**3. Advantages, disadvantages and major challenges of nanoemulsions as drug delivery systems**

The advantages of nanoemulsions drug delivery systems include [56-58]:


may be sufficient. Nanoemulsions are usually formulated with surfactants, which are approved for human consumption (GRAS), they can be taken by enteric route.


#### **3.1. Major challenges**

**• Melt granulation:** Melt granulation or pelletization is a one step-process allowing the transformation of a powder mix (containing the drug) into granules or spheronized pellets. The technique needs high shear mixing in presence of a meltable binder. This is referred to as "pump-on" technique. Alternatively, the binder may be blended with the powder mix in its solid or semi-solid state and allowed to melt (partially or completely) by the heat generated from the friction of particles during high shear mixing referred to as "melt-in" process. The melted binder forms liquid bridges with the powder particles that shape into small agglomerates (granules) which can, by further mixing under controlled conditions

**• Melt extrusion/Extrusion spheronization:** It is a solvent-free process that allows high drug loading (60%) as well as content uniformity. Applying extrusion-spheronization, SE pellets of diazepam and progesterone and bi-layered cohesive SE pellets have been

**3. Advantages, disadvantages and major challenges of nanoemulsions as**

**•** The small size of the droplets allows them to deposit uniformly on substrates. Wetting, spreading and penetration may be also enhanced as a result of the low surface tension of

**•** The very small droplet size causes a large reduction in the gravity force and the Brownian motion may be sufficient for overcoming gravity. This means that no creaming or sedimen‐

**•** The small droplet size also prevents any flocculation of the droplets. Weak flocculation is prevented and this enables the system to remain dispersed with no separation. Nanoemul‐ sions are thermodynamically stable system and the stability allows self emulsification of the

**•** The small droplets also prevent their coalescence, since these droplets are elastic, surface

**•** Nanoemulsions are suitable for efficient delivery of active ingredients through the skin. The large surface area of the emulsion system allows rapid penetration of actives. It is non-toxic

**•** The transparent nature of the system, their fluidity (at reasonable oil concentrations) as well as the absence of any thickeners may give them a pleasant aesthetic character and skin feel.

**•** Unlike microemulsions (which require a high surfactant concentration, usually in the region of 20 % and higher), nanoemulsions can be prepared using reasonable surfactant concen‐ tration. For a 20 % o/w nanoemulsion, a surfactant concentration in the region of 5 – 10 %

and non-irritant so can be easily applied to skin and mucous membranes.

The advantages of nanoemulsions drug delivery systems include [56-58]:

the whole system and the low interfacial tension of the o/w droplets.

transform to spheronized pellets [48].

88 Application of Nanotechnology in Drug Delivery

prepared [54, 55].

**drug delivery systems**

tation occurs on storage.

fluctuations are prevented.

system

Although nanoemulsions provide great advantages as a delivery system, however they suffer for some major challenges and limitations which include [56-58]:


**•** Use of a large concentration of surfactant and cosurfactant necessary for stabilizing the nano droplets.

Plurol Oleique CC 497, Poloxamer 124 and 188, Softigen 701, 767, Labrasol, Cremophor EL, Tween 20, Tween 60, and Tween 80, etc. Components of nanoemulsion-based systems are associated with toxicity concerns. Large amounts of surfactants may cause gastrointestinal and skin irritation when administered orally and topically, respectively. Therefore, the proper selection of surfactants is essential. Rational use of the minimum concentration of the surfactant in the formulation is advocated. Nonionic surfactants are relatively less toxic than their ionic counterparts and typically have lower critical micelle concentration (CMCs). Also, o/w nanoemulsion dosage forms for oral or parenteral use based on nonionic surfactants are likely to offer *in vivo* stability [64]. Therefore, proper selection of surfactants is a crucial factor. Another important criterion is the selection of surfactant with proper hydrophile-lipophilebalance (HLB) value. Hydrophilic surfactants and co-surfactants are considered to prefer the interface and to lower the necessary energy to form the nanoemulsions, thereby improving the stability. For instance, the required HLB value to form o/w nanoemulsion is greater than 10 [65]. The right blend of low and high HLB surfactants leads to the formation of a stable nanoemulsion upon dilution with water. The type and nature of the surfactant is also an important factor for consideration; nonionic surfactants are usually selected since they are known to be less affected by pH and changes in ionic strength, are generally regarded as safe, and are biocompatible; ionic surfactants are less commonly used due to toxicological concerns. Solubilization of oil with the surfactant is also an important factor. It is not necessary that the same surfactant that has good solubilizing power for drugs would have equally good affinity for the oil phase. Surfactant–oil miscibility can thus give an initial indication on the possibility

Nanoemulsions — Advances in Formulation, Characterization and Applications in Drug Delivery

http://dx.doi.org/10.5772/15371

91

Cosurfactants are added to obtain nanoemulsion systems at low surfactant concentration [66]. Short-to medium-chain-length alcohols (C3–C8) are commonly added as cosurfactants, which further reduce the interfacial tension and increase the fluidity of the interface [67,68]. They also increase the mobility of the hydrocarbon tail and allow greater penetration of the oil into this region. Alcohols may also increase the miscibility of the aqueous and oily phases due to its partitioning between these phases. Co-surfactants used in nanoemulsions include Transcutol P, glycerin, ethyleneglycol, ethanol, propanol, ethanol, isopropyl alcohol, n-butanol, PEG 400, Carbitol, and propylene glycol. Nanoemulsion area is often used as the assessment criterion for the evaluation of cosurfactants. The larger the size of the nanoemulsion field, the greater

Moreover, the most important criterion for selection of all the nanoemulsion components is that all the excipients should be pharmaceutically acceptable for oral administration or topical

As nanoemulsions are non-equilibrated systems [69-71], and so their preparation involves the input of a large amount of either energy or surfactants and in some cases a combination of both. As a result, high energy or low energy methods can be used in their formulation [70]. Although high energy emulsification method is traditionally used for the preparation of nanoemulsion formulation but low emulsion emulsification method now create an attraction

application, etc., depending upon the requirement and falling under GRAS category.

of nanoemulsion formation with this system.

the nanoemulsification efficiency of the system.

**4.2. Methods of preparation of nanoemulsions**

