Nanoemulsions: increasing possibilities in drug delivery

Surfactants

Three kinds of surfactants are used in the preparation of nanoemulsions to stabilize the system (Table 1) (8). Every surfactant molecule has two parts, a hydrophilic head and a hydrophobic tail. The surfactants are classified on the basis of the polar groups present in their heads.

A nonionic surfactant has no charge group present in its head. The ionic surfactants carry net charges. If the charge is negative in its head, the surfactant is called anionic and if the charge is positive, it is called cationic. Typical examples of aqueous soluble surfactants are nonionic surfactants (e.g., Tween 20) which are preferred because they are usually less irritating than the ionic ones (11). Biodegradable emulsifiers are used in parenteral nanoemulsions. Some biodegradable surfactants are emulsifier egg, soy lecithin, and the oleaginous substrate (e.g., soybean, safflower, structured triglycerides or miglyol oil) (12).

Oils and co-surfactants

Commonly used oils in nanoemulsion preparations are IPM (Isopropyl Myristate), glycryl triacetate, propylene glycol mono ethyl ether etc. Medium chain triglycerides (MCT) are preferred over long chain fatty acids (11). Different co-surfactants are sometimes used to consolidate the stabilization process (Table 2 lists the examples of oils and co-surfactants used in nanoemulsions) (9).

Microfluidization

It is a patented manufacturing technology where a device called microfluidizer is used (Figure 2). There is a high pressure displacement pump (500–20,000 psi) in this device which gets the materials pass through a chamber containing many microchannels. The materials move to an impingement area flowing through the microchannels and convert into very fine particles.

Figure 2

Basic concept of a microfluidizer [Regenerated from (17)].

The liquid phases (oil phase and aqueous phase) are processed in an inline homogenizer to give a coarse emulsion. Then the coarse emulsion is passed through the microfluidizer to obtain the fine nanoemulsion. This process is continued repeatedly until the desired particle size is obtained. The nanoemulsion is then filtered under nitrogen to remove the larger particles (2, 7).

High pressure homogenization

Oil in water nanoemulsions, containing oil portion <20%, can be prepared by this method. Anne Desrumaux and her team showed that average droplet diameters increase with increasing oil content because of the limitation on surface-active agents in the most oil concentrated emulsions due to the strong increase of the interfacial area created by the homogenising process. Moreover, the shear-thinning behavior of most oil-concentrated emulsions can be attributed to the formation of clusters or aggregates of droplets which eventually increases droplet size. As a result, producing nano sized droplets will not be possible in case of preparing W/O nanoemulsions by high pressure homogenization method (18). Here, very high pressure is applied on the system containing oil phase, aqueous phase and the surfactant. This process is done with the help of a high pressure homogenizer (Figure 3) or piston homogenizer (2). First, the micro particles enter the valve at a relatively low velocity. The pressure is then generated by the positive-displacement pump which provides a relatively constant rate of flow. The liquid, containing micro particles, flows between the valve and seat at high velocity. As the velocity increases, the pressure decreases at the same time. The fluid is finally discharged as homogenized nanoemulsion (18).

Figure 3

High-pressure homogenizer [Regenerated from (2)].

EIP and PIT method

The emulsion inversion point (EIP) method is a low-energy and spontaneous emulsification method. At a constant temperature, it results in diverting the intrinsic features of thermodynamically stable microemulsions or liquid crystals to be nano-structured by a progressive dilution with water or oil, respectively, for creating thermodynamically unstable but kinetically stable direct or inverse nanoemulsions. A small change in the water or oil proportion within the established microemulsion system will change the pattern of surfactant hydration and their affinity for the aqueous phase. As a result, instabilities are created in the microemulsion system which results in its breaking up into nano-emulsion (6, 19–23).

