A SYSTEMATIC REVIEW ON NANO DRUG DELIVERY SYSTEM: SOLID LIPID NANOPARTICLES (SLN)

Nanomedicine along with nano-delivery systems, are a young but fast-emerging science in which tiny materials are used as diagnostic tools or to deliver therapeutic drugs to specific targeted locations in a controlled manner. Nanotechnology has numerous advantages in the treatment of chronic human diseases through the site-specific and target-oriented delivery of precise medications. There have recently been several notable applications of nanomedicine (chemotherapeutic agents, biological agents, immunotherapeutic agents, and so on) in the treatment of various disorders. Efficient use of pricey medications and excipients, as well as cost savings in manufacturing Beneficial to patients, improved therapy, comfort, and the standard of living. Lipids have been proposed as an alternate carrier to circumvent the constraints of polymeric nanoparticles, notably for lipophilic medicines. Such small particles of lipid are known as solid lipid nanoparticles (SLNs), and they are gaining popularity among formulators all over the world. SLNs are colloidal carriers that were developed in the last decade as a replacement for traditional carriers. Lipid nanoparticles have caught the interest of researchers during the last two decades and have shown considerable therapeutic success since the first clinical approval of Doxil in 1995. Simultaneously, lipid nanoparticles have shown significant promise in conveying nucleic acid medications, as proven by the approval of two RNA treatments and an mRNA COVID-19 vaccination.


INTRODUCTION
In nanotechnologies in medicine and nano delivery systems, particles in the nanoscale range are employed as diagnostic tools or to deliver therapeutic substances to specific targeted places in a regulated manner.Nanotechnology offers various benefits in the treatment of long-term human diseases by delivering precise drugs to specific places and objectives.Nanomedicine (including chemotherapeutic medications, biological agents, immunotherapeutic agents, and so on) has recently seen several notable uses in the treatment of various diseases [1].The current study, through an in-depth examination of the discovery and use of nanomaterials in improving the efficacy of both new and old pharmaceuticals, provides an updated account of recent developments in the field of nanomedicines and nano-based drug delivery systems [2].The use of nanoparticles (NPs) to deliver medications to cells is causing a surge in interest in improving human health.Such NPs are designed to be drawn directly to damaged cells, allowing for direct therapy of those cells while boosting efficacy, reducing side effects, and thereby enhancing human health.This approach lowers pharmacological adverse effects on the body.Despite the potential of nanomedicine for all diseases, there are still some drawbacks to adopting these nano-drug delivery vehicles that should not be overlooked.those administered using nanoscale entities may act differently than those delivered via conventional means [3,4].
NDDSs are materials that have at least a single dimension at the nanoscale scale (1-100 nm) or are made of basic units in space with three dimensions.NDDSs have been a research hotspot in the fields of pharmacy and advanced biomedicine due to their effectiveness in optimizing drug delivery.For more than 40 y, researchers have been studying NDDSs, yielding a plethora of nano-drug carriers.The nanomaterials utilized in NDDSs are classified as organic, inorganic, or composite materials based on their composition.The following is a description of some common NDDSs and their distinctive features.Novel medication delivery and drug targeting are novel strategies in pharmaceutical science.Targeted drug delivery, vaccine delivery, gene therapy, and commercial development of novel carriers (liposomes) are all examples of novel drug delivery systems [5].Efficient utilization of pricey medications, excipients, and production cost reduction Patients benefit from enhanced therapy, comfort, and quality of life [7][8][9].
Drug design at the nanoscale has received extensive research and is by far the most advanced technology in the field of nanoparticle applications due to potential benefits such as the ability to modify properties such as solubility, drug release characteristics, diffusivity, bioavailability, and immunogenicity.This may result in the creation of more accessible dosing routes, lower toxicity, fewer adverse effects, enhanced biodistribution, and a longer medication life cycle [10,11].The tailored drug delivery systems are either directed at a specific place or are designed for a controlled dispensing of therapeutic substances at that location.Their development involves self-assembly, in which well-defined shapes or patterns emerge spontaneously from building blocks [12].
Nanoparticles are colloidal particles with sizes ranging from 10 to 1000 nm.They are made of synthetic/natural polymers and are ideal for optimizing drug distribution and lowering toxicity.They have developed as an alternative substitute for liposomes as drug carriers over the years.The capacity of nanoparticles to overcome many anatomical barriers, the prolonged release of their contents, and their stability in the nanometer size all contribute to the successful deployment of nanoparticles for drug delivery.However, the shortage of safe polymers with regulatory approval, as well as their high cost, have hindered the widespread use of nanoparticles in clinical treatment [13,14].

