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

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


Nanomedicine. 2010;5(10) 

In This Article

Formulation Considerations & Potential Components

Successful formulation of SNEDDS depends on the thorough understanding of the spontaneous nanoemulsification process and also on the physicochemical and biological properties of the components used for the fabrication of SNEDDS. The factors influencing the phenomenon of self-nanoemulsification are:

  • The physicochemical nature and concentration of oily phase, surfactant and coemulsifier or cosurfactant or solubilizer (if included);

  • The ratio of the components, especially oil-to-surfactant ratio;

  • The temperature and pH of the aqueous phase where nanoemulsification would occur;

  • Physicochemical properties of the drug, such as hydrophilicity/lipophilicity, pKa and polarity.

These factors should receive attention while formulating SNEDDS. In addition, the acceptability of the SNEDDS components for the desired route of administration is also very important while formulating SNEDDS. Formulation considerations with respect to the components of SNEDDS are discussed below.

Oil Phase

The oil phase has great importance in the formulation of SNEDDS as physicochemical properties of oil (e.g., molecular volume, polarity and viscosity) significantly govern the spontaneity of the nanoemulsification process, droplet size of the nanoemulsion, drug solubility and biological fate of nanoemulsions and drug.[15,26,32,41,42] Usually, the oil, which has maximum solubilizing potential for the selected drug candidate, is selected as an oily phase for the formulation of SNEDDS. This helps to achieve the maximal drug loading in the SNEDDS. At the same time, the selected oil should be able to yield nanoemulsions with small droplet size. Hence, the choice of the oily phase is often a compromise between its ability to solubilize the drug and its ability to facilitate formation of nanoemulsion with desired characteristics. It is a known fact that oils with excessively long hydrocarbon chains, such as fixed oils (e.g., soybean oil) or long-chain triglycerides, are difficult to nanoemulsify, whereas oils with moderate chain length (medium-chain triglycerides) and oils with short chains (or low molecular volume), such as medium-chain monoglycerides and fatty acid esters (e.g., ethyl oleate), are easy to nanoemulsify compared with long-chain triglycerides.[30,32] The lipophilicity of the oil and concentration of oily phase in SNEDDS are directly proportional to the nanoemulsion size. Investigations by Anton and Vandamme,[32] and Sadurni et al.,[30] support the aforementioned statement. Interestingly, long-chain triglycerides have demonstrated great ability to improve intestinal lymphatic transport of drugs (responsible for preventing first-pass metabolism of drugs) compared with medium-chain tri-, di- and mono-glycerides,[42–45] whereas medium-chain mono- and di-glycerides have greater solubilization potential for hydrophobic drugs and permeation-enhancing properties.[42,46] Hence, it may be difficult for a single oily component to have optimum properties with respect to nanoemulsification and drug delivery. In certain cases, using a mixture of oils can also be used to meet optimum properties of the oily phase. A similar concept has been utilized for nanoemulsions and microemulsions. For example, a mixture of fixed oil and medium-chain triglyceride is used in certain cases to have good balance between drug loading and emulsification.[47] Recently, a mixture of oils has also been used for the fabrication of SNEDDS containing lacidipine, a calcium-channel blocker with low oral bioavailability.[48] Vitamin E (D-α-tocopherol) has gained great interest as an oily phase owing to its ability to solubilize drugs that are difficult to solubilize using conventional oily components, for example paclitaxel, itraconazole and saquinavir.[49] However, there are no reports on vitamin E-based SNEDDS, but there is a great scope to develop such systems. Recently, Nepal et al. also employed hard fats such as Witepsol H35 (hydrogenated coco glycerides) for the fabrication of SNEDDS owing to its excellent solubilization potential for coenzyme Q10 compared with the oils that are commonly used for SNEDDS.[50] Various oily components[51,52] available for SNEDDS are listed in Table 1.


The choice of surfactant is also critical for the formulation of SNEDDS. The properties of the surfactant, such as HLB (in oil), cloud point, viscosity and affinity for the oily phase, have great influence on the nanoemulsification process, self-nanoemulsification region and the droplet size of nanoemulsion.[40,48,53,54] The concentration of the surfactant in the SNEDDS has considerable influence on the droplet size of nanoemulsions.[30,53] The acceptability of the selected surfactant for the desired route of administration and its regulatory status (e.g., generally regarded as safe [GRAS] status) must also be considered during surfactant selection. It should be noted that the surfactants are not innocuous and they have favorable and/or unfavorable biological effects depending upon the chemical nature and the concentration of the surfactant. Many nonionic surfactants, such as Cremophor EL (polyethylene glycol [PEG]-35-castor oil), have the ability to enhance permeability and uptake of drugs that are susceptible to P-glycoprotein-mediated efflux.[55–57] However, these surfactants can also have structure-dependent, concentration-dependent and route of administration-dependent adverse effects; for example, Cremophor EL can cause anaphylactic shock and histamine release on parenteral administration,[58] whereas it is well tolerated on oral administration.[42] Certain surfactants might cause irritation to the GI mucosa and skin at higher concentrations. It is also noteworthy that the unfavorable characteristics associated with the surfactant might diminish after association with oily phase; for example, hemolytic ability of surfactants was greatly reduced after their association with oily phase in submicronic emulsions.[59] Cuine and coworkers have demonstrated that the surfactant structure and surfactant concentration can have an influence on the drug precipitation in the GI tract, which in turn influences the bioavailability of the drug.[60,61] Recently, it has been observed that surfactants like poloxamer 188 can slow down the in vitro lipid digestion process.[62] Thus, the selection of surfactant is crucial for the formulation of SNEDDS and the surfactant concentration in SNEDDS should be kept at a minimal level as far as possible. A variety of surfactants are available for formulation of SNEDDS, which can be used either alone or in combination to obtain SNEDDS yielding nanoemulsions with desirable characteristics while avoiding or minimizing unfavorable effects offered by surfactants. Table 2 lists various classes of surfactants with commercial names and acceptability for oral, parenteral and dermal routes.[51,52]

Coemulsifiers, Cosurfactants or Solubilizers

Coemulsifiers, cosurfactants or solubilizers are typically employed in the SNEDDS for pharmaceutical use. Table 3 gives the list of commonly used solubilizers.[51,52] They can be incorporated in SNEDDS for different purposes, including:

  • To increase the drug loading to SNEDDS;

  • To modulate self-nanoemulsification time of the SNEDDS;

  • To modulate droplet size of nanoemulsion.