In the phase inversion temperature (PIT) method, temperature of the emulsion system is increased to change the solubilizing pattern of the surfactant (hydrophilic to lipophilic) which forms bicontinuous microemulsions followed by emulsion inversion. The process involves four steps (Figure 4). (a) Temperature is below the PIT, it presents a macro-emulsion and the nonionic surfactants, mostly hydrophilic. (b) Temperature is increased; the surfactants gradually become lipophilic and are solubilized by the oil phase. (c) Temperature is at the PIT, bicontinuous microemulsions form. (d) Temperature is brought above the PIT, the emulsion is inverted and water is dispersed into the mixture of oil and lipophilic surfactant. The system is then cooled rapidly using water dilution, making the surfactant hydrophilic instantaneously and inducing spontaneous and rapid migration to the aqueous phase. This turbulent displacement induces the generation of nanoemulsions (24).

Figure 4

Generation of nanoemulsions using the PIT method. A water/nonionic surfactant/oil system undergoes a phase inversion [Regenerated from (24)].

Sonication

Sonication is referred to as applying ultrasound energy to agitate particles in a sample. Emulsification by ultrasonic technology mainly occurs through two mechanisms. Firstly, the use of an acoustic field produces interfacial waves which become unstable, eventually resulting in the eruption of the oil phase into the water medium in the form of droplets. Secondly, the application of low frequency ultrasound causes acoustic cavitation, that is, the formation and subsequent collapse of microbubbles by the pressure fluctuations of a simple sound wave. Each bubble collapse (an implosion on a microscopic scale) event causes extreme levels of highly localized turbulence (Figure 5). The turbulent micro-implosions act as the very effective method of breaking up the primary droplets of dispersed oil into the droplets of sub-micron size (25, 26).

Figure 5

Emulsification by ultrasonic technology [Regenerated from (25)].

Methods of nanoparticle production from nanoemulsion template

Researchers are producing nanoparticles from different classes of drugs by nanoemulsification in order to give better pharmacological action and to ensure better drug delivery. Table 3 compiles the drugs from various classes that have been produced by nanoemulsification in recent researches which showed better results. The followings are the types of nanoparticles along with some manufacturing methods by nanoemulsification which seem to be very promising.

Oral delivery

Nanoemulsion can bring a great revolution in oral drug delivery system. It has overcome several limitations of the traditional systems. Drug solubility, rate of absorption, and targeted drug delivery were always the matters of concern during designing oral dosage forms. Nanoemulsified drug delivery system has come out with a one step solution for all of these problems. In case of drug solubility, both hydrophilic and lipophilic drugs can be solubilized in either O/W or W/O nanoemulsion which in turn ensures a better dissolution because of extremely small size of the particles having both hydrophilic and lipophilic units. Furthermore, these small particles can easily penetrate through the epithelial layer to ensure good rate of absorption of the drug. Small particle size facilitates the scientists to fix and control optimum dosing which prevents dose related toxicities. Therefore, nanoemulsion has created a new opportunity for the scientists to design poorly soluble and less bioavailable drugs in a more accurate way which could not be formulated through the conventional methods. Nanoemulsions have both hydrophilic and lipophilic units, thus different targeting moieties and drugs from various classes can be incorporated (36). These nanoemulsified drugs may even enter the cytoplasm and give more specific pharmacodynamic action inside the cell (cancer treatment). Thus it can be an ideal delivery system for drugs such as steroids, proteins, hormones, diuretic and antibiotics. Oils are effectively absorbed in the GIT through various lipid absorption mechanisms. Therefore, one of the best ways to increase the absorption of the protein drugs is to load them inside the oils so that the absorption of drugs can increase significantly along with the oil droplets (2, 36).

A recent research has been carried out in order to improve in vitro dissolution and in vivo absorption of itraconazole (ITZ), a poorly water-soluble drug, by means of novel pectin-based nanoparticles prepared from nanoemulsion templates. Nanoemulsion templates were prepared by a high-pressure homogenization method using pectin (high-methoxyl pectin HMP) as an emulsifier and chloroform as an oil phase. The in vivo absorption study in fasted rats demonstrated that pectin-based nanoparticles prepared from nanoemulsion templates could improve absorption of ITZ, which is about 1.3-fold higher than the ITZ commercial product. These findings suggested that HMP-based nanoparticles can be a promising formulation due to their high AUC₀–_{24 h} and C_max (37).