Liposomes
Liposomes are small vesicles made of a phospholipid bilayer that can encapsulate an active medication.The medication's properties and the encapsulation procedure determine whether the drug is encapsulated in the core or the bilayer of the liposome.Watersoluble medications are typically enclosed inside the center of the aqueous core, whereas lipid-soluble pharmaceuticals are directly integrated into the lipid membrane [15].Liposomes are spherical particles that include hydrophilic and lipophilic compounds.They can have a single, numerous, or multiple concentric membranes [8,16].Liposomes can change the drug's tissue distribution and rate of clearance by causing the drug to adopt the pharmacokinetic features of the carrier [17,18].

Dendrimers
Dendrimers' great level of control over their architecture, size, shape, branching length and density, and surface functioning make them appropriate carriers for drug delivery purposes.The bioactive agents can be encapsulated within the dendrimers or chemically bonded or physically adsorbed onto the dendrimer's surface, with the option of tailoring the carrier properties to the specific needs of the active material and its uses in therapy.A dendrimer particle is a molecule made of polymers composed of several precisely branching monomers that radiate radially from a central core, giving rise to the name.When a dendrimer's core disappears, plenty of identical fragments known as dendrons remain [19].

Nanoparticles
Nanoparticles (NPs) and nanostructured materials (NSMs) are an active area of research as well as a techno-economic industry in multiple application domains.Because of their tenable physicochemical properties such as their melting point, wettability, electrical and thermal conductivity, as well as catalytic activity, light absorption, and scattering, NPs and NSMs have gained prominence in technological advancements, resulting in improved performance over their bulk counterparts [20][21][22].A nanometres (nm) is a unit of length in the International System of Units (Système international d'unites, SI).In theory, NMs are materials with lengths ranging from 1 to 1000 nm in at least one dimension; nevertheless, they are most often defined as having diameters ranging from 1 to 100 nm [23][24][25].

Solid lipid nanoparticle (SLN)
Solid lipid nanoparticles (SLN) were invented in the early 1990s as an alternate colloidal carrier system to emulsions, liposomes, and polymeric nanoparticles for controlled drug delivery.SLN is composed of a matrix of solid lipids that are sustained in an aqueous dispersion by surfactants or polymers, and the dispersion can be spray-dried or lyophilized to form a dry product [26,27].Solid lipid nanoparticles can combine particle shape and physical integrity with both physical and chemical stabilization of delicate components.SLN are nanostructures composed of solid lipids such as glyceryl behenate (Compritol), stearic triglyceride (tristearin), cetyl palmitate, and glycerol tripalmitate (tripalmitin) with sizes ranging between 50 and 1,000 nm [28][29][30].
Lipids have been proposed as an alternate carrier to circumvent the constraints of polymeric nanoparticles, notably for lipophilic medicines.Such small particles of lipid are known as solid lipid nanoparticles (SLNs), and they are gaining popularity among formulators all over the world.SLNs are colloidal carriers that were developed in the last decade as a replacement for traditional carriers (emulsions, liposomes, and polymeric nanoparticles) [31][32][33].
In fig. 3 gives the Pictorial presentation of the structure of solid lipid nanoparticles they are a new submicron-sized lipid emulsion in which the liquid component of lipid (oil) has been replaced with a solid lipid.SLN has unique qualities such as tiny size, large surface area, high drug loading, and phase interaction at interfaces, and are appealing due to their potential to improve the performance of medicines, "Nutraceuticals" and other materials [34,35].

Drug release through SLN
The partition coefficient of the medication has an inverse connection with its release.Higher drug release is achieved by increased surface area due to reduced particle size in the nanometer range [36].When the drug is homogeneously disseminated in the lipid matrix, controlled drug release can be achieved.It is determined by the type and drug entrapment model of SLNs.The lipid's crystalline nature and the drug's high mobility result in rapid drug release.The degree of crystallization and drug mobility has an inverse relationship.

