Self-nanoemulsifying drug delivery systems

Review Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances There has been a resurgence of interest in nanoemulsions for various pharmaceutical applications since low-energy emulsification methods, such as spontaneous or self-nanoemulsification, have been described. Self-nanoemulsifying drug delivery systems (SNEDDS) are anhydrous homogenous liquid mixtures consisting of oil, surfactant, drug and coemulsifier or solubilizer, which spontaneously form oil-in-water nanoemulsion of approximately 200 nm or less in size upon dilution with water under gentle stirring. The physicochemical properties, drug solubilization capacity and physiological fate considerably govern the selection of the SNEDDS components. The composition of the SNEDDS can be optimized with the help of phase diagrams, whereas statistical experimental design can be used to further optimize SNEDDS. SNEDDS can improve oral bioavailability of hydrophobic drugs by several mechanisms. The conversion of liquid SNEDDS to solid oral dosage forms or solid SNEDDS has also been achieved by researchers. Solid SNEDDS can offer better patient compliance and minimize problems associated with capsules filled with liquid SNEDDS. KEYWORDS: nanoemulsion n oral delivery n poor bioavailability n self-nanoemulsification n solid SNEDDS n SNEDDS

Nanotechnology has become a buzzword in pharmaceutical sciences and efforts are ongoing to extend its applications in various streams of pharmaceutical sciences. Nanotechnology has dramatically influenced drug delivery research over the last two decades and several nanoscale technologies/carriers have been and are being explored for improving therapeutic performance of drugs. The several ways by which nanoscale technologies can improve therapeutic efficacy of drugs are: Improving solubility of hydrophobic drugs; Improving permeability or transport of poorly permeable drugs (class III and IV drugs as per the Biopharmaceutical Classification System [BCS]); Modulating biodistribution and drug disposition of drugs;

lipid carriers, whereas polymeric nanocarriers encompass polymeric micelles, polymeric nanoparticles and nanocapsules, dendrimers and polymer–drug nanoconjugates. Inorganic nanocarriers include nanostructures containing various inorganic metals, for example iron oxide (magnetic) nanoparticles, gold nanoparticles, calcium phosphate nanoparticles and quantum dots, whereas drugs in nanoparticulate form can be used as nanosuspensions. All these colloidal nanocarriers are extensively being studied in drug delivery research and have demonstrated great potential in improving drug delivery by various routes of administration [1–3] . The present article focuses on nanoemulsions and more specifically on the spontaneously forming nanoemulsions or self-nanoemulsifying systems for oral drug delivery.

The nanoscale technologies can be broadly classified into: lipid-based nanocarriers, polymeric nanocarriers, inorganic nanocarriers, and drug nanoparticles or nanosuspensions [1] . Lipid nanocarriers include lipid core micelles, liposomes, microemulsions, nanoemulsions, solid lipid nanoparticles and nanostructured

Nanoemulsions Nanoemulsions are heterogeneous dispersions of two immiscible liquids (oil-in-water [O/W] or water-in-oil [W/O]) having a mean droplet size in the nanometric scale (typically 20–200 nm), regardless of method of preparation [4–7] . These heterogeneous dispersions were initially referred to as submicron emulsions, miniemulsions, ultrafine emulsions and unstable microemulsions [4–7] . However, terms such as submicron emulsions/miniemulsions do not clearly represent the size of the droplets and might be confused with the microemulsions that

10.2217/NNM.10.126 © 2010 Future Medicine Ltd

Nanomedicine (2010) 5(10), 1595–1616

Preventing degradation of drugs in physio logical milieu; Enabling targeted delivery of the drugs to the site of action.

Abhijit A Date1, Neha Desai1, Rahul Dixit1 & Mangal Nagarsenker† Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India † Author for correspondence: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (East), Mumbai - 400098, India Tel.: +91 222 667 0871 Fax: +91 222 667 0816 [email protected] 1

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are thermodynamically stable systems. The term ‘nanoemulsion’ clearly indicates the nanoscale size range of the emulsion droplets and is distinctly different from the term ‘microemulsions’. Owing to their characteristic size, some nanoemulsions are optically transparent and possess very high stability against sedimentation and creaming. These nanoemulsions possess low viscosity, very high interfacial area and can have long-term colloidal stability [4–7] . Unfortunately, on several occasions such nanoemulsions have been confused with microemulsions and are used as misnomers. It is important to know that microemulsions are thermodynamically stable systems, whereas nanoemulsions (even optically transparent high-kinetic-energy nanoemulsions) are nonequilibrium systems. Furthermore, unlike pharmaceutical microemulsions, which require a high surfactant concentration (usually ~20% and higher) to enable optimal drug delivery, nanoemulsions can be fabricated with a relatively small surfactant concentration of 3–10%. These interesting features of nanoemulsions have propelled scientists to explore applications of nanoemulsions in various fields, including pharmaceutical sciences.

Overview of nanoemulsions as a novel drug delivery system Nanoemulsions offer various advantages for different applications owing to their interesting properties. However, advantages of nano emulsions pertaining to pharmaceutical research are described below. Long-term colloidal stability Nanoemulsions can have long-term colloidal stability when fabricated using optimum conditions. Owing to this property, nanoemulsions can be used as drug carriers and can impart long shelf-life to the pharmaceutical product. Ability to solubilize hydrophilic & hydrophobic therapeutic agents Nanoemulsions have the ability to solubilize hydrophobic as well as hydrophilic drugs in their nanostructure depending on the type of nanoemulsion. The O/W nanoemulsions are used for improving delivery of hydrophobic drugs, whereas W/O nanoemulsions are preferred for incorporating hydrophilic drugs. Improved stability of the therapeutic agents Encapsulation of therapeutic agents in nanoemulsions can offer improvements in the 1596