Hence, surfactants (hydrophilic or lipophilic) and/or amphiphilic solubilizers with pharmaceutical acceptability are used for this purpose. The incorporation of the coemulsifiers or solubilizers in SNEDDS may result in an expanding self-nanoemulsification region in the phase diagrams. We have explored the potential of Akoline MCM® (short-chain mono- and di-glycerides) as a coemulsifier or cosurfactant in the SNEDDS.[40] Nepal et al. evaluated the potential of Lauroglycol™ FCC (propylene glycol dilaurate; HLB 4) as a coemulsifier in SNEDDS.[50] Amphiphilic solubilizers, such as propylene glycol, PEG and glycol ethers (diethylene glycol monoethyl ether or Transcutol® P), are often used in the SNEDDS to improve drug loading and time required for self-nanoemulsification.[48,63,64] In certain cases, short-chain alcohols, such as ethanol, have also been used by investigators.[65] However, while these solubilizers can improve drug loading into SNEDDS, they might compromise droplet size of the nanoemulsion in certain cases, as observed by Anton and Vandamme.[32]

Aqueous Phase

The droplet size and stability of nanoemulsion is influenced by the nature of aqueous phase where SNEDDS would be introduced. Hence, pH and ionic content of aqueous phase should be given due importance while designing SNEDDS. The physiological milieu has diverse pH ranges varying from pH 1.2 (pH in stomach) to 7.4 and greater (pH of blood and intestine). In addition, the presence of various ions in the physiological milieu can also have considerable effect on the properties of nanoemulsions generated from SNEDDS. It is well known that electrolytes can have influence on the nanoemulsion characteristics, such as droplet size and physical stability.[66] Hence, it is advisable to evaluate the self-nanoemulsification of the SNEDDS and the characteristics of the resultant nanoemulsion in aqueous phases with varying pH and/or electrolyte concentration (depending upon the type of application). In addition to plain water, Ringer's solution, simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 6.8) and phosphate buffered saline can be used as aqueous phase to evaluate spontaneous nanoemulsification of SNEDDS. Our studies indicate that the pH of the aqueous phase can have a dramatic influence on the phase behavior of the SNEDDS, especially when a drug with pH-dependent solubility is loaded in the system.[40]

Drug It is important to know that the therapeutic agent of interest can also have significant impact on the various aspects of SNEDDS, such as phase behavior and nanoemulsion droplet size. Various physicochemical properties of the drug, such as log P, pKa, molecular structure and weight, presence of ionizable groups and also the quantity have considerable effects on the performance of SNEDDS. In fact, we observed that the incorporation of the drug (cefpodoxime proxetil) in the SNEDDS reduces the nanoemulsification region when the aqueous phase is water.[40] However, when the pH of the aqueous phase is changed to pH 1.2, the nanoemulsification region increases as cefpodoxime proxetil has pH-dependent solubility. Furthermore, we observed that incorporation of a drug into SNEDDS can lead to an increase in the nanoemulsion droplet size compared with SNEDDS without drug.[40] Similar observations have been noted by Wang et al. for flurbiprofen SNEDDS.[54] The amount of drug incorporated in SNEDDS also has an influence on its properties. The droplet size of the nanoemulsion rises with increases in the amount of the drug. Surface active drugs, such as sodium salicylate, ascorbic acid and tricyclic amines, may show different behavior with increasing quantity. In our study, we observed an increase in the self-nanoemulsification region when the concentration of simvastatin was increased from 10 to 40 mg during phase behavior studies (Figures 2 & 3). These results suggested simvastatin may have mild cosurfactant activity at the interface of oil and water because of its amphiphilic nature.[53] Owing to the acidic nature of the self-nanoemulsifying system, simvastatin prodrug may get converted to simvastatin acid. In silico studies suggest that a greater number of rotatable bonds in simvastatin acid make the molecule flexible enough to interact with the surfactant and cosurfactant molecules. Flexibility of a molecule helps in forming a closed pack, stable interfacial film that yields highly stable nanoemulsions. In summary, properties and amount of the drug have a considerable influence on various aspects of SNEDDS, such as phase behavior and final droplet size.

Figure 2.

Phase diagram of self-nanoemulsifying system containing simvastatin 10 mg and ezetimibe 10 mg. (A) CAP, CRC and TP. (B) CAP, CRC and LAB. (C) CAP, CRC and SHS.
CAP: Capryol 90™; CRE: Cremophor EL®; LAB: Labrasol®; NE: Nanoemulsion; SHS: Solutol HS 15®; TP: Transcutol® P.
Reproduced with permission from [53].

Figure 3.

Phase diagram of self-nanoemulsifying system containing simvastatin 40 mg and ezetimibe 10 mg. (A) CAP, CRE and TP. (B) CAP, CRE and LAB. (C) CAP, CRE and SHS.
CAP: Capryol 90™; CRE: Cremophor EL®; LAB: Labrasol®; NE: Nanoemulsion; SHS: Solutol HS 15®; TP: Transcutol® P.
Reproduced with permission from [53].


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