**4.1. SMEDDS vs SNEDDS**

vase®) containing medium‐chain mono‐ and diglycerides, povidone and α‐tocopherol was able to increase bioavailability threefold higher than Invirase® in humans [23, 24]. Several other published [10, 25, 26] and unpublished case studies are also available that established the significance of rational approach in designing SMEDDS/SNEDDS which can improve the *in vivo* absorption of the PWSDs. The commercial product such as amprenavir (agenerase), ciprofloxacin (cipro), fenofibrate (fenogal), liponavir/ritonavir (kaletra, norvir), etc., have been

**Figure 1.** The encapsulated SNEDDS designed for oral administration of PWSDs. \*Adapted with permission from Ref.

The potentiality of nanoemulsions within lipid‐based drug delivery systems was explored almost four decades ago. In simple term, nanoemulsions are the emulsions comprising nanosized droplets and they are well dispersed, transparent and kinetically stable for several months. Their physical stability can be improved by careful selection of surfactants and the ratio of oil/water/surfactant and also the efficiency of equipment used to reduce droplet sizes.

**4. Concept of nanoemulsions within lipid‐based formulation**

formulated using suitable SMEDDS/SNEDDS [24, 27].

36 Advanced Technology for Delivering Therapeutics

[21].

SMEDDS and SNEDDS are almost similar lipid dosage form which can be prepared from same materials comprising a simple mixture of oils, surfactants and possibly cosolvents. SMEDDS have the ability to form fine oil in water (O/W) microemulsion, and SNEDDS produce nanoemulsion upon mild agitation in the presence of an aqueous (preferably intestinal) media [28]. The structure provides both SMEDDS and SNEDDS as good candidates for oral delivery of PWSDs with adequate solubility in oil only or oil/surfactant blends and establishes the desired reproducible pharmacokinetic profile. Upon dilution, SMEDDS form transparent microemulsions, with a droplet size of <50 nm [11], while SNEDDS produce transparent dispersions of oil and water stabilized by surfactants, with droplet sizes between 20 and 250 nm and kinetically but not thermodynamically stable systems [29]. These two systems are the most famous colloidal dispersions within lipid‐based systems but physicochemically different. Structures and properties of nanoemulsion can be changed on long‐term storage but not for microemulsions at same temperature, pressure and composition. The formation of SMEDDS is spontaneous, and SNEDDS need high‐energy methods for their fabrication, but both systems need some external energy to overcome kinetic energy barriers and support mass transport. In comparison, SNEDDS need lesser surfactant‐to‐oil ratio than SMEDDS. The preparation of SNEDDS involve specific mixing order in which surfactant must be mixed first with oil phase, whereas SMEDDS do not need any specific mixing order for their preparation. Ternary phase diagrams are required to have a suitable selection of both systems which should be coherent with different phases involved in preparation.

An important best‐known example is Sandimmune Neoral® which was introduced in 1994 became the turning point for development of SMEDDS in oral lipid‐based formulations of PWSD [30]. This formulation contains Cremophor RH40 (polyoxyl hydrogenated castor oil), corn oil glycerides, propylene glycol and ethanol, which emulsifies spontaneously into a microemulsion with a particle size smaller than 100 nm. This new formulation (Sandimmune Neoral®) resulted in a twofold increase in the bioavailability compared to the earlier product Sandimmune® [31]. Recent years, SMEDDS and SNEDDS have gained lots of interest as potential drug delivery vehicles largely due to their clarity, simplicity of preparation, thermo‐ dynamic stability and their abilities to be filtered and to incorporate a wide range of drugs of varying lipophilicity.

## *4.1.1. SMEDDS/SNEDDS within lipid formulation classification systems*

By considering several factors in mind, Pouton [20, 32] introduced a lipid formulation classification system (LFCS) into four Types (I–IV) which differentiate lipid‐based formula‐ tions from one to another that is being used as a framework to categorize nanoformulations. These four Types of formulations were classified on the basis of formulation compositions, their aqueous dispersibility and the potential effects of lipid digestion and possible drug precipitation from lipids. Among the LFCS, Type III systems are the most attractive formula‐

tions as they produce microemulsions/nanoemulsions (SMEDDS and SNEDDS) of lipid‐ surfactant mixtures with particle sizes in the range of 0–250 nm upon dispersion. The microemulsions can be used for many other drug delivery/application systems, such as topical, intra venous, trans‐dermal, etc. There are several marketed products available which were developed as Type III formulations since the drugs may be absorbed from the microemulsions and or nanoemulsions without the digestion of lipids and/or surfactants present. Type III systems further divided into subtype IIIA and IIIB according to the hydrophilic content of the SMEDDS and SNEDDS. Type IV systems are efficient formulations as they also produce SMEDDS and/or SNEDDS and have high drug loading ability but may loss solvent capacity upon dilution with aqueous media.

## **4.2. Solidification of SMEDDS/SNEDDS**

The excipients commonly used in designing SNEDDS are liquid at room temperature, and their compatibility with semi‐solid and solid dosage forms allows encapsulating into soft/hard gelatin capsules for oral delivery. This could be a great challenge as the interaction between liquid formulation and capsule shell may result in either brittleness or softness of the shell [33]. In addition, the stability of liquid formulations could be another major issue (e.g., leaching and rancidity) since some drugs might suffer significant chemical instability in both aqueous and oily formulations. Apart from that, manufacturing liquid‐filled soft gelatin capsules is a slow process and requires specialized equipment, having risk of formulation components migrating into capsule shell [23].

Therefore, to address this limitation, incorporation of liquid lipid formulations into a solid dosage form is convincing and desirable. Liquid lipid formulations could be transformed into acceptable free flowing fine powder by loading the formulation on a suitable solid carrier as solid SNEDDS [34, 35]. Only few studies have attempted to investigate the conversion of such formulations into free flowing powders by adsorption using various inorganic high surface area materials (i.e., neusilin, syloid, aeroperal and aerosol) that are amenable to encapsulation or tableting [36, 37]. On the other hand, the final powder preparation should have acceptable flow properties to achieve the best content uniformity and weight variation. The current interest in solidification technique by both the industry and academia is raised enormously due to the attractive properties including independence of gastric transit, flexibility in dose dividing, decrease in intra‐ and inter‐subject variability, highest safety profile and physical/ chemical stability improvement.