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chemical and/or enzymatic stability of therapeutic agents, such as 10-methoxy-9-nitrocamptothecin [8] and cefpodoxime proxetil [9] , leading to improvement in shelf-life and/or therapeutic efficacy. Greater esthetic appeal & skin feel The low viscosity and transparent (or translucent) nature of nanoemulsions can offer good esthetic appeal, patient compliance and skin feel, and with suitable viscosity modifications, nanoemulsions could be used in patientfriendly ‘roll-on’-type formulations, sprays and nanoemulsion gels. Improved dermal & mucosal transport Nanoemulsions have demonstrated the ability to enhance the dermal, transdermal and mucosal transport/permeation of various drugs [10,11] . Improved oral bioavailability Nanoemulsions have demonstrated tremendous potential in improving oral bioavailability of several therapeutic agents, for example ramipril, ezetimibe, cefpodoxime proxetil and curcumin [9,12–14] . This aspect is discussed below in greater detail. Use as a template to fabricate nanoparticulate systems The large interfacial area and small droplet size of the nanoemulsions enable them to act as a template for facile fabrication of pharmaceutical nanoparticulate systems, such as solid lipid nanoparticles, polymeric nanoparticles/ na nocapsules and drug nanosuspensions [15] . Ease of manufacture & scale-up The methods employed for the fabrication of nanoemulsions enable ease of manufacturing and scale-up of nanoemulsions. Limitations of the nanoemulsions Nanoemulsions are not very suitable for controlled drug release applications. Furthermore, the palatability of the nanoemulsion components and compatibility with other excipients could be a major limiting factor in the case of oral drug delivery.

Methods used for fabrication of nanoemulsions The methods used for fabrication of the nano emulsions (F igur e 1) are divided into highenergy emulsification methods or low-energy emulsification methods. future science group

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Nanoemulsion fabrication methods High-energy emulsification methods Ultrasonification

Using microfluidizers

High-pressure homogenization

Low-energy emulsification methods Phase inversion temperature method

Solvent displacement method

Phase inversion composition method

Using high-pressure homogenizers

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 homo genization, 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 nano emulsions 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 macroe mulsion 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] . future science group

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 temperaturedependent 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 www.futuremedicine.com

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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 (transitionalphase 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 1598


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. future science group


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 nano emulsions 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 future science group

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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 selfnanoemulsifying systems that are relevant to pharmaceutical sciences and drug delivery.

Spontaneously forming nanoemulsions or selfnanoemulsifying drug delivery systems for oral drug delivery The oral route is the most convenient and preferred route of drug delivery as it offers a high degree of patient compliance. However, 50% of drugs delivered via the oral route have limited therapeutic efficacy owing to poor water solubility [33] . Furthermore, a majority of the new chemical entities being generated through drug discovery programs also exhibit poor water solubility. The problems associated with such drugs include poor oral bioavailability, erratic absorption profile, high intra- and inter-subject variability and lack of dose proportionality [34] . Furthermore, drug candidates with high water solubility and poor permeability, such as atenolol and metformin (belonging to BCS class III), also exhibit low oral bioavailability and ultimately low therapeutic efficacy. Similarly, most of the therapeutic peptides, such as insulin and calcitonin, are difficult to deliver via the oral route owing to their extreme hydrophilicity, poor permeability and instability in the gastrointestinal (GI) environment. Conventional techniques, such as salt formation, micronization and solubilization using cosolvents, use of permeation enhancers [35] , oily solutions and surfactant dispersions [36] , that were previously employed to increase the oral bioavailability have shown limited utility. Although recently developed strategies, such as solid dispersion technology [37] and inclusion complexes employing cyclodextrins [38] , exhibit good potential, they are successful in some instances and are specific to drug candidates. The ability of nanosized emulsions or sub micronic emulsions to improve the GI absorption of hydrophobic drugs was demonstrated almost three decades ago [39] . However, the use of submicronic emulsions or nanoemulsions in oral delivery was limited owing to disadvantages such as poor palatability due to their www.futuremedicine.com

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lipidic composition. Furthermore, nanoemulsions would have to be consumed in a higher volume to achieve the necessary therapeutic concentration of drugs, for example carbamazepine and quercetin, which have limited solubility in all the oils with pharmaceutical acceptability. This may severely limit patient compliance. Nanoemulsions with high water content cannot be delivered through soft gelatin, hard gelatin or hydroxypropylmethylcellulose capsules for oral delivery. The water content of nanoemulsions may promote hydrolysis and/or precipitation of certain drugs on long-term storage, which could affect their utility in oral delivery. The advent of the spontaneous nanoemulsification approach has reinstated the interest of drug delivery scientist for exploring applications of nanoemulsions for oral drug delivery.

Self-nanoemulsifying drug delivery systems Self-nanoemulsifying drug delivery systems (SNEDDS) are nanoemulsion preconcentrates or anhydrous forms of nanoemulsion. These systems are anhydrous isotropic mixtures of oil, surfactant(s) and drug, which, when introduced into aqueous phase under conditions of gentle agitation, spontaneously form O/W nanoemulsions (usually with globule size less than 200 nm) [40] . In the body, the agitation required for formation of nanoemulsions is provided by digestive motility of the GI tract. SNEDDS can also contain coemulsifier or cosurfactant and/or solubilizer in order to facilitate nanoemulsification or improve the drug incorporation in SNEDDS. Compared with ready-to-use nanoemulsions, SNEDDS can offer advantages such as: Improved physical and/or chemical stability profile upon long-term storage; Possibility of filling them into unit dosage forms, such as soft/hard gelatin or hydroxypropylmethylc ellulose capsules (unlike ready-to-use nanoemulsions), which improves their commercial viability and patient compliance/acceptability; No palatability-related issues, as SNEDDS can be filled into capsules.

Formulation considerations & potential components Successful formulation of SNEDDS depends on the thorough understanding of the spontaneous nanoemulsification process and also 1600


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-tosurfactant 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 nano emulsions 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 future science group


[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-, diand mono-glycerides [42–45] , whereas mediumchain 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 nano emulsions 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-a-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

Review

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. Surfactants 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, selfnanoemulsification 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

Table 1. Commonly used oily phases. General class

Examples

Commercial name

Acceptability

Fixed oils MCTs

Soybean oil, castor oil Triglycerides of capric/caprylic acids

– Miglyol 810, 812, Labrafac CC Crodamol GTCC, Captex 300, 355 Captex 500 Capmul MCM, Imwitor 742 Akoline MCM Peceol, Capmul-GMO Maisine-35 Capryol 90, Capmul PG-8, Sefsol 218 Lauroglycol 90, Capmul PG-12, Lauroglycol FCC Miglyol 840, Captex 200 Crodamol EO Crossential O94

P/O/T/Oc/M P/O/T/Oc/M

Medium-chain mono- and diglycerides Long-chain mono-glycerides PG fatty acid esters

Fatty acid esters

Fatty acids Vitamins

Triacetin Mono- and di-glycerides of capric/ caprylic acids Glyceryl monooleate Glyceryl monolinoleate PG monocaprylate PG monolaurate/dilaurate PG dicaprylate/caprate Ethyl oleate Isopropyl myristate Isopropyl palmitate Oleic acid Caprylic acid Vitamin E

O/T O/T O/T O/T

P/O/T/Oc/M P/T/Oc/M P/T/Oc/M O/T/M O/T/M P/O/T/Oc/M

M: Mucosal; MCT: Medium-chain triglyceride; O: Oral; Oc: Ocular; P: Parenteral; PG:Propylene glycol; T: Topical (dermal). Adapted from [51,52].