Advantages of SLN
Due to their nano-size range, reticuloendothelial system (RES) cells are unable to take up SLNs, allowing them to avoid spleen and liver filtration [8,9].Provide integrated medications with great stability.The ability to include both hydrophilic and lipophilic medicines [47].Increase the bioavailability of weakly water-soluble compounds.Facilitate sterilization and scale-up.Immobilizing drug molecules into solid lipids protects sensitive pharmaceuticals from photochemical, oxidative, and chemical degradation, with reduced drug leakage.Lyophilization drying is possible.Allow for targeted and regulated drug release.Compositional components that are biocompatible and biodegradable [4].No special solvent is required and Easy for Preparations.Application versatility [54].

Disadvantages of SLN
SLNs are densely packed lipid matrix networks (perfect crystalline structure) with little room for drug encapsulation, resulting in low drug loading capacity [10][11][12][13].A variety of factors influence drug loading or encapsulation in SLNs, including drug-lipid melt interaction, the composition or state of the lipid matrix, drug miscibility with the lipid matrix, and the drug being distributed or dissolved in the lipid matrix.Drug release after polymeric transformation during storage [14,15] The dispersion particles have a high water content (70-90%) [16].

Applications of solid lipid nanoparticles [1, 52-58, 60]
There are various Applications of Solid Lipid Nanoparticles widely used SLN as Listed below

Composition of solid lipid nanoparticle
Solid lipid nanoparticle contains various compositions.Given below table lists the most used compositions in solid lipid nanoparticles.

High shear homogenization
The high shear homogenization technique was originally used to prepare solid lipids, which was originally used to prepare solid lipid Nano dispersions [47,48].Both methods are common and easy to handle.However, the presence of microparticles often reduces the quality of the dispersion.A rapid homogenization method is used to produce SLN by melt emulsification [49].Olbrich et al. investigated the effects of various process parameters, including emulsification time, stirring speed, and cooling conditions, on particle size and zeta potential.A higher mixing speed did not significantly change the particle size but slightly improved the polydispersity index.

Hot homogenization
Hot homogenization is performed at temperatures above the melting point of lipids and is similar to emulsion homogenization.Preemulsion of the drug-loaded lipid melt and the aqueous phase of the emulsifier (same temperature) is obtained with a high-shear mixer (for example, a silver-type homogenizer).The quality of the preemulsion greatly affects the quality of the final product, and it is desirable to obtain droplets of a few micrometers in size.Highpressure homogenization of the pre-emulsion is carried out above the melting temperature of the lipids.Smaller particle sizes are usually obtained at higher processing temperatures due to the reduced viscosity of the lipid phase [50], although this can also accelerate drug and carrier degradation.Better products are obtained after several passes through the High-Pressure Homogenizer (HPH), usually after 3-5 runs.High-pressure treatment always increases the temperature of the sample (about 10 ° at a pressure of 500 bars) [51].In most cases, 3-5 homogenous cycles at 500-1500 bar are sufficient.Increasing homogenization leads to an increase in particle size due to particle coalescence due to the high kinetic energy of the particles.

Cold homogenization
The cold homogenization process is carried out on a solid lipid and is, therefore, similar to high-pressure suspension milling.Effective temperature control is necessary to ensure the solid state of lipids during homogenization [52][53][54][55].Cold homogenization was developed to solve the following problems of the heat homogenization technique, such as temperature-mediated accelerated degradation of the drug load, distribution and thus drug loss during aqueous phase homogenization, and unstable lipid polymorphic transitions.the complexity of the drug.nanoemulsion crystallization step leading to multiple modifications and/or supercooled melts.The first preparation step is the same as in the hot homogenization procedure and involves dissolving or dispersing the drug in the lipid melt.However, the next steps are different.The drug-containing melt is rapidly cooled (using dry ice or liquid nitrogen) to promote homogeneous distribution of the drug in the lipid matrix.The solid lipid drug is ground into microparticles by ball/mortar milling.Typical particle sizes achieved are in the range of 50-100 microns.The cold treatment further facilitated particle milling by increasing lipid fragility.SLNs are dispersed in a chilled emulsification solution.The dispersion is homogenized at high pressure at room temperature or at a lower temperature with appropriate temperature control taking into account the normal temperature rise in high pressure processing.However, compared to hot homogenization, cold homogenized samples are characterized by larger particle sizes and a wider size distribution [56,57].The cold homogenization method minimizes heat deposition of the sample, but it does not avoid it due to the melting of the lipid/drug mixture at an early stage.

