SNEDDS AS LIPID-BASED NANOCARRIER SYSTEMS: CONCEPTS AND FORMULATION INSIGHTS

Approximately 40 % of newly discovered chemical entities have low solubility and possess low bioavailability after oral administration. Lipid-based drug delivery systems (LBDDS) have recently become very popular because of their remarkable ability to deliver drugs with poor absorption using lipids as carriers. Self-emulsifying drug delivery (SEDDS) systems are one type of LBDDS employed for the incorporation of hydrophobic drugs. SEDDS are classified into self-micro emulsifying drug delivery systems (SMEDDS) and self-nano emulsifying drug delivery systems (SNEDDS) based on the droplet size of the dispersed phase. The present review focus on the mechanism of drug absorption from lipid-based nanocarriers systems, in vitro assessment of self-emulsification, insights of SNEDDS, factors affecting the formulation of SNEDDS, and its applications.


INTRODUCTION
The oral route is commonly used for drug delivery because of its safety [1], comfort [2], minimum effort [3], and greater patient compliance [4]. However, many drugs have difficulty in developing as oral dosage forms because of their low solubility, low permeability [6], poor bioavailability, delayed onset of action, high inter/intra subject variability [5], and lack of dose linearity [6]. Different parameters, such as aqueous solubility, and rate of dissolution, influence the oral bioavailability of drugs. Susceptibility to efflux mechanisms, first-pass metabolism, and systemic metabolism has all been aspects to consider [7].
Combinatorial chemistry and high throughput screening (in vitro approaches) are used to identify the potent molecules in drug discovery process [8]. In the pharmaceutical research, more than 40% of NCEs (new chemical entities) are practically insoluble in water. Hence many of these promising active compounds are not considered in clinical-stage development [6]. Solubility of the drug is one of the major parameter to achieve the desired drug concentration in systemic circulation to produce therapeutic activity when administered [9]. The drug dissolution and gastro-intestinal permeability are the fundamental properties controlling the rate and extent of drug absorption [8]. Based on these properties, the biopharmaceutical classification system (BCS) classifies the drugs into four categories: Class I. High solubility-high permeability [2]; Class II. Low solubility-high permeability [3]; Class III. High solubility-low permeability [4]; Class IV. Low solubility low permeability [10]. Since many of the drugs belong to BCS II and IV their solubility and permeability problems are addressed by using conventional and novel techniques [11].
The conventional techniques are salt forms, solid dispersions [16], use of co-solvents [12], hydrotropy, micronization, change in dielectric constant of solvent, amorphous forms [7], chemical modification of drug, use of surfactants, inclusion complex [3], alteration of pH of solvent, use of hydrates or solvates [6], use of soluble prodrugs [8], application of ultrasonic waves [9], functional polymer technology, controlled precipitation technology [12], evaporative precipitation in aqueous solution [18], use of precipitation inhibitors, solvent deposition [4], precipitation [2], selective adsorption on insoluble carriers [9]. However, conventional approaches have many limitations like for example salt formation [12] of drugs is commonly used but always unattainable. Therefore weak acid and weak base synthesis are not practical [13]. Moreover, the formed salts might be converted into their original form [14], and it may cause the assembling of a weak acid and weak base in the gastrointestinal tract [4]. Reducing particle size might not be advisable because some of the processing problems may arise for amorphous powders [15]. In this direction novel techniques are developed to overcome the problems associated with conventional techniques. These includes lipid-based formulation system, micellar systems, porous micro particle, and nanoparticle technologies developed by using various polymers [14].
From the last decade onwards, lipids are used as carriers to modify solubility and permeability characteristics of drugs and is gaining attention [17].
Fats and oils are two common terms for lipids. At room temperature, fats are solid, while oils are liquid. Lipids [oils, greases, fats, and fatty acids (FAs)] are a key component of many natural foods as well as synthetic substances and emulsions. Various lipids that are employed to make lipid nanocarriers are biodegradable and show biocompatibility in physiological media or biological fluids [14]. Lipid based formulations are developed by dissolving the drug in mixture of two or more lipids.
To date, several studies have focused on lipid-based formulations for increasing the solubility and permeability of BCS II and class IV drugs by oral administration [15]. The present review focuses on the mechanism of drug absorption from lipid-based nanocarriers systems, in vitro assessment of self-emulsification, an overview of SNEDDS, factors affecting the formulation of SNEDDS, formulation insights, and its biopharmaceutical applications.

