PDEA’s Shankarrao Ursal College of Pharmaceutical Sciences and Research Center Kharadi, Pune.
Solid lipid nanoparticles (SLNs) are a medication delivery method that shows great promise. Their unique properties and advantages over other nanoparticle formulations have garnered significant interest. The goal of this review study is to provide a comprehensive overview of all that is currently known about solid lipid nanoparticles, including their preparation, characterization, drug delivery applications, and most recent advancements in the field. The paper also highlights the challenges and potential advantages of solid lipid nanoparticles, emphasizing how they have the potential to revolutionize the area of nanomedicine.
Colloidal drug carrier systems include solid lipid nanoparticles. In this case, liquid lipids used in emulsion are substituted with solid lipids. Lipospheres, another name for solid lipid nanoparticles, are nanocarriers for the regulated administration of medications. Lipidic components that are safe and biodegradable are used to make SLN. Both lipophilic and hydrophilic drugs are carried by SLN. It offers superior physical stability, precise drug delivery, and drug protection. The field of science and engineering known as "nanotechnology" is concerned with creating, manufacturing, and applying structures, apparatuses, and systems by the manipulation of atoms and molecules at the nanoscale, or with one or more dimensions on the order of 100 nanometers (100 millionth of a millimetre) or less. Products utilizing nanotechnology can present fresh difficulties in the fight against environmental contamination. Within the pharmaceutical and medical industries, nanotechnology is regarded as a relatively new and quickly expanding industry. Together with information technology and biotechnology, which are already well-established fields, nanotechnology is acknowledged as a developing enabling technology for the twenty-first century. When it comes to increased efficacy and less adverse medication reactions, nanoparticles provide a number of benefits as drug delivery vehicles.[1]
Figure1; Solid Lipid Nanoparticles
1.1Aims of SLN:
It has been stated that SLN avoids the drawbacks of other colloidal carriers while combining their virtues. [3]
1.2Advantages of SLN:
1.3Disadvantages of SLNs:
2.Solid lipid nanoparticles: Formulation and preparation Techniques
2.1 General ingredients:
A solid lipid emulsifier and water are the typical components. The broader definition of "lipid" used here includes triglycerides (tristearin), partial triglycerides (imwitor), fatty acids (stearic acid), steroids (cholesterol), and waxes (cetyl palmitate). Emulsifiers of all classes with respect to charge and molecular weight have been used to stabilize the lipid dispersion. Combinations of emulsifiers have been found to have the ability to more successfully prevent particle agglomeration. One clear benefit is that the lipid matrix in SLN is made up of physiological lipids, which reduces the possibility of both acute and long-term damage. The choice of emulsifier depends on the delivery method, with parenteral administrations receiving more weight. [2]
Table 1; Lipids and Emulsifiers Used for Preparation of Solid Lipid Nanoparticles
|
Triglycerides |
Tripalmitin[4] Tristearin[5] Trilaurin[6] Tricaprin[7] Hydrogenated coco- - glycerides[8] |
|
Emulsifiers/Co-emulsifiers |
Poloxamer 188[9] Poloxomer 407[10] Poloxamine 908[11] Polysorbate 80[8] Polysorbate 60[12] Polysorbate 20[13] Sodium cholate [14] Sodium glycocholate[4] Butanol [13] Butyric acid [15] Soyabean lecithin[16] Phosphatidylcholine[17] |
|
Hard fat types |
Glyceryl monostearate ( Imwitor 900) [18] Glyceryl behenate ( Compritol 888 ATO) [14] Cetyl palmitate[14] Acidan N12[19] Stearic acid [20] Palmitic acid [21] Decanoic acid [21] Behenic acid [19] Glyceryl palmitostearate (precirol ATO 5)[11] Witepsol H 35[5] Witepsol H 42[22] Witepsol E 85[16] Witepsol W 35[23] |
2.2 Formulation techniques;
2.2.1 High pressure homogenization
2.2.2 Emulsification dispersion followed by Sonification
2.2.3 Microemulsion
2.2.4 Solvent evaporation
2.2.5 Solvent Diffusion
2.2.6 Solvent Injection
2.2.7 Double emulsion
2.2.8 Spray drying method
2.2.1 High pressure homogenization:
For the preparation of SLN, high pressure homogenization (HPH) has proven to be a dependable and effective method. Various manufacturers offer commercially available homogenizers in various sizes at fair costs. For many years, parenteral nutrition has utilized HPH to produce nanoemulsions. In most situations, scaling up poses no challenge, in contrast to other strategies. High pressure homogenizers force a liquid under high pressure (between 100 and 2000 bar) through a tiny opening (a few microns). about a very short distance, the fluid accelerates to a very high velocity (about 1000 km/h). Particles are disrupted down to submicron levels by extremely high shear stress and cavitation forces. Lipid contents typically range from 5 to 10% and pose no issues for the homogenizer. Lipid nano-dispersions have been homogenized to even higher lipid contents (up to 40%) [24]. Two general approaches of the homogenization step, the hot and the cold homogenization techniques, can be used for the production of SLN.
