Self-nanoemulsifying Drug Delivery Systems: Formulation Insights, Applications and Advances

Abhijit A Date; Neha Desai; Rahul Dixit; Mangal Nagarsenker

Disclosures

Nanomedicine. 2010;5(10) 

In This Article

Methods Used for Fabrication of Nanoemulsions

The methods used for fabrication of the nanoemulsions (Figure 1) are divided into high-energy emulsification methods or low-energy emulsification methods.

Figure 1.

Various methods for nanoemulsion fabrication.

High-energy Emulsification Methods

As the name suggests, high-energy emulsification methods make use of devices that use very high mechanical energy to create nanoemulsions with high kinetic energy. These methods include high-pressure homogenization and ultrasonic emulsification.

High-pressure homogenization is the most common method used for the fabrication of nanoemulsions. During high-pressure homogenization, the coarse macroemulsion is passed through a small orifice at an operating pressure in the range of 500 to 5000 psi. During this process, several forces, such as hydraulic shear, intense turbulence and cavitation, act together to yield nanoemulsions with extremely small droplet size. The resultant product can be resubjected to high-pressure homogenization until nanoemulsion with desired droplet size and polydispersity index is obtained.[4–7,15] Microfluidization employs a high-pressure positive displacement pump operating at very high pressures, up to 20,000 psi. This pump forces macroemulsion droplets through the interaction chamber consisting of a series of microchannels. The macroemulsion flowing through the microchannels collides with high velocity on to an impingement area resulting in very fine nanoemulsions. The nanoemulsions with desired size range and dispersity can be obtained by varying the operating pressure and the number of passes through interaction chambers like high-pressure homogenization.

Ultrasonic emulsification uses a probe that emits ultrasonic waves to disintegrate the macroemulsion by means of cavitation forces. By varying the ultrasonic energy input and time, the nanoemulsions with desired properties can be obtained. High-energy emulsification methods can be employed to fabricate both O/W and W/O nanoemulsions. High-pressure homogenization and microfluidization can be used for fabrication of nanoemulsions at laboratory and industrial scale, whereas ultrasonic emulsification is mainly used at laboratory scale.[4–7]

Although high-energy emulsification methods yield nanoemulsions with desired properties and have industrial scalability, they may not be suitable for thermolabile drugs, such as retinoids and macromolecules, including proteins, enzymes and nucleic acids.[16,17] Furthermore, high-energy methods require sophisticated instruments and extensive energy input, which considerably increases the cost of nanoemulsions fabrication. This is particularly significant in the pharmaceutical sciences. Hence, researchers started focusing on the low-energy emulsification methods for fabrication of nanoemulsions.

Low-energy Emulsification Methods

As the name suggests, low-energy emulsification methods require low energy for the fabrication of nanoemulsions. These methods are mainly dependent on modulation of interfacial phenomenon/phase transitions and intrinsic physicochemical properties of the surfactants, coemulsifiers/cosurfactants and oil to yield nanosized emulsion droplets. The most commonly used low-energy emulsification methods are given below.

Phase Inversion Temperature Method The phase inversion temperature (PIT) method was first described by Shinoda and Saito as an alternative to high shear emulsification methods.[18,19] The method employs temperature-dependent solubility of nonionic surfactants, such as polyethoxylated surfactants, to modify their affinities for water and oil as a function of the temperature. It has been observed that polyethoxylated surfactants tend to become lipophilic on heating owing to dehydration of polyoxyethylene groups. This phenomenon forms a basis of nanoemulsion fabrication using the PIT method. In the PIT method, oil, water and nonionic surfactants are mixed together at room temperature. This mixture typically comprises O/W microemulsions coexisting with excess oil, and the surfactant monolayer exhibits positive curvature. When this macroemulsion is heated gradually, the polyethoxylated surfactant becomes lipophilic and at higher temperatures, the surfactant gets completely solubilized in the oily phase and the initial O/W emulsion undergoes phase inversion to W/O emulsion. The surfactant monolayer has negative curvature at this stage.[4–7,15] At an intermediate temperature (also termed hydrophilic–lipophilic balance [HLB] temperature), the nonionic surfactant has similar affinity for aqueous and oily phase, and this ternary system has extremely low interfacial tension (in the order of 10−2–10–5 mNm−1) and spontaneous curvature typically reaches zero. The ternary system at this stage typically consists of a D-phase bicontinuous microemulsions[4–6,15] or a mixture of a D-phase bicontinuous microemulsion and lamellar liquid crystalline phases.[20–22] It has been observed that nanoemulsions with very small droplet size and polydispersity index can be generated by rapid cooling of the single-phase or multiphase bicontinuous microemulsions maintained at either PIT or a temperature above PIT (transitional-phase inversion).[20–22] This phenomenon has been explained in greater detail in the review by Solans et al..[5] Nanoemulsions can also be generated by rapidly diluting the single bicontinuous microemulsions with the aqueous or oil phase (catastrophic phase inversion) to obtain either O/W nanoemulsion or W/O nanoemulsion. It has been observed that the characteristics of the nanoemulsion are mainly dependent on the structure of the surfactant at HLB temperature (bicontinuous or lamellar) and also on the surfactant/oil ratio.[4–6,20–22] Initially, PIT method was believed to be useful for fabricating O/W nanoemulsions. However, in recent years, the application of the PIT method has been established for fabricating W/O emulsions and nanoemulsions.[23,24] It is noteworthy that use of lipophilic polyethoxylated surfactants and appropriate modifications in the typical PIT protocol are required for obtaining W/O nanoemulsions.[23,24] A detailed discussion of the formation of W/O nanoemulsions using the PIT method is beyond the scope of this article.