Lipid-based nanocarriers
The term "nano" was derived from the Greek word that refers to microscopic dimensions beyond the naked eye's ability to see [12]. Nanocarriers are important transport agents because of their small size and capacity to change physical properties like charge and shape to transfer therapeutically active agents to tissues [15]. Nanocarriers provide several advantages, such as preventing active drugs from degrading, allowing for higher and more efficient concentrations in the target tissue, and reducing the severity of toxic side effects [16]. The lipid-based nanocarriers have greater importance due to their low toxicity [17], high drug-loading capacity [18], improved bioavailability [19], high biocompatibility [20], high protection from degradation in the gastrointestinal tract (GIT [21], controlled-release behavior [3], ease to scale-up and sterilize [6], easy to validate [2], and also useful for the administration of drugs through different routes [17]. Unique properties like, tailorable surface to apply any targeting strategy, and an improved bio distribution and pharmacokinetic profile makes lipid-based system as a unique approach. Lipid nanocarriers are developed by using various types of biodegradable and biocompatible materials [20].
Lipid-based nanocarriers with complex nanostructures in the matrix can be made by properly blending solid lipids with liquid oil [7]. These systems are good at immobilizing substances and keeping particles from aggregating beneath the solid matrix [17].

Classification of lipid-based nanocarriers
Based on the physical state, lipid-based nanocarriers are classified as self-emulsifying drug delivery systems(SEDDS) [23], vesicular approaches, and non-vesicular approaches [19]. The sub classification of the same depicted in fig. 1. [14]. When introduced into the aqueous fluids of the gastrointestinal tract (GIT), SEDDS undergo emulsification and produce oil-in-water or water-in-oil emulsions [22]. Vesicular systems consists of a mixture of phospholipids, polymeric materials, and solvents [21]. One or more concentric bilayers are formed by self-assembling of amphiphile [19]. The drug is enclosed in between the phosphor-lipid bilayer. Non-vesicular systems are colloidal preparations containing physiological lipids and surfactants in which the drug in encapsulated within the solid lipid matrix [18]. Table 1 illustrates the difference between the various types of lipid-based nanocarriers.  Contain a mixture of phospholipids, polymeric materials, and solvents.
Composed of lipids and surfactants. [14] Undergoes self-emulsification in presence of aqueous fluids.
Phospholipids completely cover the aqueous core.
Dispersion of lipids in an aqueous surfactant solution. [24]

Mechanism of drug absorption from lipid-based nanocarrier systems
In the GIT, various enzymes (gastric lipase and pancreatic lipase) and intestinal components like phospholipids, proteins, polysaccharides, and amphiphilic materials are present [17]. Lipid formulations undergo emulsification in the GIT after its oral administration [19]. Gastric motility, gastric emptying speed, intestinal components and various enzymes play a major role in the emulsification of lipids [10]. Triglycerides undergo hydrolysis by gastric lipase and produce diglycerides and free fatty acids(FFAs) and then further undergo degradation by pancreatic lipase and form complex structures like mixed micelles [12]. The formed complexes are not absorbed completely. These complexes help to enhance the absorption of lipophilic moieties into enterocytes by passive diffusion [25] or by protein carriers placed on the membrane's outer surface [6]. Lipids helps in overcoming the first pass metabolism of the drug there by enhancing its gastric emptying time in the GIT and prolonging its residence time in the small intestine [1,26]. Finally, lipids lead to better dissolution and enhanced drug absorption. Generally, lipid systems contain unsaturated long-chained fatty acid esters [3]. These ester groups undergo hydrolysis and enhances the bioavailability of the drugs [27], and thereby cause lymphatic transport [2].