A) Hot pressure homogenization:
Hot homogenization can be thought of as the homogenization of an emulsion since it occurs at temperatures higher than the lipid's melting point. A high-shear mixing apparatus (Ultra-Turrax) is used to create a pre-emulsion of the drug-loaded lipid melt and the aqueous emulsifier phase (same temperature). It is ideal to obtain droplets in the range of a few micrometres in size, as the quality of the pre-emulsion greatly influences the quality of the final product. HPH of the pre-emulsion is done at temperatures higher than the lipid's melting point. Because the inner phase becomes less viscous at higher temperatures, particle sizes often decrease [25]. High temperatures, however, may also quicken the drug's and the carrier's rate of deterioration. It is possible to repeat the homogenization process multiple times. It is important to remember that high pressure homogenization raises the sample's temperature (to about 108C at 500 bar [26]). Three to five homogenization cycles at 500 to 1500 bar are usually adequate. The high kinetic energy of the particles causes particle coalescence, which is a common consequence of increasing the homogenization pressure or the number of cycles [27]. This process increases the size of the particles. The lipid's liquid condition causes a nano-emulsion to be the main byproduct of the heat homogenization process.
The sample should next be cooled to room temperature or lower, which is when solid particles should form. The sample may remain as a supercooled melt for several months due to the small particle size and the presence of emulsifiers, which can dramatically inhibit lipid crystallization [28].
B) Cold homogenization techniques:
To create drug-loaded lipid, the drug is dissolved in the melted lipid and quickly cooled using dry ice or liquid nitrogen. The medication forms a solid solution (uniform distribution) in the lipid matrix as a result of the quick cooling. A mortar or ball mill is then used to grind the solid solution into tiny particles. After that, solid lipid micro -particles are homogenized at room temperature after being distributed in a cool aqueous phase containing emulsifiers. The issues of temperature-induced drug degradation and drug dispersion into the aqueous phase during homogenization are resolved by cold homogenization.
Due to the medication's solubilization in melting lipid and the heat produced during the homogenization process, thermal exposure to the drug cannot be totally avoided. [29,30]
1. Drug deterioration caused by temperature
2. Dispensing of medication during homogenization into the aqueous phase
3. Complexity of the nanoemulsion's crystallization phase, which results in several modifications and/or supercooled melts
2.2.2 Emulsification dispersion followed by sonification:
This straightforward process involves dissolving the drug, lipid, and emulsifier in a common solvent, which is then evaporated under low pressure to produce a drug-dispersed lipid phase free of solvent. After homogenizing this phase with a hot aqueous surfactant solution using a homogenizer, the nanoemulsion is produced by ultrasonography. When the material cools to room temperature, the SLN are created. Using this technique, cisplatin66 and mitoxantrone5 have been encapsulated.