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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 sub micronic 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. 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 diglycerides) as a coemulsifier or cosurfactant in the SNEDDS [40] . Nepal et al. evaluated

Table 2. Commonly used surfactants. General class

Examples

Commercial name

Acceptability

Polysorbates

POE-20-sorbitan monooleate POE-20-sorbitan monolaurate Sorbitan monooleate Sorbitan monolaurate Sorbitan monostearate Poloxamer 188 Poloxamer 407 POE-35-castor oil POE-40-hydrogenated castor oil

Tween® 80, Crillet 4 Tween 20, Crillet 1 Span® 80, Crill 4 Span 20, Crill 1 Span 60, Crill 3 Pluronic® /Lutrol F 68 Pluronic/Lutrol F 127 Cremphor® EL, Etocas 35 HV Cremophor RH 40, HCO-40, Croduret™ 40 LD Cremophor RH 60, HCO-60 Solutol HS 15® Vitamin E TPGS Labrafil® 2125 CS Labrafil 1944 CS Labrasol® Plurol® oleique CC 497 Gelucire® 44/14 Gelucire 50/13

P/O/T/Oc/M P/O/T/Oc/M P/O/T/Oc/M P/O/T/Oc/M O/T/M P/O/T/Oc/M O/T/Oc/M P/O/T/Oc/M P/O/T/Oc/M

Sorbitan esters PEO–PPO– block copolymers POE castor oil POE hydrogenated castor oil POE-stearate POE-vitamin E Sucrose esters Polyglycolyzed glycerides Phospholipids

POE-60-hydrogenated castor oil PEG-660-12-hydroxystearate Tocopheryl-PEG 1000-succinate Sucrose laurate Sucrose palmitate Linoleoyl macrogol glycerides Oleoyl macrogol glycerides Caprylocaproyl macrogol glyceride Polyglyceryl oleate Lauroyl macrogol glycerides Stearoyl macrogol glycerides Soybean lecithin

P/O/T/Oc/M P/O/T/Oc/M T/O/Oc/M O/T O/T O/T O/T O/T O/T O/T O/T All routes

M: Mucosal; O: Oral; Oc: Ocular; P: Parenteral; PEG: Polyethylene glycol; POE: Polyoxyethylene; T: Topical (dermal); TPGS: Tocopheryl polyethylene glycol 1000 succinate. Adapted from [51,52].

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Table 3. List of commonly used solubilizers. General class

Examples

Acceptability

Short-chain alcohols Alkane diols and triols

Ethanol, benzyl alcohol Propylene glycol Glycerol PEG 400 Diethylene glycol monoethyl ether (Transcutol®)

P/O/T/Oc/M P/O/T/Oc/M P/O/T/Oc/M P/O/T/Oc/M O/T

Polyethylene glycols Glycol ethers

M: Mucosal; O: Oral; Oc: Ocular; P: Parenteral; PEG: Polyethylene glycol; T: Topical (dermal). Adapted from [51,52].

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 nano emulsion 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] . future science group

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 www.futuremedicine.com

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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.

Component screening, optimization & characterization of SNEDDS As previously mentioned, the components of SNEDDS and their concentrations have profound effects on the various characteristics of nanoemulsions, such as droplet size, polydispersity index, self-nanoemulsification time and in vitro drug release. Hence, it is important to optimize the quantities of the SNEDDS components after initial selection. The initial selection of the components can be on the basis of their ability to solubilize the drug of interest and also on their ability to form spontaneous emulsions/nanoemulsions. We have developed a systematic protocol based on a simple turbidimetric method that evaluates emulsification efficiency or ease of emulsification ability of various excipients [40] . This protocol gives quick information regarding the potential components of SNEDDS and it has been adopted by a few other researchers [48,67] . After selecting potential components of SNEDDS, the phase behavior of the components should be studied to identify various phases and phase transitions. After studying phase behavior and identifying probable concentrations of the components that might yield spontaneous nanoemulsions, it is important to plot a ternary diagram with surfactant, oil and coemulsifier or solubilizer to identify the self-nanoemulsification region. The self-nanoemulsification region in the ternary A

B

TP 0.0 100.0 25.0

100.0 0.0 CAP90

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diagram is identified by evaluating droplet size of the emulsions/nanoemulsions resulting after diluting various compositions in the ternary diagram with the fixed amount of water. All the points in the self-nanoemulsification region yield spontaneous nanoemulsion with droplet sizes of approximately 200 nm or lesser. It is important to study the influence of the drug on the self-nanoemulsification region of the ternary diagram. We have observed that drugs such as cefpodoxime proxetil can considerably reduce the self-nanoemulsification region in the ternary diagram [40] . It is also important to study the influence of the pH of the aqueous phase on the self-nanoemulsification region. We have observed that the pH of the aqueous medium has considerable influence on the selfnanoemulsification region [40] . Thus, determination of the self-nanoemulsfication region (in addition to the phase behavior study) helps in the optimization of SNEDDS and also helps in finalizing the SNEDDS composition for in vitro and in vivo studies. The optimization of SNEDDS can also be accomplished with the help of optimization techniques, such as statistical experimental design or response surface methodology. The major advantage of the response surface methodology is that they can yield optimal SNEDDS (composition) with a minimal number of experiments without compromising the final product characteristics. In response surface methodology, the influence of several variables on the characteristics of SNEDDS (e.g., droplet size, self-nanoemulsification time and in vitro dissolution) can be studied with a limited number of experiments. The statistical analysis is used to identify the

25.0

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0.0 100.0 CRE

75.0 100.0 0.0 CAP90

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Figure 2. Phase diagram of self-nanoemulsifying system containing simvastatin 10 mg and ezetimibe 10 mg. (A) Capryol 90™, Cremophor EL® and Transcutol® P. (B) Capryol 90, Cremophor EL and Labrasol®. (C) Capryol 90, Cremophor EL and Solutol HS 15®. CAP: Capryol 90; CRE: Cremophor EL; LAB: Labrasol; NE: Nanoemulsion; SHS: Solutol HS; TP: Transcutol P. Reproduced with permission from [53] .