Solution emulsification-evaporation method
The solvent emulsification-evaporation method involves two steps: (i) preparation of oil/water nanoemulsions and (ii) solvent evaporation.In this method, the lipids and medicine are dissolved in a solvent or a mixture of solvents to form an oil phase, which is then emulsified into an aqueous phase.Solvents are water-immiscible organic solvents such as dichloromethane, chloroform, cyclohexane, and toluene [58,59].After oil-in-water-in-water Nanoemulsions are formed, the organic solvent is evaporated.Evaporation of the solvent is usually done using a rotary evaporator or mechanical stirring.As the solvent evaporates, the lipid concentration in the droplets gradually increases, leading to lipid precipitation and the formation of SLNs [60].This method involves the use of toxic organic solvents; therefore, additional steps are necessary to remove the solvents and evaluate the toxicity of the formulations in vitro and in vivo.The resulting SLNs usually have a high water content and should be concentrated by ultrafiltration or evaporation.On the other hand, the solvent emulsification-vapor method is well suited for heatsensitive medicines because it does not require high temperatures and physical stress, such as high-pressure homogenization and rapid mixing.The prepared SLNs generally have a narrow size distribution, with an average particle size of about 100 nm [61].

Solution emulsification-diffusion method
The solvent emulsification-dispersion method is mainly used to prepare polymeric nanocarriers.In 2003, Trotta et al. first used this technique to fabricate SLNs and NLCs.Partially water-miscible organic solvents such as methyl acetate, ethyl acetate, isopropyl acetate, benzyl alcohol, and butyl lactate are commonly used to carry out this method.Initially, the organic solvent and water are saturated with each other to achieve an initial thermodynamic equilibrium of both phases.Lipids and drugs are dissolved in a water-saturated solvent, which is then emulsified into an aqueous phase (solvent-saturated water containing a stabilizer) by stirring to form an o/w emulsion.The emulsion is diluted with water (1:5 to 1:10 by volume) to allow diffusion of the solvent into the continuous phase.SLNs and NLCs are formed spontaneously by lipid precipitation and then the solvent is removed by lyophilization or vacuum distillation [65,66].

Spray drying method
This is an alternative method to lyophilization to convert SLN aqueous dispersion into a medicinal product.It is a cheaper method than freeze drying.This method causes particle aggregation due to high temperature, shear forces, and partial melting of particles.
Freitas and Mullera recommend using a lipid with a melting point>700 for spray.The best results were obtained with SLN concentrations of 1% trehalose in water or 20% trehalose in ethanol-water mixtures (10/90 v/v).Double emulsion method: A new method based on solvent emulsification by evaporation was used to prepare hydrophilically charged SLN [67].Here, the drug is encapsulated with a stabilizer to prevent the drug from partitioning into the external aqueous phase upon evaporation of the solvent in the external aqueous phase of the w/o/w double emulsion.

Solution injection method
The solvent injection method used to prepare SLNs and NLCs was first described by Schubert et al. in 2003 [68].In this method, lipids and drugs are dissolved in a water-miscible solvent (e. g., methanol, ethanol, isopropanol, or acetone) or a water-miscible solvent mixture.The aqueous phase is usually prepared by adding an emulsifier or a mixture of emulsifiers to water or a buffer solution.
The organic phase is then rapidly injected into the aqueous phase using continuous mechanical agitation using a needle.This approach and the solvent emulsification-diffusion methodology have similar fundamental ideas.A scheme of the formation of SLNs and NLCs using the solvent injection method is described in After injection, two main mechanisms occur simultaneously and help each other to form SLNs and NLCs.First, the solvent is used from the droplets to the aqueous phase, which leads to a decrease in droplet size.As a result, the lipid content in the droplets increases, leading to the formation of local supersaturated regions stabilized by emulsifiers in the aqueous phase [69].Second, emulsifiers reduce the surface tension between water and solvent, which causes the formation of small solvent-lipid droplets at the injection site.Due to interfacial pulsation and turbulence during solution diffusion, these droplets break up into smaller droplets with essentially the same lipid concentration [70].The free energy released when the solvent is 9/35 redistributed to its equilibrium state provides the energy required for droplet distribution [71].Therefore, in the solvent injection method, solvent diffusion leads to the formation of small droplets and precipitation of lipids.Emulsifiers play an important role in determining PS and size distribution.

