lipid carriers (NLCs) are a smart second-generation carrier system consisting of solid and liquid lipids. As we know, SLNs are the first-generation lipid nanoparticle that caused issue such as decreased drug encapsulation and storage instability. Later research turned towards the modification of SLNs that lead to the development of NLCs. This system consists of biodegradable and biocompatible lipids (solid and liquid); surfactants are approved for use in different drug delivery systems by regulatory authorities [16, 40]. NLCs have a whole range of unique benefits as compared to other systems such as higher drug loading capacity, more appropriate drug delivery system for various routes (topical, nasal, lung, ophthalmic, and parenteral), flexibility to modulate drug release, potential drug carrier in the future [41], minimal use of surfactants, etc. The usual diameter of NLCs range from 10 to 1000 nm. The amount of liquid lipid generally increases in such a way that nanoparticles evolve in the development of unusual shape, a non-perfect lattice, and create an amorphous structure. The solubility of the drug improves with the increase in the liquid lipid [42-45]. Nanorepair Q10 Serum (Dr. Rempler, Wedemark, Germany) and Nanorepair Q10 Cream (Dr. Rempler, Wedemark, Germany) were the first two marketed products of NLCs introduced by Muller in 1999/2009 and took 5 years to launch. More than 30 products are available in the market over the decades. The scientific community is also interested in the development of NLCs as an innovative drug delivery system. They are generally divided into three types and are described in Table 1.1 and shown in Figure 1.3.
Figure 1.2 A graphical representation of solid lipid nanoparticle.
Table 1.1 Types of NLCs classified based on structure.
| S. No. | Types | Description |
| 1. | Imperfect type | Disordered structure.The lipid arrangement between the crystal and the liquid lipid is unordered, which enhances the drug’s capacity to penetrate. |
| 2. | Amorphous type | Lack of crystalline structure, which prevents/decreases drug leakage. |
| 3. | Multiple type | Provides higher levels of liquid lipid than other systems.Achieves slow drug release and high drug loading capacity, thereby avoiding decomposition of solid lipid.Similar to w/o/w microemulsion. |
Figure 1.3 Type of the nanostructured lipid carrier.
1.3.4 Nanoemulsion
Nanoemulsion is an o/w type of emulsion with an average droplet diameter of 50–500 nm. The term “nanoemulsion” is used to define the dispersions of water and oil that are two immiscible liquids to form a thermodynamically stable and isotropically transparent system along with surface molecules involved in interfacial film formation. In addition, it should have an inner core of water or oil as an o/w or w/o emulsion. Nanoemulsion is composed of ingredients that are generally recognized as safe (GRAS) by FDA, approved surfactants for human use. The nanoemulsions consist of water-immiscible oil phase prepared under high shear pressure, or by mechanical extrusion system available throughout the world. Large-scale production of emulsion is easy. The use of nanoemulsion across various routes is favored due to their large surface area; thus, it is used for efficient drug delivery throughout the body [46]. Nanoemulsions are stable and have the ability to dissolve an increased amount of lipophilic drug along with certain vectors that prevent their enzyme degradation and hydrolysis [47, 48]. Reducing the size of droplets to nanoscale results in several fascinating physical properties such as visual transparency and peculiar elastic behavior. They are very promising in the non-material sector, as they are useful for the dispersion of deformable nanoscale droplets from fluid to highly solid and deformation of optical characteristic from opaque to nearly transparent [49].
Preparation of nanoemulsion contains oil and aqueous phase along with drug as well as surfactants/co-surfactant and additives. The physical and chemical characteristics of these components play an important role in formulation stability and their performances. The choice of surfactant must also be taken into account as per the hydrophilic lipophilic balance (HLB) and critical factor. Strong HLB (8-18) surfactants are used in nanoemulsion preparation, while surfactant with low HLB (3 to 6) can be used in w/o nanoemulsion preparation. The right combination of high and low HLB surfactants results in the formation of stable nanoemulsion.
The hybrid nanoemulsion preparation process combines low-energy emulsifying and high-energy emulsifying applications. Due to their drug solubilizing capacity in oil core without premature leakage, they are particularly preferred as the drug delivery system. The interactions between the lipid droplets on administration routes also reveal their targeting properties such as oral drug delivery, parental drug delivery, transdermal drug delivery, anticancer drug delivery, and vaccine drug delivery. Nanoemulsion can be used for both local and systematic targeting effectively, e.g., delivery through skin, lungs, brain, and ligand mediated drug targeting.
1.3.5 SMEDDS, SEDDS, and SNEDDS
Various techniques are used to increase the oral bioavailability of poor soluble drugs [50-52]. As it gives high degree of patient tolerance, the oral route is the main route in the chronic treatment of various kinds of diseases. Nonetheless, 50% of drugs are mainly obstructed by oral delivery due to their high lipophilicity [53]. In recent years, various types of lipid-based carrier system such as self-micro emulsifying drug delivery system (SMEDDS), self-emulsifying drug delivery system (SEDDS), and self-nano emulsifying drug delivery system (SNEDDS) are the most promising approaches for improving bioavailability of drugs that are in insoluble lipophilic phase [54]. SMEDDS often provides a different feature. SMEDDS is defined as isotropic formulation of fine oil-in water (o/w) microemulsion formed by surfactants, co-surfactants, or drug and lipid mixtures, when combined with gentle stirring in aqueous media. These systems are important in improving oral bioavailability and are of primary interest to researchers, as a result of being a potential drug delivery through the incorporation of a wide range of drug molecules inside the vehicle. SMEEDS produce clear microemulsions of less than 50 nm of oil concentration and surfactant with HLB>12. SEDDS have been used to enhance the absorption of the drug via oral route [55-59]. Such formulations form fine oils rapidly in water emulsion or micro-emulsions when diluted in water [60], which are responsible for a negative free energy demand for forming emulsion [61]. Therefore, SEDDS are quickly dispersed throughout the GI tract and offer the agitation required for emulsification due to stomach and small intestine motility. SEDDS comprise the combination of oil, surfactant, and other chemicals and drugs. The selection of the lipid and the surfactant is done with their maximum ratio for optimum self-emulsifying property for the formulation [62-65]. In addition, it has been often shown that surfactant blending has superior emulsifying properties in comparison with the use of one single hydrophilicity–lipophilicity balance (HLB)-containing surfactant to attain the HLB quality, essential in emulsification process. The smooth mixing of aqueous media produces emulsion in the
