticles is created when the solvent evaporates under lower pressure, causing the lipid to precipitate in the aqueous media. The fat load and emulsifier utilized can produce particles with typical sizes ranging from 30 to 100 nm. This method has the significant benefit of not producing any heat. The restricted solubility of the lipids in the organic solvents utilized, however, results in somewhat diluted solvent emulsification–evaporation suspensions ^[25].

4. Solvent Emulsification Diffusion Technique:

The drug and the lipid are dissolved in a partly water-miscible organic solvent in the internal phase of a pre-emulsion, which is typically prepared as an aqueous solution of the stabilizer. The solubility of the lipid in the organic phase determines whether a cold or hot solvent is used for this step. Nanoparticles (NP) are then created when water is added to the system, causing the solvent to diffuse into the exterior phase. Techniques like under-reduced pressure or cross-flow filtering can be used to get rid of the remaining solvent ^[26].

5. Melting Dispersion Technique (Hot Melt Encapsulation Method):

In order to produce a homogeneous output, raw ingredients are continuously pumped at high temperatures and pressures using hot-melt extrusion (HME) technology. Compared to traditional pharmaceutical manufacturing methods, this technique has numerous advantages. Along with faster and more effective processing times to create the finished product, it offers environmental benefits by doing away with the need for solvents. As a result, HME has surpassed conventional methods as a cutting-edge technology for producing pharmaceutical dosage forms such tablets, capsules, implants, and films ^[27].

6. Ultrasonication Technique:

Before being introduced to a mixture of water and surfactants that had already been prepared to the same temperature, the solid lipid was heated 5–10⁰C over its melting point. A pre-emulsion was produced while being stirred for five minutes at 8000 rpm using an Ultra-Turrax T25. This pre-emulsion was sonicated using a VCX130 ultrasonic processor to insert a sonication probe (6 mm diameter). After 20 minutes of application of a power output with an amplitude of 70%, acoustic cavitation caused droplets to shatter, resulting in the creation of nanoparticles. After transferring the o/w nanoemulsion to glass vials, it was promptly allowed to cool to room temperature in order to produce SLN ^[28].

7. Double Emulsion Technique:

Lipids are dissolved in organic solvents during this process, while hydrophilic proteins are initially dissolved in the inner water phase. A primary emulsion (w/o) is created by dispersing the water phase in the organic phase, and a double emulsion (w/o/w) is created by further dispersing this emulsion in the external water phase. After the solvent has been removed from the double emulsion, protein-loaded SLNs are produced. The system is nonhomogeneous during this process, transitioning from two phase (water-in-oil) to three phases (water-in-oil-in-water) then back to two phases (solid-in-water) ^[29].

8. Membrane Contactor Technique:

A novel method for making SLN with a membrane contactor that enables large-scale manufacturing. The creation of tiny droplets is made possible by pressing the lipid phase through the membrane pores at a temperature higher than the lipid's melting point. By flowing tangentially to the membrane surface, the aqueous phase separates the lipid droplets from the membrane pores. After the preparation is cooled below the lipid melting point, the SLN are created ^[30].

9. Solvent Injection Technique:

A modified solvent injection approach was used to prepare LNP. After dissolving the lipids in a water-miscible solvent and a water-miscible solvent mixture (1–-100 mg/ml), they were quickly injected via an injection needle into an aqueous phase that was being agitated (330 rev./min) with or without surfactant. A paper filter was then used to remove any extra fat from the resultant dispersion ^[31].

10. Supercritical Fluid Technique:

This process begins with a solid solute saturation of a supercritical fluid. When
A heated nozzle expands the supercritical fluid into a low-pressure chamber, causing the solution's density to drop rapidly and the solute to precipitate uniformly as a result of high supersaturation ^[32]. After that, the gaseous stream produces and collects ultrafine, porous particles. To ensure sufficient product recovery, the solid active medicinal ingredient needs to be well soluble in the supercritical fluid ^[33].

11. Microchannel/Microfluidic Technique:

Microfluidics, also known as lab-on-a-chip (LOC), is a cutting-edge technology that uses a device with microchannels to regulate the flow characteristics of tiny fluid volumes inside the microchannels. The ethanol injection method, which uses a microfluidic device with a micromixer to mix an aqueous solution with dissolved surfactant/lipid molecules in an alcohol solution, is comparable to this microfluidic-based technique. of order to maintain a homogenous environment, the microchannels of the microfluidic device allow two miscible fluids to flow laminarly into the interfacial and mixing zones, where they are quickly combined. Compared to traditional bulk mixing methods, microfluidic technology allows for the efficient and affordable creation of a variety of micro- and nanoparticles made of different materials and therapeutic agents utilizing a little number of ingredients and solvents. Solid lipid nanoparticles were created using microfluidics, and their capacity to load proteins was examined ^[34].

Therapeutic Applications of Drug-Loaded SLNS In Dermatology:

Figure No: 7: Therapeutic applications of SLN in Dermatology

Challenges And Limitations of Drug-Loaded SLN:

Although Solid Lipid Nanoparticles (SLNs) have several benefits as a drug delivery system in dermatology, such as greater skin penetration, controlled release, and increased drug stability, a number of issues and restrictions need to be resolved before their full potential in clinical practice can be realized ^[38]. Formulation, stability, regulatory approval, and patient-related issues are all affected by these difficulties. The main drawbacks and restrictions of utilizing SLNs loaded with anti-inflammatory drugs in dermatology are listed below.

Figure No: 8: Challenges and opportunities of Anti-inflammatory drugs in Dermatology

Previously Studied Various Solid Lipid Nanoparticles Containing Anti-Inflammatory Drugs:

Table No: 1

The use of Solid Lipid Nanoparticles (SLNs) as carriers for various drugs in dermatology is an evolving field with significant eventuality for invention. As exploration progresses, there are many chances to enhance SLN articulations and enhance their medicinal issues in the treatment of dermatological conditions. Below are some crucial future directions shown in Figure No:  and inventions that may address being challenges and open new avenues for SLN- loaded drug delivery systems.

Figure No: 9: Future directions of Anti-inflammatory drug-loaded SLNs