2.2.3 Microemulsion:
Methods for preparing SLNs based on microemulsion dilution were developed by Gasco and colleagues It should be noted that views among the scientific community regarding the dynamics and structure of microemulsions vary widely. Recently, Moulik and Paul published an expanded review [31]. According to Gasco and other scientists, microemulsions, such as o/w-microemulsions, are two-phase systems made up of an inner and an outer phase. To make them, one must stir an optically transparent mixture that contains water, co-emulsifiers (such as butanol, sodium monooctylphosphate), a low melting point fatty acid (such as stearic acid), and an emulsifier (such as polysorbate 20, polysorbate 60, soy protein-tightlcholine, taurodeoxycholic acid sodium salt). While churning, the heated microemulsion is distributed throughout the cold water (2–3°C). The hot microemulsion typically has a volume ratio of 1:25 to 1:50 with cold water. The makeup of the microemulsion has a major impact on the dilution process. The literature [32,33] claims that since the microemulsion already contains the droplet structure, no energy is needed to produce submicron particle sizes. Different mechanisms might be taken into consideration in light of the similarities in the synthesis process of polymer nanoparticles as detailed by French scientists [34]. Fessi diluted polymer solutions in water to create polymer particles. Fessi asserts that a key determinant of particle size is the distribution processes' velocity. Larger particle sizes were created with more lipophilic solvents, whereas nanoparticles were only formed with solvents that spread very quickly into the aqueous phase (such as acetone). The acetone in the production of polymer nanoparticles and the hydrophilic cosolvents in the microemulsion may be related in the formation of lipid nanoparticles.When it comes to microemulsions, the pH level and temperature gradient determine the product quality in addition to the microemulsion's content. Gradients of high temperature promote quick lipid crystalization and inhibit aggregation [35,36].
Figure2: Microemulsion Techniques [37]
Achievable lipid contents are presumably lower than with the HPH-based formulations because of the dilution process.
2.2.4 Solvent emulsification / evaporation:
A production technique for creating nanoparticle dispersions via precipitation in o/w emulsions was reported by Sjostrom and Bergenstahl [38]. The lipophilic substance is dissolved in an organic solvent that is water-immiscible and emulsified in an aqueous phase, such as cyclohexane , choloroform. Lipid precipitates in the aqueous media, creating a nanoparticle dispersion when the solvent evaporates. The cholesterol acetate model medication was used to create particles with a mean diameter of 25 nm, which were then emulsified using a lecithin/sodium glycocholate combination. Westesen confirms that these results are reproducible. [39] The cholesterol acetate nanoparticles were made in accordance with Sjostrom's instructions using readily available technology, and their mean particle size was 29 nm (PCS number distribution). Westesen dissolved the triglyceride in chloroform to create tripalmitin nanoparticles. HPH emulsified this solution in an aqueous phase. By evaporating the organic solvent under low pressure (40–60 mbar), the organic solvent was extracted from the formulation. Depending on the lecithin/co-surfactant combination, the average particle size varies between 30 and 100 nm. Bile salts were used as co-surfactants to produce particles with average diameters as low as 30 nm. Melt emulsification of equal composition cannot provide comparable tiny particle size distributions. The amount of lipid present in the organic phase determines the mean particle size. Only very modest amounts of fat (5 w%) in relation to the organic solvent could be recovered. Because of the increased viscosity of the dispersed phase, homogenization efficiency decreases with increasing lipid concentration. The lack of any heat stress makes this approach superior to the previously stated cold homogenization method. The usage of organic solvents is unquestionably disadvantageous.
2.2.5 Solvent Diffusion
Preparing a solvent in water emulsion using a partly water miscible solvent containing the lipid is the first stage in the solvent diffusion technique's synthesis of lipid nanoparticles. Solvents that were water miscible and low toxic, like butyl lactate or benzyl alcohol, were used. Diffusion of the organic solvent causes droplets of the dispersed phase to solidify as lipid nanoparticles when a transitory oil-in-water emulsion is transferred into water and continuously stirred. Additionally, the solution undergoes ultrafiltration purification, removing nearly 99.8% of the benzyl alcohol. Using this method, Trotta et al. created SLNs by combining glceryl monostearate with various combinations of surfactant mixtures. With benzyl alcohol and butyl lactate, the mean diameters of the SLNs produced were 205 and 320 nm, respectively, utilizing lecithin and taurodeoxycholic acid sodium salt and glcerylmonostearate (2%–5%) [40]. A unique solvents diffusion approach was used to create monostearin SLNs integrated with clobetasol propionate. Following a 508C acetone and ethanol dissolution of the drug and lipid, the organic solution was added to a pH 1.1 acidic aqueous solution containing 1% polyvinyl alcohol while being stirred mechanically at ambient temperature. Centrifugation was used to quickly and simply separate the drug-loaded SLNs [41].