Lipid-based formulations (LBFS)
Lipid based formulations are developed by dissolved and encapsulated the drug in the mixture of oil, surfactants, and co-surfactants [1]. LBFs helps to enhance the solubility and bioavailability of poorly watersoluble drugs; suitable for both liquid and solid dosage forms while protecting the drug from the gut. Also, these systems ensure high drug loading capacity [26]. Among the LBFs, self-emulsifying drug delivery systems(SEDDSs) have gained great attention [12].

Lipid-based formulation classification system (LBFCS)
Pouton and Porter introduced the lipid classification system [6] based on the type and amount of excipients [1] used and by considering the morphology of lipid aggregates [3]. This classification helps in the selection of lipids based on their properties in formulation development [20]. As per their classification, the LBFCS are divided into four types. In Type I systems drug is incorporated in a single or mixture of triglycerides and excluding the surfactant [25]. These systems are easily digested and absorbed completely on administration [12] and are suitable for highly lipophilic drugs whose log P-value is greater than 4 [1].

In vitro assessment of self-emulsification
When the SEDDS come in contact with aqueous medium with gentle agitation, the energy is released [2]. The released entropy is larger than the required energy to extend the surface area between the system's immiscible phases [1]. The best method for assessing selfemulsifying ability is by dilution method with visual observation. Based on the system's physical appearance, they are grading as A to E, and fig. 3 depicts the distinct differences among the different types of systems [12].
Grade A: These systems rapidly form as nanoemulsions within one minute. These are clear and slightly dark blue colored in appearance.
Grade B: These systems form rapidly as emulsions but appear turbid with dark-blue to white color.
Grade C: These systems form within two minutes and look like a milky emulsion.

Grade D:
Emulsions are formed gradually, and the formed emulsion appears to be grayish-white and has a slightly oily appearance.
Grade E: These systems have poor emulsification properties, and large oil globules are present on the emulsion surface. The visual method helps to observe the emulsification speed and emulsion's stability with varied periods [33].

Self-emulsifying drug delivery systems (SEDDS)
These systems are lipid-based systems containing homogenous mixtures of oils, surfactants, and co-solvents [24]. Generally, these are anhydrous and are known as preconcentrates [34]. Under gentle agitation in an aqueous phase, the SEDDS has undergone selfemulsification spontaneously to form o/w microemulsions or nanoemulsions with an average particle size of 200 nm or less [24]. Fig. 4 shows the graphical representation of SEDDS prepared under gentle agitation employing a magnetic stirrer.

Types of SEDDS
Based on the droplet size SEDDS are categorized into two types [1]: A) self-micro emulsifying drug delivery systems (SMEDDS) [34], B) self-nano emulsifying drug delivery systems (SNEDDS) [16]. SEDDS refers to all forms of self-emulsifying systems [2], containing a mixture of oils, surfactants, and co-solvents (or) co-surfactants [25]. When the mixture of SMEDDS come in contact with the aqueous environment in GIT, they form a microemulsion under gentle agitation provided by the digestive motility of the stomach and intestine [34]. At the same time, SNEDDS refers to systems that generate nanoemulsions when dispersed in aqueous media [16]. The differences between SEDDS, SMEDDS and SNEDDS systems are given in table 3. Self-nano emulsifying drug delivery systems [30] Oil droplet size ranges from 200 nm-5 µm [10] Oil droplet size is 100-250 nm [32]. Oil droplet size is ˂100 nm [29]. Appearance is turbid Appearance is optically clear to translucent Optically clear appearance Required HLB value is ˂ 12

Fig. 4: SEDDS preparation using a magnetic stirrer
Required HLB value is ˃ 12 Required HLB value is ˃ 12 Development may require the characterization of the ternary phase diagram [23].
Development may require the characterization of pseudo ternary phase diagrams [10].
Development may require the characterization of pseudo ternary phase diagrams. A ternary phase diagram shows possible phases and equilibrium according to the composition of a mixture of three components at constant temperature and pressure.
Construction of pseudo ternary phase diagram is a critical step for developing SMEDDS/SNEDDS lipid-based formulation [16], which self-disperses as thermodynamically stable nano-drug carrier in GI lumen. It will provide information on phase behavior between different formulation components.