Topical delivery

Topical drug delivery has some advantages over the oral route which include no drug loss by first pass metabolism, no damage of the drug in GI environment, no gastric irritation, no unpleasant taste or difficulty to administer and no need of disintegration and dissolution step. The main difficulty regarding topical drug delivery is the skin barrier which prevents the drug entering the systemic circulation. Nanoemulsion-based topical drug delivery can significantly overcome this barrier. Usually, drugs penetrate through the skin in three routes which are hair follicle, sweat duct and directly through the stratum corneum. The small sized nanoparticles in nanoemulsions can pass through the pores easily (Figure 6). Moreover, the hydrophobic and hydrophilic units facilitate to penetrate through the hydrophobic stratum corneum as well as the hydrophilic sweat ducts. Ropinirole, a drug with low oral bioavailability and frequent dosing, shows better penetration and greater extended release when prepared as nanoemulsion gel. The relative bioavailability of ropinirole was found to be enhanced more than two folds than the conventional marketed gel (38). Nanoemulsion can be used effectively against dermatitis and psoriasis (39). Positively charged nanoemulsions were found to be better penetrable and performable than the negatively charged nanoemulsions because positively charged nanoparticles interact more with the negatively charged skin to penetrate through (40, 41).

Figure 6

Comparison of nanoemulsion with the conventional transdermal formulations in case of crossing skin barrier.

Ophthalmic delivery

Conventional eye drops as ophthalmic drug delivery result in poor bioavailability and pharmacological action because of lacrimal secretion and nasolacrimal drainage in the eyes. Tear drainage of the eyes transports the significant part of the administered drug via the nasolacrimal duct to the gastrointestinal tract. As a result, it may be absorbed, sometimes causing side effects. The drug needs to be in contact with the eyes for a longer period of time to overcome this problem. Other preparations like ointment or aqueous gels cause blurred vision. From this point of view, dilutable nanoemulsions are potent drug delivery for ophthalmic administration because of their numerous advantages as sustained effect and high ability of drug penetration into the deeper layers of the ocular structure and the aqueous humor (42). The use of nanoemulsion as ophthalmic drug delivery also solves the problems regarding drug solubility. Cationic nanoemulsions are better vehicles for ophthalmic drug delivery since they interact with the negatively charged corneal cells and improve drug absorption (43) (Figure 7). Dorzolamide hydrochloride, a potential antiglucoma drug, was prepared as ocular nanoemulsion in an investigation and found high therapeutic efficacy and prolonged effect (42).

Figure 7

Three advantages of cationic nanoemulsions for ophthalmic delivery [Regenerated from (43)].

Parenteral delivery

Drugs with low solubility are always considered unsuitable for parenteral administration, however, with the help of nanoemulsification techniques, they can now be formulated as parenteral dosage form. The use of biodegradable surfactants ensures good pharmacological action with no interference to the regular biological activities of the body. A recent research shows that Carbamazepine, a widely used anticonvulsant drug which is poorly soluble, can be prepared as nanoemulsion by spontaneous emulsification method containing 2 mg/mL where about 95% drug is released within 11 h (44). Another study shows that IV preparation of thalidomide (0.01%–0.05% w/w) by spontaneous emulsification releases 95% drug within 4 h (45).

Nanoemulsions as nanocarrier

The principle of nanocarrier is based on the idea that extremely small size of the nanoparticles can pass through the biological barriers. Nanocarriers are polymers, amphiphillic lipids or solid colloidal particles which enclose the targeted drugs. Some examples of nanocarriers are gold nanoparticles, ceramic nanoparticles, liposomes, solid lipid nanoparticles, polymer-drug conjugates and carbon nanotubes. There are several different techniques by which drugs can be enclosed in nanoparticles. Nanocarriers are engineered in such a way as it can evade the immunological response and deliver the drug to targeted tissues (46). Nanoemulsion system can be used as a means to prepare nanocarriers for entrapping the drug. Drugs can either be entrapped in nanocarriers or bound with the surface of nanocarriers. Various emulsification methods are being used to prepare the nanocarriers. Nanocarriers can even be used very effectively to deliver the drug crossing the Blood Brain Barrier (BBB) (47).