2.2.6 Solvent Injection:
The solvent diffusion method and the production of SLNs have a similar basic mechanism. On the other hand, SLNs are created by quickly infusing water with a solid fat solution in a solvent that is water miscible. Solid lipids can be dissolved by mixing water miscible solvents. In this procedure, acetone, ethanol, isopropanol, and methanol are typically employed as solvents. Muller-Goymann and Schubert created SLNs by depending on the preparation conditions, this approach produced particles ranging in size from 80 to 300 nm [42]. Approximately 96.5% of the lipid used was converted into SLNs, and it appears that diffusion control is involved in the creation of SLNs.
2.3 Drying techniques of SLNs:
2.3.1 Spray drying
To turn an aqueous SLN dispersion into a dry product, spray drying could be a better method than lyophilization. Despite being less expensive than lyophilization, spray drying has not been utilized much for SLN formulation. Freitas used spray drying to create a redispersible powder that meets all of the specifications for intravenous injections, including those for ingredient selection and particle size [43]. Particle aggregation may result from spray drying's high temperatures, shear pressures, and partial melting of the particles. Freitas suggests using lipids for spray drying that have melting points of at least.708C. Furthermore, low lipid content and the inclusion of carbohydrates help to preserve the size of the colloidal particles during spray drying. Because ethanol–water combinations have lower inlet temperatures than pure water, they can be used as a dispersion medium to avoid lipid melting. The optimal outcome was attained with 1% SLN concentrations in solutions containing 30% trehalose in water or 20% trehalose in combinations of ethanol and water (10/90 v/v).
2.3.2 Lyophilization
Physical stability of SLN aqueous dispersions may be compromised with time, and storage may modify the drug's release characteristics. Such aqueous dispersions must be lyophilized or spray dried into a dry product in order to prevent these issues. Testing was done on the lyophilization and recrystallization of several SLN formulations. One option for SLN administration by IV is freeze-drying. Testing several kinds and concentrations of cryoprotectants (such as glucose, mannose, and trehalose) revealed that trehalose was the most successful in stopping the growth of particles during the freezing and thawing process as well as the freeze-drying procedure. Optimizing the freezing velocity and redispersion method, two key lyophilization process factors, could reduce the amount of particle size change that occurs during the process. The quality of SLNs for intravenous injection was reduced by loading with model drugs (tetracaine, etomidate) [44]; however, the lyophilisate quality was adequate for oral delivery. Another study freeze-dried injectable SLNs dispersions while maintaining their small particle size by maximizing crucial process variables such the use of cryoprotectants, freezing velocity, and heat treatment [45]. The diameter and zetapotential of SLNs containing azidothymidine palmitate do not significantly alter after autoclaving, lyophilizing, and reconstitution [46] Before freezing, the SLNs dispersions were diluted (1:1) with the 15%–30% w/w cryoprotectant solution. A 20 ml glass vial containing 5 ml of the diluted dispersion was used for gradual freezing on the freeze drier's shelves (shelf temperature: -25°C). Either adding the SLNs dispersion dropwise to the liquid nitrogen or submerging the entire vial containing the SLNs preparation in liquid nitrogen allowed for the sample to freeze quickly. When glucose and trehalose were used as cryoprotectants, fast freezing was shown to be the most successful technique; adding by dropwise method was marginally less effective than dipping the entire vial [44]. Before being used, lyophilized SLNs must be reconstituted. The usage of these kind of dispersions in clinics is made easier by redispersion through manual shaking. When trilaurin SLNs are formulated under ideal circumstances, it seems feasible to produce a manually redispersible product. Regarding the size distribution, lyophilized SLNs can be reconstituted at a quality deemed appropriate for intravenous injection. After reconstitution, Heiati et al. found that 100% of the drugs were retained in SLNs [46]. As a result, lyophilization and reconstitution of drug-loaded SLNs can be accomplished without appreciable alterations to size and zetapotential. Table 1 lists the several cryoprotectants that have been explored. To find the ideal concentration, multiple formulations of cryoprotectants are tested with varying concentrations (2.5%, 5%, 10%, 12.5%, and 15%).