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A

B

TP 0.0 100.0 25.0

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NE

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SHS15 0.0 100.0

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NE 75.0

C

LAB 0.0 100.0

25.0 0.0 100.0 CRE

NE

75.0 100.0 0.0 CAP

50.0

25.0

50.0

25.0

75.0

0.0 100.0 CRE

Figure 3. Phase diagram of self-nanoemulsifying system containing simvastatin 40 mg and ezetimibe 10 mg. (A) Capryol 90™, Cremophor EL® and Transcutol® P. (B) Capryol 90, Cremophor EL and Labrasol®. (C) Capryol 90, Cremophor EL and Solutol HS 15®. CAP: Capryol 90; CRE: Cremophor EL; LAB: Labrasol; NE: Nanoemulsion; SHS: Solutol HS; TP: Transcutol P. Reproduced with permission from [53] .

impact of each variable on the characteristics of the SNEDDS. Once the mathematical correlation is established between the variables and the response, response surface methodology can be used to develop a product with desired characteristics. Thus, SNEDDS composition with much reduced self-nanoemulsification time, small droplet size and higher dissolution rate can be obtained with statistical experimental design techniques. Various optimization techniques such as Box-Behnken design and D-Optimal design have been employed by the investigators to optimize various characteristics of SNEDDS [48,68–71] . It is important to characterize the final SNEDDS for various parameters. The droplet size and polydispersity index, colloidal stability and self-nanoemulsification time of the SNEDDS as a function of extent of dilution and variation in the pH/electrolyte content of aqueous phase should be carefully studied. The zeta potential of the SNEDDS should be evaluated as it may further give an idea of the colloidal stability. The morphology of the nanoemulsion droplets can be evaluated by transmission electron microscopy. The SNEDDS should be characterized for in vitro dissolution profile in various dissolution media. The chemical stability of the drug in SNEDDS should be evaluated by carrying out long-term storage stability studies as per the guidelines suggested by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH guidelines). The effect of the SNEDDS on Caco-2 cell permeability and toxicity, and also on GI permeability, can be studied by in vitro future science group

techniques [72] . Recently, Fatouros and coworkers have developed an in vitro lipolysis model, which simulates digestion in the small intestine [73,74] . They successfully applied this model to study the digestion of the SNEDDS and propensity of drug precipitation. Interestingly, they could rank order various SNEDDS formulations on the basis of in vitro lipolysis and drug precipitation. This method would also help in optimizing/correcting SNEDDS formulation before subjecting it to in vivo efficacy or pharmacok inetic studies. Furthermore, this model could also be used for establishing in vitro and in vivo correlation of SNEDDS formulations.

Factors limiting oral bioavailability of drugs & potential of SNEDDS in oral drug delivery Dissolution rate-limited absorption As presviously described, approximately 40% of the existing therapeutic agents have poor solubility in physiological milieu. These therapeutic agents belong to BCS class II and IV (e.g., cyclosporine, celecoxib and artemether, among others). The poor dissolution rate of these compounds is responsible for the poor absorption from the GI tract. The components used for the fabrication of SNEDDS have high solubilization potential for various hydrophobic drugs. The drug solubilized in SNEDDS has a very high dissolution velocity compared with the pure drug. Furthermore, SNEDDS spontaneously present the drug in very fine nanodroplets offering very high surface area for absorption. This helps with quick absorption of the drug and improves oral bioavailability. www.futuremedicine.com

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Poor permeability Poor permeability is also one of the major factors that limits oral bioavailability of several drugs, such as atenolol and acyclovir (BCS class III). Owing to poor permeability, such drugs have to be administered at significantly higher doses. Interestingly, several SNEDDS components have the ability to enhance the membrane permeation of the therapeutic agents. For example, oily phases (e.g., oleic acid, monoglycerides of caprylic acid and propylene glycol esters of caprylic acid [46]), surfactants (e.g., Labrasol®, vitamin E tocopheryl polyethylene glycol 1000 succinate [TPGS] and polysorbate 80 [75–77]) and cosurfactants (e.g., PEG 400, Transcutol and alcohol [78]) are known to have permeationenhancing properties. Bruesewitz et al. have evaluated the effect of poloxamer-based nanoemulsions on Caco-2 permeability of various drugs, such as danazol (BCS class II), atenolol (BCS class III) and metoprolol (BCS class I) [79] . Interestingly, they observed that nanoemulsions could significantly improve the Caco-2 permeability of all these drugs without causing any appreciable damage/toxicity to Caco-2 cells. This clearly indicates the potential of SNEDDS in oral delivery. High degree of presystemic & hepatic first-pass metabolism Oral bioavailability of a vast number of molecules, such as antihypertensive and cardiovascular agents (b‑blockers, calcium-channel blockers and angiotensin-converting enzyme inhibitors), antihyperlipidemic agents (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors), antidiabetic agents (repaglinide) and antibiotics (cephalosporins), is limited by presystemic and/or hepatic first-pass metabolism. Several SNEDDS components including Gelucire ® 44/14 (lauroyl macrogol glycerides) and Labrasol (caprylocaproyl macrogol glycerides) have the ability to modulate/inhibit activity of cytochrome P450 and gut metabolizing enzymes [56,80,81] , whereas long-chain tri- and mono-glycerides (glyceryl monooleate) have demonstrated the ability to improve the intestinal lymphatic transport of the hydrophobic drugs [44,45] . Both these mechanisms are responsible for reducing/preventing the first-pass or presystemic metabolism of the drug resulting in improvement of oral bioavailability; for example, the oral bioavailability of cefpodoxime proxetil (an antibiotic with a high degree of gut metabolism) showed twofold improvement after encapsulation in submicronic emulsions [9] . We and others have also 1606