What are SNEDDS?
Self-nano emulsifying [12] drug delivery systems (SNEDDS) are nanoemulsion preconcentrates [10] or anhydrous sorts of nanoemulsion [25]. These systems are homogenous isotropic mixtures [16] of a pharmaceutical component, either natural or synthetic lipids, surface-active agents (surfactants), co-surfactants, and cosolvents [12]. When the mixture of these components undergoes gentle agitation in an aqueous solution, like GI fluids, it immediately forms an o/w nanoemulsion in which the drug is encapsulated [16]. Fig. 5 summarizes the process of self-nano emulsification.

Advantages of SNEDDS
Based on the composition and formulation, SNEDDS offer some advantages when compared to other lipid-based formulations:  Upon long-term storage, physical/chemical stability is not effected [25].
 Possibility of filling them into unit dosage forms, like soft/hardgelatin capsules [10].
 Ability to carry the drug in liquid forms, all through the GIT, for adequate time and permits its absorption [25].

Factors affecting the formulation of SNEDDS
Generally, SNEDDS has been formulated as a combination of oils, surfactants, and co-surfactants or co-solvents; based on their properties, various factors affect the formulation of SNEDDS.
 Drugs administered at a very high dose are not suitable for SNEDDS unless they exhibit extremely good solubility in at least one of the components of SNEDDS, preferably the lipophilic phase. The drugs with limited solubility in water, and lipids are most difficult to formulate by SNEDDS [30].
 The ability of SNEDDS to maintain the drug in solubilized form is greatly influenced by its solubility in the oily phase [5]. Suppose if the surfactant or co-surfactant is contributing to a greater extent in drug solubilization, there could be a risk of precipitation, as dilution of SNEDDS will lower the solvent capacity of surfactant or cosurfactant [16].

Formulation considerations
In the selection of formulation ingredients care must be taken. Preformulation experiments (e. g., solubility, emulsification efficiency) should be conducted in order to choose the best constituents for SNEDD formulation.
The variables factors affecting the phenomenon of self-nano emulsification are:  The physicochemical nature and convergence of oil phase, surfactant, and emulsifier [36].
 The proportion of the mixture, particularly oil-to-surfactant [12].
 The temperature and pHof the aqueous phase where nano emulsification would happen [25].
 Physicochemical properties of the selected oily, surfactant, and emulsifier and their concentration [29]. The formulated droplet size and its polar nature can regulate the coherent release of the core from the system [10]. The routes of administration also play a major role in selecting the formulation ingredients and their ratios [31].
The general components used in the development of SNEDDSs are listed below.

Drug molecule
It is important to remember that the therapeutic agent can impact SNEDDS in various ways, including phase behavior and nanoemulsion droplet size [10]. The efficiency of SNEDDS is affected by various physicochemical properties of the compound, including log P, pKa, molecular structure and weight, the existence of ionizable groups, and quantity [12].

Potential components
Excipients used in the formulation of SNEDDS have been developed due to advances in pharmaceutical science w. r. t solubility, safety and toxicity [29]. When selecting appropriate excipients, consider irritation potential, safety for administration into the body [10]. A perfect oil, surfactant, and co-surfactant ratio contributes to stable and efficient SNEDDS [30]. The length of the fatty acid carbon chain and degree of unsaturation of the selected oil and surfactant will greatly determine the formed emulsion's stability [30]. The various components used are as follows:

Oils
The oil phase is necessary to formulate SNEDDS because oil's physicochemical properties regulate the nano-emulsification process's spontaneity [31]. Oils with excessively long hydrocarbon chains, such as fixed oils, are considered difficult for nanoemulsions [23]. In contrast to medium-chain, tri-, di-, and monoglycerides(examples are glycerol mono caprylocaprate, acetic, citric, diacetyl tartaric acids), long-chain triglycerides have shown a greater capacity to enhance intestinal lymphatic transport of drugsas these are reported to be responsible for preventing the firstpass metabolism of drugs [12], while medium-chain mono-and diglycerides have greater solubilization potential for hydrophobic drugs with permeation-enhancing properties [10]. When a single oily component have optimal nano emulsification and drug delivery properties, a combination of oils could be used to achieve a good oily phase property [30]. Nanoemulsions and microemulsions are generally made using a similar concept by using a combination of oils to have high solubility for the added drug.
A mixture of fixed oil and medium-chain triglyceride are used in some situations to maintain a good balance between drug loading and emulsification. SNEDDS containing lacidipine [10], a calciumchannel blocker with poor oral bioavailability, has recently been produced using a mixture of oils(based on a three-component system: the oil phase X1 (a mixture of Labrafil®/Capmul®, 2:1, w/w), the surfactant X2 (a mixture of Cremophor®/Tween® 80, 1:1, w/w) and the co-surfactant X3 (Transcutol®)) and the authors reported high solubility of the drug in the selected components [38].

Surfactants
Surfactants, known as surface-active agents, are amphiphilic compounds containing polar (water-soluble) and non-polar (waterinsoluble) groups. Surfactants adsorb at interfaces due to their amphiphilic nature, decreasing surface and interfacial tension and leads to emulsification. Khan et al. developed naringenin SNEDDS by proper selection of surfactant and co-surfactants, thereby enhancing the drugs solubility [38].
Emulsification results have shown that many surfactants have different emulsification abilities [25]. A proper mixture of low and high hydrophilic lipophilic balance (HLB) surfactants is needed to develop a stable self-nano emulsifying system [1]. A sufficient ratio of surfactants with an HLB value of 14-16 helps in the most effective emulsification when diluted with water [16]. A high HLB surfactant does have the advantage of increasing interfacial fluidity and emulsification of SNEDDS [39].

Co-emulsifiers, co-surfactants, or solubilizers
Co-emulsifiers [10], co-surfactants [40], or solubilizers [16] are widely used in the formulation of SNEDDS [30]. These are included during the formulation for various reasons, such as in increasing the drug loading [10], controlling the self-nano emulsification time, regulating the size of nanoemulsion droplets [30], and increasing the size of the self-nano emulsification area in phase diagrams [29]. Solubilizers, for example, ethanol, propylene glycol, polyethylene glycol, and glycol ethers, are utilized to upgrade the disintegration of vast amounts of hydrophilic surfactants.

Aqueousphase
The formation of SNEDDS occurs when a combination of oils, surfactants, co-solvents, and drug molecules are added into the aqueous media [6]. The stomach's pH is usually acidic (pH 1.5 to 2.5), and various ions in the GITsignificantly impact nanoemulsions' properties in terms of their size and stability [25].
The various components, along with examples, are mentioned in table 4.

Advantages of snedds/ssnedds over micro/nanoemulsions
SNEDDS/SSNEDDS demonstrates many advantages when compared with micro/nanoemulsions. Some of the advantages are discussed below.

Stability
The stability assessment has done based on the droplet size, polydispersity index (PDI), and zeta potential (ZP) of SNEDDS [25]. When compared to nanoemulsions, SNEDDS have excellent physical and chemical stability during long-term storage [43].

Drug loading
As natural lipids have a lower solubility of compounds with intermediate partition coefficients (log P 1-3) than amphiphilic surfactants/co-surfactants [31], SNEDDS has a higher drug-loading capacity than lipids solution due to higher surfactant and cosurfactant concentrations and less oil [29]. As compared to those formulated with long-chain (LC) lipids, SNEDDS prepared with medium-chain (MC) lipids with Cremophor RH40 as a surfactant were able to dissolve more drugs. The high drug-loading capacity of commercial products like Fortovase ® , which contains 200 mg of drug per capsule, is critical in their performance [23].

Quick onset of action
Quick action is required in various conditions, such as aggravation, hypertension, and angina [12]. SNEDDS can provide quick onset of action when administered via the oral route as it undergoes spontaneous emulsification in the gastrointestinal tract (GIT) [15]. In comparison to traditional formulations, pharmacokinetic studies of SNEDDS revealed a strong reduction in tmax (an indirect measure of the fast onset of action) in the case of SNEDDS [30].