3. Release of active compounds from SLN;
Mehnert, Muller, and Zur Muhlen [47-48] conducted extensive research on the effects of formulation parameters and production conditions on the release profile from SLN. For instance, they examined the release profile as a function of production temperature. In summary, they found that the release profiles were frequently biphasic, with an initial burst release followed by a prolonged release. The burst release was greatest when producing at the highest temperatures and using the hot homogenization method; it decreased with decreasing production temperature and was practically non-existent when using the cold homogenization method. The amount of surfactant used in the formulation could also control the burst release, with high surfactant concentration leading to higher burst release. This was explained by how the active ingredient was redistributed between the lipid and the water phase during the heating process and then cooled down after the hot oil in the water emulsion was produced during the hot homogenization process. When the lipid/water mixture is heated, the active ingredient divides from the melted lipid droplet to the water phase, becoming more soluble in the water phase. Following homogenization, the lipid core begins to crystallize while the oil in water emulsion cools down and there is still a sizable amount of active ingredient in the water phase. A solid core has already begun to form, leaving just the liquid outer shell for compound accumulation. Additional cooling causes the compound to become supersaturated in the water phase, at which point the molecule attempts to partition back into the lipid phase. This suggests that the burst effect is more noticeable the higher the solubility in the water phase during manufacturing. Both the manufacturing temperature and the surfactant concentration (which increases only after the surfactant solubilizes the active compound) cause the solubility to increase. As a result, when generating at low temperatures, low surfactant medium concentrations, or in surfactant-free mediums, little to no burst will be achieved.
4. Applications OF SLNs
4.1 Improved Bioavailability: By adding various poorly soluble medications to SLNs, their oral bioavailability was increased.Piribidil SLNs were produced by Demirel et al. and given orally to rabbits. When piribidil was given in SLNs, its bioavailability was enhanced more than twofold when compared to piribidil in its pure form [49]. After oral delivery to wis tar rats, the relative bioavailability of cyclosporin A stearic acid nanoparticles was about 80% as compared to the microemulsion technique. Cyclosporine A SLNs may have a lower bioavailability than microemulsion because of their 10-fold larger particle size [50]. Rats given idarubicin SLNs intraduodenally had better bioavailability than rats given idarubicin solution [51].
4.2 Cosmetic application: While UV-B radiation (290–320 nm) causes skin burns,erythema, and the development of cancer, UV-A radiation (320–400 nm) promotes elasticity loss and accelerated aging (wrinkles). UV blockers work through both physical (UV reflection) and chemical (absorbance) mechanisms. SLNs are presented as the next generation of makeup carriers, particularly for UV blockers. Without the need of chemical sunscreens, photo protection can be achieved by the crystalline cetylpalmitate SLNs' inherent capacity to reflect and scatter UV rays. Sunscreens provide synergistic photo protection when added to SLNs. Adding the molecular sunscreen 2-hydroxy-4-methoxy benzophenonoe (Eusolex 4360) to the SLNs dispersion tripled the impact of photoprotection. It is also possible to incorporate physical sunscreens (such titanium dioxide) into the composition of SLNs. When SLNs were compared to conventional emulsions, they demonstrated better UV light reflectance. Molecular sunscreens have a synergistic effect on absorption capacity in addition to being an additive [52]. Compared to similarly sized emulsions, the rate of release was demonstrated to be reduced by up to 50% when the molecular sunscreen oxybenzone was included into SLNs [53]. The tape stripping method was used to measure the drug's penetration into the stratum corneum. The type of formulation was found to have a significant influence on the rate of release. According to in vivo experiments, the emulsion released and allowed oxybenzone to enter human skin more quickly and thoroughly. Sunscreen stays longer on the skin's surface, where it is meant to, thanks to SLNs' ability to create a sustained release carrier system.