demonstrated that SNEDDS can improve the therapeutic efficacy/bioavailability of ezetimibe, a lipid-lowering agent with a high degree of presystemic metabolism [13,82] . P-glycoprotein efflux P-glycoprotein (P-gp) is an efflux pump present at several sites in the body, including the GI tract. P-gp prevents the entry of the drugs in the systemic circulation, thus hampering the oral bioavailability of the drugs. A considerable number of molecules, such as amphotericin B, paclitaxel, digoxin and doxorubicin, are known P-gp substrates and their bioavailability is hampered owing to the P-gp-mediated efflux. Many surfactants, for example vitamin E TPGS, Solutol® HS 15, Labrasol, Cremophor EL, Gelucire 44/14 (lauroyl macrogol glycerides) and Polysorbate 80, and oily phases, including Imwitor® 742 and Akoline MCM® (mono-, and di-glyceride of caprylic acid) and Peceol® (glyceryl monooleate), have the potential to inhibit P-gp efflux [57,83–86] . Hence, SNEDDS can also inhibit the P-gp efflux process and improve oral bioavailability of drugs.

Advantages of SNEDDS in oral delivery Reduction in inter- & intra-subject variability & food effects There are several drugs, such as cyclosporine and ezetimibe, that show large inter- and intra-subject variation in absorption leading to decreased performance of the drug and patient noncompliance. It has been demonstrated that fed and fasted state dissolution media have negligible effects on the droplet size of the SNEDDS [65] . Hence, it can be anticipated that SNEDDS (fabricated with proper optimization) can offer a reduction in ratio of bioavailability between fed and fasted state and can offer reproducibility in plasma profiles of drugs in fed and fasted conditions. Nielsen et al. demonstrated that bioavailability of probucol is not affected by fed and fasted state in minipigs when administered as SNEDDS, whereas powder formulation shows considerable variation in fed and fasted state bioavailability [87] . Quick onset of action Quick onset of action is required in many conditions, such as inflammation, hypertension and angina. SNEDDS can facilitate oral absorption of the drug, which would result in quick onset of action. The comparative pharmacokinetic analysis of SNEDDS to conventional formulation has future science group


demonstrated that there is considerable reduction observed in t max (an indirect measure of quick onset of action) in case of SNEDDS [50] . Reduction in the drug dose The ability of the SNEDDS in improving Cmax and oral bioavailability or therapeutic effect has been established for various hydrophobic drugs. The improvement in bioavailability can be translated into reduction in the drug dose and dose-related side effects of many hydrophobic drugs, such as antihypertensive and antidiabetic drugs. Ease of manufacture & scale-up Ease of manufacture and scale-up is one of the most important advantages that make SNEDDS unique when compared with other novel drug delivery systems, such as solid dispersions, liposomes and nanoparticles. SNEDDS require very simple and economical manufacturing facilities, such as simple mixer with an agitator and volumetric liquid filling equipment for large-scale manufacturing.

SNEDDS: potential explored The ability of SNEDDS to improve oral delivery of several therapeutic agents (belonging to various therapeutic classes) has been established by various in vitro and/or in vivo methodologies. The potential mechanisms responsible for improvement in oral bioavailability by SNEDDS are shown in Figure 4. Most of the investigations described so far have evaluated the pharmacokinetics of the drug when incorporated in SNEDDS and very few investigations

Review

have demonstrated pharmacodynamic efficacy. Although pharmacokinetic studies are sufficient to establish proof of concept for SNEDDS, the results of the pharmacokinetic study should preferably be corroborated by pharmacodynamic studies. This is particularly important for drugs such as simvastatin, atorvastatin and ezetimibe, which do not show pharmacokinetic–pharmacodynamic correlation. Hence, although potential of nanoemulsions/SNEDDS in improving oral bioavailability of atorvastatin and ezetimibe has been established [13,88] , the increase in the drug bioavailability need not translate into increases in the pharmacodynamic effects of these drugs [89] . Such aspects should be carefully considered while planning investigations on the SNEDDS. The key investigations that describe the potential of SNEDDS in oral drug delivery are listed in Table 4 and some of them have been discussed below [12,48,50,54,63–65,67,68,71,87,90–98] . Improving oral delivery of proteins Oral delivery of peptides is a very challenging task owing to their extreme hydrophilicity, poor permeability and poor stability in the GI environment. Several strategies are being explored for improving oral absorption of proteins. Recently, Shao and coworkers evaluated the ability of SNEDDS to improve oral bioavailability of b-lactamase, a model protein [90–92] . In order to improve the loading of the hydrophilic protein in the SNEDDS, investigators adsorbed the protein on the hydrogenated phospholipids. The phospholipid-adsorbed protein was incorporated into SNEDDS, and the potential of SNEDDS to improve Caco-2 cell permeability and oral SNEDDS Self-nanoemulsification in gastrointestinal fluid Nanoemulsion

Greater chemical/ enzymatic stability

Enhanced drug dissolution

Greater interfacial area for absorption

Enhanced drug permeation

Reduced gastrointestinal metabolism

Reduced drug efflux

Enhanced lymphatic transport

Reduced hepatic metabolism Enhanced drug absorption Enhancement in oral bioavailability

Figure 4. Potential mechanisms of improvement of oral bioavailability by SNEDDS. SNEDDS: Self-nanoemulsifying drug delivery systems.



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Table 4. Potential of self-nanoemulsifying drug delivery systems in oral drug delivery. Drug

Theraputic use

Components

b-lactamase

A model protein

Biphenyl dimethyl dicarboxylate Coenzyme Q10

Hepatoprotective

Hydrogenated lecithin, Cremophor® EL, 2–3‑fold BA increment compared Transcutol®, Lauroglycol™ FCC with solution Tween® 80, Transcutol, Miglyol® 812 1.7–6-fold improvement in BA

Matrine†

Natural alkaloid

Probucol

Antihyperlipidemic

Zedoary turmeric oil

Essential oil

Oleanolic acid

Witepsol® H35, Lauroglycol FCC, Solutol HS 15® Cremophor EL, Transcutol, Lauroglycol FCC

Ref. [90–92] [94] [50]

Cremophor RH 40, Maisine™ 35, Seasme oil Transcutol, Ethyl oleate, Tween 80

5-fold BA increment compared with powder Greater BA compared with matrine powder and matrine phospholipid complex 1.5–3-fold improvement in BA compared with powder Improvement in bioavailability