Reduction in the drug dose
The SNEDDS has improved Cmax, oral bioavailability, and therapeutic effect [31]. Many hydrophobic pharmaceuticals (antihypertensive and anti-diabetic), improved the bioavailability when manufactured as SNEDDS with reduced drug dosage and dose-related side effects [12].

Simple manufacture and scale-up
Industrial applicability determines any drug delivery system's success. Simple manufacturing and scale-up are essential factors in industrialization's success [15]. SNEDDS requires basic and costeffective manufacturing facilities [22], such as a simple mixer with an agitator and volumetric liquid filling equipment; they can be mass-produced easily and affordably [44].
SNEDDS can form acceptable o/w emulsions on mild agitation, dilution in media(GI fluids) [12]. SNEDDS overcomes the initial ratelimiting stage of particulate dissolution within the GI tract as the formulation is pre-dispersed in a suitable solvent [31]. The system can present the drug in a single unit dosage form with increased solubility while retaining dose uniformity [8].

Applications of snedds
When a drug is formulated as a SNEDDS, the dissolution process is bypassed, which increases the drug's solubility and bioavailability [22]. In SNEDDS, the lipid matrix readily combines with water to produce a fine particulate o/wemulsion [16]. The medication would be administered in a dissolved state to the GI mucosa, allowing it readily absorbable. The bioavailability and Cmax of several drugs, when present as SNEDDS, is increased [1].
Glyburide is an oral second-generation sulfonylurea medication employed throughout the treatment of type II diabetes. The addition of glyburide to SNEDDS improved the drug's solubility significantly [8].
The preparation of docetaxel-loaded SNEDDS by Y. G. Seoet al. resulted in a 6-fold increase in docetaxel bioavailability [45]. The significant increase in bioavailability showed that SNEDDS could improve drug absorption by inhibiting the(permeability glycoprotein)p-GP efflux mechanism [1].
Ziprasidone sustained-release pellets with SNEDDS were designed to increase oral bioavailability and overcome the drug's food impact [46]. From the drug release test it was found that the pellets provided sustained release, with 90% of the pellets being released within 10 h. Pharmacokinetic tests in beagle dogs revealed that ziprasidone had prolonged the action and improved bioavailability with no food impact. Findings showed that the effects of schizophrenia and bipolar depressive medication persisted for a long time [46].
SNEDDS is a method for increasing drug solubility that is independent of the pH effect on solubility. Cefpodoximeproxetil (CFP), a poorly bioavailable high-dose antibiotic with pH-dependent solubility, was developed into self-nano emulsifying drug delivery systems. Resulted SNEDDS have a greater release rate when compared with a pure CFP [47].
A similar technique was used to increase the oral bioavailability of the model protein beta-lactamase (BLM). The theory is that the amphiphile will encircle the protein and form a micelle structure within the oil, allowing it to dissolve more frequently. Cell line studies revealed that the SNEDDS significantly increased fluorescein isothiocyanate-betalactamase transport across the Madin-Darby Canine Kidney monolayers.
SNEDDs could also be a possible effective delivery system for noninvasive protein drug delivery. Insulin was used as a model protein to support a complex between a hydrophilic moiety and a phospholipid. The insulin phospholipid complex (IPC SNEDDS) showed a strong ability to lower glucose levels in diabetic rats. The relative bioavailability reached 7.15 percent after oral administration, significantly higher than the 0.11 percent of MDCK cells monolayers-phosphate buffered saline (PBS) [48]. Table 5 enlist the SNEDD Sreported for the different routes of administration along with reports related to SSNEDDS.

Formulation of snedds
The formulation of SNEDDS pseudo-ternary phase diagrams plays a major role in selecting optimal oil concentrations, surfactant/cosurfactants, co-solvents needed to solubilize and stabilize the SNEDDS [28]. These systems are prepared on a simple vortex mixer. The drug's required amount is solubilized in the surfactant and co-surfactant mixture followed by oil addition. In general, soft/hard gelatin or hydroxypropyl methylcellulose capsules deliver liquid SNEDDS [16]. When filled into capsules, limitations were noticed and are as follows: a) Component incompatibility with the capsule shell may occur during long storage [5].
b) Drug can precipitate during the manufacturing process and when stored at low temperatures [41].
c) A critical production method is needed compared to other conventional dosage forms [47]. d) SNEDDS may well not be effective for hydrophobic drugs that are subjected to pH-catalyzed or solution-state degradation during accelerated storage (hydrolytic degradation) [27,50].  [24].