Quick mixing and ultrasonication methods
Rapid mixing (high shear homogenization) is a simple and costeffective method to prepare SLNs [72].This method involves three steps: (i) preparation of aqueous and lipid phases, (ii) homogenization, and (iii) cooling.In the first step, the lipids and the drug are homogeneously dispersed at a high temperature (5-10 C higher than the melting point of solid lipids), while an aqueous phase containing surfactants is prepared at the same temperature.
In the second step, the two phases are mixed and dispersed homogeneously with a high-shear mixer to form a hot oil/water emulsion.The third step is to cool this emulsion to form SLNs.This method is usually combined with sonication at the end of the second step to reduce the size of the emulsion.The advantages of rapid mixing and ultrasonic methods are the free operation of organic solvents and ease of use.However, these methods are associated with large amounts of surfactant [73], drug exposure at high temperatures, and metal contamination of ultrasound probes [74].These methods have been successfully used to incorporate various drugs such as linagliptin, quercetin and resveratrol, amphotericin B, buspirone, clozapine, piribedil, primaquine, and astaxanthin into SLNs.

Particle size
The physical stability of SLNs is determined by particle size.The most potent approaches for determining particle size are photon correlation spectroscopy (PCS) and laser diffraction (LD).The fluctuation in the intensity of dispersed light is induced by particle movement.Photon correlation spectroscopy (PCS) detects particle sizes ranging from 3 nm to 3m, and laser diffraction detects particle sizes ranging from 100 nm to 180 m.Although PCS is an excellent technique for characterizing nanoparticles, it is also capable of detecting bigger microparticles.The LD approach is based on the diffraction angle's dependence on particle size.Smaller particles scatter more intensely at high angles than larger ones [75-77].

Zeta potential
A zeta potential analyzer or zeta meter can be used to measure zeta potential.For size characterization and zeta potential measurement, dispersions of SLN are diluted 50-fold with their original dispersion preparation media before measurement In the absence of any complicating elements, such as steric stabilizers or hydrophilic surface appendages, a higher zeta potential value may lead to particle diaggregation.Predictions concerning storage can be made using zeta potential measurements.Colloidal dispersion stability [78].The zeta potential's significance value is connected to the stability of colloidal dispersions.In the dispersion phase, the ZP represents the degree of repulsion between nearby charged particles.Because the molecules and particles are tiny enough, a high zeta potential will provide stability, implying that the solution or dispersion will resist aggregation [79-81].

Surface morphology
Electron microscopy validated the morphological characterization of solid lipid nanoparticles.The surface morphology of solid lipid nanoparticles was studied using scanning electron microscopy.Scanning electron microscopy (SEM) provides 3D images of the particles and superficial morphology, and TEM (transmission electron microscopy) provides information on the shape and size of nanoparticles as well as their interior structure [82][83][84][85][86][87].

Degree of crystallinity
Differential scanning calorimetry (DSC) can be used to evaluate the degree of crystalline structure of lipid particles.It is a thermoanalytical methodology that provides a quick and accurate method for evaluating the degree of crystal structure of lipids based on lipid enthalpy.Powder X-ray diffractometry (PXRD) is an additional nondestructive technology used to describe crystalline materials and examine the crystal structure of SLN [88][89][90].

Nuclear magnetic resonance (NMR)
NMR can be used to determine the size and qualitative nature of nanoparticles. 1 H NMR spectroscopy was used to examine the prepared Solid Lipid Nanoparticles SLN.The nanoconjugates were dissolved in D2O and measured at 300 MHz using a 1 H NMR Spectrometer model Avance-II (Bruker, Germany).Several shifts and peaks were noted, which were interpreted differently for different groups [91].Carbonyl proton from an amide bond and nitrogen proton from an ester bond both appeared.Chemical shift selectivity augments sensitivities to molecular movement to offer information regarding the physicochemical condition of nanoparticle components [92].