Hepatoprotective

Cremophor EL, Labrasol®, Transcutol, Sefsol® 218, Cremophor RH 40, PG

2.7-fold BA increment compared with tablets

[96]

Ramipril

Antihypertensive

Tween 80, Sefsol 218, Carbitol

[12]

Glibenclamide

Antidiabetic

2.29-fold improvement in BA compared with capsules Greater in vitro dissolution rate

Lutein Lacidipine

Antioxidant

In vitro/In vivo observation

Capmul® MCM, Tween 20, Cremophor RH 40 Carotenoid Labrasol, MCT, PEG 400, Transcutol Calcium channel blocker Labrafil® 1944 CS, Capmul, MCM, Cremophor EL, Tween 80, Transcutol

Retinol acetate

Antioxidant

Danazol Halofantrine

Antiandrogen Antimalarial

Ibuprofen

Anti-inflammatory

Tamoxifen

Anticancer

Genistein

Natural antioxidant

Cyclosporine A

Immunosupressant

Anethole trithione

Chemopreventive

Soybean oil, Capmul, MCM, Cremophor EL Maisine 35, Cremophor EL, ethanol Tween 80, Span 20, Octanediol, IPM, ethanol Cremophor RH 40, PG, Maisine 35, Capryol 90 Labrafac Lipophile™ 1349, Maisine 35, Transcutol, Cremophor EL, Labrasol Cremophor EL, Capmul, MCM C8, Orange oil Tween 80, PG, Cremophor RH 40 MCT

[93]

[87] [95]

[97]

Greater in vitro dissolution rate Greater in vitro dissolution rate

[64]

Improvement in dissolution rate

[98]

Greater in vitro dissolution and no effect of fed and fasted state dissolution media on droplet size Greater in vitro dissolution rate

[65]

[54]


[67]

100% in vitro drug release in 5 min

[71]


[68]

Improved stability and in vitro dissolution profile

[63]

[48]

† Matrine-phospholipid complex was incorporated in self-nanoemulsifying drug delivery systems. BA: Bioavailability; MCT: Medium-chain triglyceride; PG: Propylene glycol.

bioavailability was evaluated. Interestingly, peptide-loaded SNEDDS could significantly improve the permeability and oral bioavailability of the b‑lactamase. However, investigators also observed that the bioavailability of the protein-loaded SNEDDS when coadministered with the phosphate buffered saline was considerably lower than that of protein-loaded SNEDDS diluted with water (and administered as is). This clearly indicates the influence of the electrolyte content on the in vivo performance of the SNEDDS. Hence, evaluating electrolyte tolerance of SNEDDS before finalizing the formulation for in vivo studies is a critical step in SNEDDS design. Another problem observed was leakage of the protein from SNEDDS after 1608


dilution with aqueous phase. This problem can be anticipated as protein was adsorbed on the phospholipids and was not inside the phospholipid core. It could be possible to solve this problem using an appropriate ion pair for the protein, which would increase the lipophilicity of the protein and reduce leakage. Alternatively, protein can be conjugated to phospholipids or any other suitable lipids, as evidenced by Ruan and coworkers [93] . Improving oral delivery of natural phytochemicals Natural phytochemicals are drawing great attention from clinicians owing to their multitude of actions. Natural phytochemicals future science group


have demonstrated potential in the prevention and/or treatment of various diseases, such as cancer, arthritis, diabetes and hepatitis. The majority of phytochemicals suffer from problems such as poor water solubility and poor metabolic stability, which limit their use in the clinic. As mentioned previously, SNEDDS can be an attractive approach for drugs with poor water solubility and/or poor metabolic stability. Researchers have established that SNEDDS can significantly improve the oral bioavailability/therapeutic efficacy of several natural phytochemicals belonging to diverse classes, such as natural antioxidants [50,71] , triterpenoids [73] , essential oils [95] , alkaloids [93] , carotenoids [64] and hepatoprotective agents [96] .

Nanoemulsions & SNEDDS: controversy regarding the role of nano-size in augmenting the drug transport across biological membranes There are numerous examples in the literature that establish potential of the nanoemulsions and SNEDDS in augmenting efficacy of various therapeutic agents. However, enhanced therapeutic efficacy obtained with the nanoemulsions is a combined result of a multitude of factors. In general, it is believed that nanoscale offers better transport properties and is a major driving factor for the augmented therapeutic efficacy of drugs. However, the role of nanoscale in improving the transport of drug across biological membranes and therapeutic efficacy is debatable in the case of nanoemulsions. Almost two decades ago, Tarr and Yalkowsky established that the size of emulsion has a significant effect on the absorption of the cyclosporine through rat intestine, suggesting the rationale behind development of nanoscale emulsions [99] . In another investigation, de Smidt et al. demonstrated that penclomedine nanoemulsions (droplet size ~160 nm) have greater bioavailability compared with that of penclomedine emulsions (droplet size ~750 nm) [100] . However, few recent reports suggest that the nano-size of the nanoemulsion may not have significant influence on the drug permeation/ absorption and pharmacokinetics of the drug. Yap and Yuen evaluated pharmacok inetics of tocotrienol emulsion and nanoemulsion (with significant difference in the droplet size and digestibility) in humans [101] . Interestingly, tocotrienol emulsion and nanoemulsion did not show any difference in pharmacokinetic parameters. In another study, Nielsen et al. compared the pharmacokinetics of probucol self-emulsifying future science group

Review

formulation (droplet size ~4.5 µm) and self-nanoemulsifying formulation (droplet size ~45 nm) in minipigs and no significant difference was observed in the pharmacokinetics of self-emulsifying and self-nanoemulsifying formulations [87] . In an intriguing study, Izquierdo et al. systematically compared the ability of emulsions and nanoemulsions to improve the skin permeation of tetracaine, a topical anesthetic agent [102] . The emulsions and nanoemulsions employed in the study had significantly different droplet sizes but had the same composition of the surfactant and oil phase. Interestingly, the authors observed no significant difference in the tetracaine dermal and transdermal permeation for emulsions and nanoemulsions. This report clearly indicates a need for reassessing the role of the specific nanosize of the nanoemulsions in dermal/transdermal delivery and warrants generation of more data in this area. Thus, the role of nano-size of the nanoemulsions in improving drug transport across biological membranes and pharmacokinetics needs to be evaluated extensively and critically.