Preparation of solid SNEDDS
Solid SNEDDS are typically prepared using any of the three methods.
I) Adsorption on a solid inert carrier [16].
II) Spray drying [27] III) Extruder-Spheronization [46] The liquid formulation is introduced to the carrier by mixing it in a blender during the adsorption process. The free-flowing powder is resulted [16]. Spray drying is a procedure for rapidly drying a liquid or slurry into a dry powder. The volatile fraction of the microemulsion, i.e., the organic solvent or water, is evaporated by spraying a liquid solution into a hot-air chamber. The basic machine consists of a spinning friction disc that spins at high speed at the bottom of a cylindrical pipe designed to maximize friction with the product [52]. In the Extruder-Spheronization method, the wet mass is passed through an extruder at 30 pm. The extrudates were then placed in a spheronizer fitted with a cross-hatched plate rotated at 1800 rpm for 15 min [11]. Table 6: shows some of the examples of S-SNEDDS by using three methods. Adsorption on a solid inert carrier DFX loaded SNEDDS would be incorporated into S-SNEDDS formulation by adsorbing into different porous carriers to compare their dissolution behavior with the commercially available tablet formulation of DFX. To create and characterize a new DFX-S-SNEDDS to increase its solubility and possibly improve its oral bioavailability. [43] 6. Sertraline hydrochloride [27] The hydrophilic solid carrier PVP or lactose Spray drying Liquid sneddsof sertraline HCl are converted into solid snedds by using the spray drying method. The developed solidsnedds have a fine particle size and show greater drug release bioavailability. [27] 7. Irbesartan (IRB) [52] Aerosil 200 as solid carrier spray drying technique Liquid snedds are suspended in the solid carrier using ethanol as a solvent with continuous stirring until forming an isotropic mixture. The formed suspensions are spray dried. The formed s-snedds have oral bioavailability when compared with pure IRB. [51] 8. Loratadin [53] Aerosil,Crosscarmellose Extrusion-Spheronization The developed Loratadin S-SNEDDS have a uniform size and spherical shape. These have improved drug release when compared with L-snedds. [52]

Future perspective
From the last decade onwards, research on SNEDDS has increased, and various studies have appeared in the literature. For the enhancement of solubility and bioavailability of oral drugs SNEDDS have been developed. Based on the literature, SNEDDS are used to administer other than the oral route. The routes of drug distribution have been the focus of extensive research. The conversion of liquid SNEDDS to solid dosage forms like tablets and pellets has been extensive research. However, a suitable highly porous amphiphilic carrier that can change liquid SNEDDS into a solid powder without significant volume or bulk density increase is required. The drug is released for an extended period by incorporating polymers into SNEDDS. Even though there is much study being done in this field, the ability of drug delivery researchers to handle these issues of SNEDDS technology would be critical to its commercialization.

CONCLUSION
Many promising active compounds are not considered in clinical-stage development due to their low solubility and oral bioavailability. Solubility of the drug is one of the major parameters to achieve the desired drug concentration in systemic circulation to produce therapeutic activity when administered orally. Solubility of the NCMs (new chemical moieties) is one major challenge present in front of pharmaceutical researchers. From the last decade onwards, lipids have had much more interest as carriers to modify poorly water-soluble drugs' solubility and permeability characteristics. The development of lipid-based formulations in general and SNEDDS can increase poorly aqueous soluble drugs' solubility, stability, and bioavailability.

ACKNOWLEDGMENT
I am very grateful to my guide and mentor, Dr. S. Sunitha Assistant professor, Gitam School of pharmacy, Hyderabad, AVS Gupta HOD of the department, Joginpally B. R. Pharmacy College, Hyderabad. For their valuable support for this paper.

AUTHORS CONTRIBUTIONS
All authors have contributed equally.