Atomic force microscopy (AFM)
A probing tip with microscopic sharpness is photographed across a sample to generate a topological map based on forces between the tip and the surface.This method provides ultra-high resolution, which, combined with the capacity to map a sample based on features other than size, such as colloidal attraction or resisting deformation, makes AFM a valuable tool [93,94].

Entrapment efficiency
The level of concentration of the drug alone in the dispersion medium is used to calculate the drug's entrapment efficiency.
Centrisart was used for ultracentrifugation, which consists of a filter membrane (molecular weight cutoff 20,000 Da) at the bottom of the sample recovery chamber.The SLNs and encapsulated medication stay in the outer chamber while the aqueous phase enters the sample-collecting chamber.HPLC or a UV spectrophotometer is used to determine the amount of medication contained in the aqueous phase [95][96][97][98][99].

Dialysis tubing
Dialysis tubing could be used to achieve in vitro medication release.
The solid lipid dispersion of the nanoparticle is inserted in hermetically sealed dialysis tubing that has been pre-washed.The dialysis sac is then dialyzed at room temperature against a suitable dissolution medium; samples are collected from the dissolution media at appropriate intervals, centrifuged, and tested for the presence of drugs using a suitable analytical method [100,101].

Reverse dialysis
Several tiny dialysis sacs containing 1 ml of dissolving medium are inserted in SLN dispersion in this procedure.After that, the SLNs are shifted into the medium [102,103].

Stability testing
Plain SLN and linked SLN formulations held at 41 °C were more stable than those kept at room temperature, according to storage stability testing.The average particle size of nanoparticles has been demonstrated to increase throughout storage, which could be attributed to particle aggregation under varying storage circumstances [104].This effect was minimal in formulations held at 41 °C, indicating that aggregation can be managed by temperature, with 41 °C being the best storage temperature.The various SLN formulations were kept at 41 °C and at room temperature, and the amount of leftover drug content was estimated after 30, 60, and 90 d, assuming that the initial drug content was 100% [106][107][108][109].

Solid lipid nanoparticles delivery by various routes of administration
Solid lipid nanoparticles are given by various routes in which Parenteral administration is the most often suggested route of administration for lipid-based nanosystems, with oral administration coming in second.Although the trend described is at odds with how pharmaceutical products are currently distributed in the market, where oral drug administration is the most popular and preferred method, both administration routes aim to achieve systemic effects of the encapsulated drugs [110][111][112][113]. Contrarily, parenteral methods, including intramuscular and/or subcutaneous routes, allow the transport of medications straight to the systemic circulation with little to no limits and no need to overcome absorptive obstacles.In the therapeutic field of anticancer drugs, the IV route remains predominant despite its non-negligible negative aspects, including invasiveness, associated risks, inability to selfmanage, and higher technological requirements to be manufactured with appropriate microbiological quality.Of the lipid nanosystems assayed by parenteral routes, 46 out of 81 correspond to anticancer drugs [114,115].

Fig. 5: Various routes that can be deliver solid lipid nanoparticles [100, 114, 115]
There are various tremendous works on solid lipid nanoparticles.This study listed some works done on solid lipid nanoparticles by researchers throughout the world.The listed works are shown in table 2 given below.

CONCLUSION
With their outstanding characteristics and benefits over other traditional forms of administration, SLNs have radically captured the attention of several researchers, and other colloidal equivalents of SLN have proven to be an important development in nanotechnology due to their efficacy and as a secured vehicle in pharmaceutical administration.Both hydrophilic and lipophilic medicines can be carried by lipid nanoparticles.They can be delivered by a variety of methods, including topical, oral, parenteral, ophthalmic, pulmonary, and brain drug administration.These nanoparticles offer advantages and disadvantages for each method of administration that should be evaluated.Using surface modification, the system demonstrates a robust and safe pharmaceutical platform for the future management of several awful disorders such as cancer, HIV, tuberculosis, Malaria, and others.SLN as a colloidal drug carrier, combines the benefits of polymeric nanoparticles and liposomes, such as better physical stability, the feasibility of incorporating lipophilic and hydrophilic medicines, economics, and ease of scale-up and production.SLNs can achieve site-specific and sustained drug release.SLNs are created using a variety of advanced approaches.SLNs have been widely used in drug discovery applications.Medication distribution, diagnostics, and many other applications in the medical field.

ABBREVIATIONS
Fig. 1 gives pictures Structure of different types of Nanocarriers.