Limitations of liquid SNEDDS Self-nanoemulsifying drug delivery systems, being liquid in nature, need to be delivered through either soft/hard gelatin or hydroxypropylmethylcellulose capsules. There are few issues associated with these systems when presented in capsules, such as incompatibility of components with the capsule shell in the long term, precipitation of drugs during fabrication and storage at low temperature and critical method of production, among others [103] . In addition, SNEDDS may not be useful for hydrophobic drugs that can undergo pH catalyzed or solution-state degradation. We observed that modified oily phases used for SNEDDS fabrication have acidic pH owing to the presence of traces of free fatty acids. These acids can catalyze the degradation of pH-sensitive drugs, such as cefpodoxime proxetil on long-term storage. We observed that cefpodoxime proxetil undergoes hydrolysis to a completely insoluble product (cefpodoxime acid) on 3 months of storage as per the ICH guidelines [Date AA, Unpublished Data] . We also observed that simvastatin SNEDDS formulation was susceptible to hydrolytic degradation at accelerated conditions of storage owing to reactive ester and lactone moiety [Dixit RP, Unpublished Data] and on long-term storage of SNEDDS. In view of our experience, we believe that chemical stability of drugs in SNEDDS needs to be studied at accelerated conditions. www.futuremedicine.com

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Solid SNEDDS The researchers realized that it may be possible to obviate disadvantages associated with liquid SNEDDS handling, manufacturing and stability should one convert them to solid state. Hence, the concept of solid SNEDDS was developed. Solid SNEDDS in the form of dry, solid powders would help in overcoming the limitations associated with liquid SNEDDS. Solid dosage forms are most stable and are convenient for handling; therefore, attempts are made to convert the liquid systems into solid SNEDDS. Various techniques, such as spray drying, freeze drying and adsorption on carriers, can be employed to convert liquid SNEDDS into solid SNEDDS compressed into tablets. The selection of a particular process for preparation of solid SNEDDS would depend on the content of oily excipient of the formulation, properties of active pharmaceutical ingredients, such as solubility, heat stability and compatibility with other ingredients. The simplest technique to convert liquid SNEDDS to solid SNEDDS is by adsorption onto the surface of carriers or by granulation using liquid SNEDDS as a binder. This technique is uncomplicated, cost effective, easily optimized and industrially scalable. It can be used for heat- and moisture-sensitive molecules, thus providing an advantage over other techniques, such as spray drying and freeze drying. Various excipients utilized for the preparation of solid oral dosage forms can be employed for adsorption. The excipients should possess large surface areas to adsorb sticky and sometimes viscous oily SNEDDS formulation.

60 Reduction in TC levels (%)

B 200

70 50 40

4 days 7 days 14 days 21 days

Reduction in TC levels (%)

A

30 20 10 0 -10 -20 -30

We have studied the ability of different excipients, such as dibasic calcium phosphate, lactose, microcrystalline cellulose, colloidal silicon dioxide and Neusilin, to adsorb cefpodoxime proxetil SNEDDS. Neusilin was found to give free-flowing powder with high bulk density [Date AA, Unpublished Data] . Conversion to solid form did not significantly alter the dissolution profile. In another study, we successfully developed and evaluated self-nanoemulsifying granules (SNG) of ezetimibe and ezetimibe–simvastatin combination. In both cases, Aerosil 200 was utilized for adsorption of SNEDDS. X-ray diffraction studies indicated loss of crystallinity and/or solubilization of drug in the SNGs. This result was supported by scanning electron microscopy studies, which showed no evidence of drug precipitation on the surface of the carrier. A remarkable improvement was observed in dissolution of the drug from SNGs compared with pure drug. In vivo evaluation in rats showed a significant decrease in total cholesterol levels compared with the drug suspension [53,82] . The percentage protection offered by the combination of simvastatin and ezetimibe is depicted in Figures 5 & 6 . Taha et al. adsorbed vitamin A SNEDDS on microcrystalline cellulose and compressed the powder to obtain tablets [104] . The self-nanoemulsifying tablet exhibited a higher relative bioavailability of 143.68% when compared with tablets in which vitamin A oily solution was incorporated. The peak plasma concentration and area under the curce of vitamin A self-nanoemulsifying tablet was found to be higher in

4 days 7 days 14 days 21 days

150 100 50 0 -30

Control

Drug’s F1 SNG suspension

F2 SNG

F3 SNG

Control Drug’s F1 SNG suspension

F2 SNG

F3 SNG

Figure 5. Percentage changes in the levels of total cholesterol and triglyceride of experimental groups at different time intervals. (A) Percentage changes in the levels of total cholesterol. (B) Percentage changes in the levels of triglycerides. Ezetimibe and simvastatin were used in the concentration of 10 mg in the formulation. SNG: Self-nanoemulsifying granule; TC: Triglyceride. Reproduced with permission from [53] .

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B

60 4th day 7th day 14th day 21st day

40 30 20 10 0 -10

80 70 60 50 40 30 20 10 0

G SN F6

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SN

G

G SN F4

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on

G F6

SN

G F5

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G SN F4

tro l r u su g sp ’s en si on Pl fo ac rm eb ul o at io n D

on C

tro l r su ug sp ’s en si on Pl fo ac rm eb ul o at io n

-10

-20

C


50


A

Review

Figure 6. Percentage changes in the levels of total cholesterol and triglycerides of experimental groups at different time intervals. (A) Percentage changes in the levels of total cholesterol. (B) Percentage changes in the levels of triglycerides. Ezetimibe and simvastatin were used in the concentration of 10 and 40 mg in the formulation. SNG: Self-nanoemulsifying granule; TC: Triglyceride. Reproduced with permission from [53] .

comparison with tablets of vitamin A oily solution. Lutein SNEDDS were adsorbed on Aerosil 200 to obtain solid SNEDDS by Yoo et al. [64] . Dissolution of lutein from the solid SNEDDS was effected in less than 5 min in distilled water and no signs of precipitation or aggregation of the drug were observed. Mahmoud et al. have identified the use of superporous hydrogel as a solid carrier for carvedilol SNEDDS [105] . The same group of scientists have reported selfnanoemulsifying tablet formulation of carvedilol, where granulated aerosil and microcrystalline cellulose were used as adsorbents and processed into liquisolid tablets [106] . These tablets retained the nanoparticle size of the nanoemulsion. The self-nanoemulsifying tablet possessed drug release properties similar to that of immediate-release dosage form. Few reports have been published in the literature where solid self-emulsifying systems are formulated using techniques such as spray drying, freeze drying and extrusion spheronization [107–111] . Patil and Paradkar have employed polystyrene beads to deposit self-emulsifying loratidine [112] . In a similar manner, solid selfnanoemulsifying formulations can be developed utilizing these techniques.