4.3 Adjuvant to vaccines:
In order to boost the immune response, adjuvants are added to vaccines. Fluid and adjuvanted vaccinations with aluminum hydroxide were less durable against heat inactivation than polymer vaccines [54]. Because they are in a solid state, the lipid components in SLNs break down more gradually, giving the immune system a longer period of exposure. Sterically stabilizing surfactants that prevent enzyme complexes from anchoring can still be used to slow down degradation. SLNs have advantages over conventional adjuvants due to their biodegradation and superior body tolerance [55]. Lysozyme is a model peptide that Almeida et al. attempted to include in SLNs. The majority of SLNs excipients do not seem to harm protein molecules when in contact with lysozyme. SDS-PAGE, or sodium dodecyl sulfate-polyacrylamidegel electrophoresis, was used to validate this [56].
4.4 The SLN application as a nucleic acid vaccine: The increasing usage of nucleic acid vaccinations is driving the demand for novel delivery strategies to improve the stability and efficacy of DNA vaccines. SLNs are a particular kind of particle carrier system made up of a solid lipid core and a cationic lipid surface that can attach to negatively charged DNA. SLN delivery techniques can enclose DNA to create an SLN/DNA combination, or "lipoplex," which may one day be used as a vaccine [57].
4.5 The SLN application in cancer therapy: Doxorubicin may be delivered to breast cancer cells via the magnetic SLN. A SLN made of iron oxide coated with tripalmitin and stearic acid was created by Soltani et al. This SLN nanoparticle was loaded with doxorubicin using an emulsification dispersion-ultrasonic method. Due to the interaction between the drug and the magnetic nanoparticles, the magnetic SLN may have an impact on the drug's release. Moreover, the cultivated tumor cell line was not cytotoxically affected by encapsulated doxorubicin. Doxorubicin was therefore successfully delivered into the breast cancer cell by means of this magnetic SLN [58].
4.6 The SLN application in ophthalmology: A PEGylated carrier containing latanoprost was used in a study to improve contact lens potential and preservation. The spherical-shaped latanoprost PEGylated SLNs (LP-pSLNs) showed a zeta potential of –29.1 to –26.7 mV with a size range of 105–132 nm. When compared to non-PEGylated SLN and other regular contact lenses, the LP-pSLN could eliminate the contact lens's bulge, transmission, and stickiness [59].
4.7 The SLN application in wound healing: In one trial, SLNs containing the hydrophobic medication simvastatin were used to treat wounds. Drug molecules may become more soluble in SLN-simvastatin and release more gradually over a period of up to three days. Additionally, in this study, SLN and a hydrogel were mixed to generate an appropriate platform with the porosity, flexibility, elasticity, and exudate management needed for wound healing. The toxicity of SLN-hydrogel was assessed in vitro. The findings showed that no signs of inflammation or toxicity were found. In an animal model, perfect wound recovery was observed for up to eleven days; the wound healed ten times better than with iodopovidone disinfection [60].
Figure3: Biological Applications of SLNS [61]
5. CONCLUSION:
SLNs are a viable substitute for colloidal drug delivery methods. Controlled release and entrapment efficiency can be attained by choosing the right lipid matrices, such as triglycerides, and emulsifier concentrations. A good technique for making SLNs is high-pressure homogenization, which is also easily scaled up for large-scale industrial production. High pressure homogenization techniques can be used to integrate both hydrophilic and lipophilic medicines into solid-liquid nanoparticles (SLNs). SLNs can be sterilized by autoclaving, much like with other parental dose forms. It is feasible to obtain a powder form through lyophilization of an aqueous dispersion of SLNs, which can then be added to gels or creams or transformed into a tablet or capsule depending on the needs. In comparison to other colloidal drug delivery methods, the entrapment effectiveness and loading capacity of SLNs are found to be satisfactory. Multiple routes of administration are available for carefully prepared SLNs. The circulation period of SLNs can be extended by adding hydrophilic polymers, such as polyethylene glycol, poloxamine 908, and poloxamer 407, to their surface. By combining SLNs with appropriate ligands, it is possible to target certain locations, such as brain and tumor cells.
REFERENCES
Nikhil Kumar*, Dr. Sujit Kakade, Solid Lipid Nanoparticles; A Comprehensive Review of Preparation, Drying Techniques and Applications, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 3165-3181 https://doi.org/10.5281/zenodo.15285779
10.5281/zenodo.15285779