It should be noted that the step of rapid cooling or dilution of the single-phase or multiphase bicontinuous microemulsion is important as polydisperse emulsions with greater propensity to coalescence have been obtained when rapid cooling or dilution was not performed.[4–6,15] Extensive investigation on the various aspects of the PIT method, such as the influence of component properties and ratio, electrolyte concentration, temperature and mechanisms of PIT nanoemulsification, have been reviewed elsewhere.[4–6] In short, the PIT method has gained great interest in colloidal science owing to its simplicity. However, the PIT method does involve heating of the components and it may be difficult to incorporate thermolabile drugs, such as tretinoin and peptides, without affecting their stability. Although it may be possible to reduce the PIT of the dispersion using a mixture of components (surfactants) with suitable characteristics, in order to minimize degradation of thermolabile drugs, such examples using pharmaceutically acceptable components have not been reported. Recently, Anton et al. have described fabrication of nanoemulsions that contain reverse micelles loaded with hydrophilic drug.[25] This approach may be useful for incorporating labile drugs, nucleic acids and peptides in nanoemulsions using the PIT method.

Solvent Displacement Method The solvent displacement method for spontaneous fabrication of nanoemulsion has been adopted from the nanoprecipitation method used for polymeric nanoparticles. In this method, oily phase is dissolved in water-miscible organic solvents, such as acetone, ethanol and ethyl methyl ketone.[26,27] The organic phase is poured into an aqueous phase containing surfactant to yield spontaneous nanoemulsion by rapid diffusion of organic solvent. The organic solvent is removed from the nanoemulsion by a suitable means, such as vacuum evaporation. Bouchemal et al. have studied various factors that influence fabrication of nanoemulsion by the solvent displacement method.[26] Interestingly, spontaneous nanoemulsification has also been reported when solution of organic solvents containing a small percentage of oil is poured into aqueous phase without any surfactant. This phenomenon is known as the 'Ouzo effect'.[27] This phenomenon has mainly been used for fabricating polymeric nanoparticles or nanocapsules using nanoemulsion as a template.[15,27] Solvent displacement methods can yield nanoemulsions at room temperature and require simple stirring for the fabrication. Hence, researchers in pharmaceutical sciences are employing this technique for fabricating nanoemulsions mainly for parenteral use.[28] However, the major drawback of this method is the use of organic solvents, such as acetone, which require additional inputs for their removal from nanoemulsion. Furthermore, a high ratio of solvent to oil is required to obtain a nanoemulsion with a desirable droplet size. This may be a limiting factor in certain cases. In addition, the process of solvent removal may appear simple at laboratory scale but can pose several difficulties during scale-up.

Phase Inversion Composition Method (Self-nanoemulsification Method) This method has drawn a great deal of attention from scientists in various fields (including pharmaceutical sciences) as it generates nanoemulsions at room temperature without use of any organic solvent and heat. Forgirani et al. observed that kinetically stable nanoemulsions with small droplet size (~50 nm) can be generated by the stepwise addition of water into solution of surfactant in oil, with gentle stirring and at constant temperature.[29] Although the components used in the aforementioned investigation were not of pharmaceutical grade, the investigation opened doors to design pharmaceutically acceptable nanoemulsions using a similar approach. The spontaneous nanoemulsification has been related to the phase transitions during the emulsification process and involves lamellar liquid crystalline phases or D-type bicontinuous microemulsion during the process.[5,15] Sadurni et al. studied spontaneous nanoemulsification of Cremophor® EL and Miglyol® 812 mixture and confirmed the occurrence of liquid crystals during the process by small-angle x-ray scattering.[30] It is important to study or know the phase behavior of the system in order to identify the conditions suitable for generating nanoemulsions by this process. It has also been established that physicochemical properties of the components and ratio of the surfactant to oil are major determinants of the properties of the nanoemulsion obtained by this method. The detailed mechanistic aspects of the self-nanoemulsification process can be found in various reviews.[5,15,31] It should be noted that the nanoemulsions obtained from the spontaneous nanoemulsification process are not thermodynamically stable, although they might have high kinetic energy and long-term colloidal stability.[5,30]

Recently, Anton and Vandamme, in an interesting investigation, demonstrated that the nanoemulsion generated by the spontaneous nanoemulsification method and PIT method may actually depend on the surfactant-to-oil ratio in the system.[32] In the same investigation, the authors have also established that nanoemulsions fabricated by solvent displacement technique have greater droplet size as compared with those fabricated by spontaneous nanoemulsification. However, more studies in this area will add information on how the method of preparation influences the properties of spontaneously formed nanoemulsions. In short, the spontaneous nanoemulsification method is a very attractive and low-cost option for fabrication of nanoemulsion. The following part of this article focuses on various aspects of spontaneously forming nanoemulsions or self-nanoemulsifying systems that are relevant to pharmaceutical sciences and drug delivery.

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