Controlled-release SNEDDS The self-nanoemulsifying system can also be employed to fabricate extended-release delivery systems for poorly soluble drugs. Patil et al. developed an extended-release future science group

felodipine self-nanoemulsifying system where Aerosil 200 was used as the gelling agent and the gelled SNEDDS were encased in hydrophobic Gelucire 43/01 [113] Eutectic-based solid SNEDDS of Coenzyme Q10 was prepared using the tableting technique by Nazzal and Khan, where Kollidon® VA 64, Glucidex® IT 12, and Avicel® PH-112 were used [114] . This study demonstrated that a tablet dosage form could be manufactured to release a lipid formulation in a controlled-release pattern without the need for any complicated manufacturing techniques. Common processing parameters, such as amount of colloidal silicon dioxide, magnesium stearate, mixing time and compression force, have a profound effect on the release of lipid formulations from their solid carriers.

Characterization of solid SNEDDS As the final dosage form of the solid SNEDDS is a tablet or a capsule, the powder properties of the solid emulsion particles are important. The nature and the quantity of liquid SNEDDS adsorbed on the surface of a particular excipient would influence the properties of the obtained solid particles. The ratio of liquid:adsorbent quantity is important. Powder properties, such as density, angle of repose, flow, compressibility index and particle size distribution, are important for processing into dosage form. The globule size of spontaneously formed nanoemulsion would govern its performance in vivo. The desorption of SNEDDS from the www.futuremedicine.com

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surface of the solid particles and its conversion into nanoemulsion is the rate-limiting step for the dissolution and absorption of the drug. In our study, an increase in the globule size of the nanoemulsions was observed when the solid nanoemulsifying particles were dispersed in water. Increase in size was not only related to the carrier used but also to the composition of SNEDDS and properties of the drug [53] . It is necessary to carry out physical characterization of the solid SNEDDS using x-ray diffraction spectroscopy, differential scanning calorimetry and scanning electron microscopy to ensure there is no drug precipitation during preparation of solid SNEDDS. The absence of characteristic drug melting endotherm in differential scanning calorimetry suggests that the drug is in a solubilized state in solid SNEDDS. X-ray diffraction is a useful technique employed in the characterization of crystalline materials. The formation of a diffuse diffraction pattern and the disappearance of characteristic drug peaks indicate that the drug is in a solubilized state in solid SNEDDS. Scanning electron microscopy is useful to investigate the surface properties of the particles and their physical form. In vitro dissolution studies would give an idea about the fate of the formulation in the GI tract.

Conclusion Drug discovery programs yield a large proportion of new chemical entities that are lipophilic and poorly soluble. Self-nanoemulsifying formulations have shown tremendous potential in improving the bioavailability of such therapeutic agents with limited aqueous solubility. The nanosize of these formulations is responsible for

facilitating enhancement of drug dissolution and absorption, owing to the large surface area. The lipidic nature of these systems allows delivery of drugs to the lymphatic system. However, certain issues, such as drug–excipient inter action, oxidation of vegetable oils, toxicity and safety warrant attention during the development of SNEDDS. The amenability of converting SNEDDS into solid self-nanoemulsifying systems enables development into solid dosage form. Thus, the solid self-nanoemulsifying system can serve as platform technology for delivering poorly soluble drugs. Although a lot of research is being carried out in this area, other aspects, such as in vitro/in vivo correlation, need to be established.

Future perspective Research on SNEDDS technology has accelerated in the last 5 years and several reports have appeared in the literature. SNEDDS have primarily been explored for enhancement of bioavailability in oral drug delivery. The pHcatalyzed and solution-state degradation of drugs in SNEDDS needs to be evaluated. The conversion of SNEDDS to a solid state can reduce drug degradation but cannot eliminate it in many cases. Hence, it is important to identify microenvironment-modulation strategies for improving the stability of pH-sensitive drugs. Considerable investigations have been carried out to convert liquid SNEDDS to a solid dosage form such as tablets and pellets. However, there is a need to identify a suitable highly porous amphiphilic carrier that can convert liquid SNEDDS into a solid powder without significant increase in the volume or bulk density. The applications of SNEDDS

Executive summary Nanoemulsions can be easily fabricated by low-energy emulsification methods, such as the phase inversion temperature method and phase inversion composition method (spontaneous nanoemulsification method). Self-nanoemulsifying drug delivery systems (SNEDDS) are homogenous anhydrous liquid mixtures that spontaneously form oil in water nanoemulsions upon dilution with water under gentle stirring. The components of the SNEDDS are selected with objectives, such as: - To achieve maximal drug loading; - To achieve minimal self-nanoemulsification time and droplet size in the gastric milieu for maximal absorption; - To reduce variation in the nanoemulsion droplet size as a function of pH and electrolyte content of the aqueous medium; - To prevent/minimize drug degradation/metabolism in physiological milieu. Statistical experimental designs can be employed to obtain SNEDDS with desired characteristics and in vitro lipolysis model can help in understanding the in vivo fate of the SNEDDS. SNEDDS have demonstrated a good potential to improve oral bioavailability/therapeutic efficacy of various hydrophobic drugs and also hydrophilic proteins. Liquid SNEDDS can be converted to solid oral dosage forms, such as granules, tablets and pellets, with no or moderate effects on the in vivo behavior of SNEDDS. It may be possible to develop controlled-release SNEDDS by suitable variations in the composition or fabrication process of tablets or pellets.

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in other routes of delivery apart from the oral route can be explored. The commercialization of SNEDDS technology would depend on the ability of drug delivery scientists to address these aspects of SNEDDS. Acknowledgements The authors would like to thank Gattefosse India Ltd, Subhash Chemicals, Chika Pvt. Ltd., Gangwal Chemicals Ltd, Signet Chemicals Ltd, BASF India Ltd, Karlshamns AB and Sasol GmBH for providing gift samples of various excipients for our research on self-nanoemulsifying drug delivery systems. The authors would also like to thank

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