INTRODUCTION:

More than 70% of the entire dosage forms used by humans are delivered through the oral route, this is due to the safety and convenience of the patients. However, 50% of the drugs are poorly water-soluble, which comes under BCS (Biopharmaceutical Classification System) class Ⅱ having a serious difficulty in bioavailability. For these drugs to reach the systemic circulation it has to overcome the solubility problem[1,2]. Various approaches were developed to solve this problem including cyclodextrin complexation[3], particle size reduction[4], solid dispersions[5], and lipid-based formulations. Among all these approaches, lipid-based formulations, predominantly self-nanoemulsifying drug delivery systems (SNEDDS) have been used widely[6,7].

SNEDDS is thermodynamically stable, it consists of the drug and SNEDDS preconcentrate (combination of oil, surfactant, and co-surfactant). SNEDDS have several benefits like; (ⅰ) increases drug solubilization, (ⅱ) inhibits p-glycoprotein (P-gp) mediated drug efflux, (ⅲ) avoids first-pass metabolism by promoting lymphatic transport, (ⅳ) improves gastrointestinal (GI) membrane permeation. Besides these advantages, it undergoes certain disadvantages like less drug loading capacity and precipitation of the drug. These problems can be overcome by going for a supersaturable SNEDDS (S-SNEDDS) method. S-SNEDDS consists of polymeric precipitation inhibitor (PPI) incorporated with the actual composition of SNEDDS. PPI inhibits the nucleation process which is required for the formation and growth of the crystals by adsorbing onto the hydrophobic nuclear surface. Additionally, PPI does not allow the drug to precipitate out of the solution. Solid S-SNEDDS have certain advantages than the liquid dosage form, namely; (ⅰ) improved transportability, (ⅱ) high stability, (ⅲ) reduced manufacturing cost, (ⅳ) good patient compliance, therefore it is necessary to convert the liquid S-SNEDDS to solid S-SNEDDS [8,9,10]. The conversion to solid dosage form can be done using one of the successful techniques like solid carrier adsorption, in this technique the liquid formulation is added onto the solid carrier and mixed using a blender [11].

Fundamental components of SNEDDS:

Oil (solubility studies):

Solubility study is done to identify the proper vehicles that have better solubilizing property, oil can solubilize the drug to a particular limit. Oil is an important agent because it increases drug absorption from the GI tract by promoting drug transport through the intestinal lymphatic system [12]. The important factor that should be considered during the selection of oil is the drug loading capacity, the solubility of the drug in the oily phase is directly proportional to the drug loading capacity. The solubility of drugs in synthetic oils/Medium Chain Triglycerides (MCT) is remarkably greater than the naturaloils/Long Chain Triglycerides (LCT), this may be due to the shorter chain length and good fluidity [8].

Surfactant and Co-Surfactant (Emulsification Study):

The selection of surfactants and co-surfactants should be based on their emulsifying ability than the solubilizing capacity [13]. Flask inversions, transmittance, and turbidity are some of the tests used to identify the proper surfactant and co-surfactant to formulate SNEDDS. Mostly, non-ionic surfactants were preferred than the ionic one due to its reduced toxicity. Also, surfactants which have higher hydrophilic-lipophilic balance form oil in water (o/w) increases the solubility of the drug [14]. The performance of the co-surfactants highly depends on its structure and chain length [15]. The co-surfactants with shorter molecular chain length were most widely used because it induces the penetration of water into the interface which causes the formation of spontaneous emulsion. Compared to hydrophilic co-surfactants the lipophilic co-surfactants (like Imwitor 988) have better emulsifying ability, this is because lipophilic co-surfactants have better miscibility with medium-chain triglycerides (MCT) and due to its shorter molecular chain length [8]. Some of the oils (LCT and MCT), surfactants and co-surfactants list is given below(table1) [5,16,17].

Table: 1 List of some oils, surfactants, and co-surfactants

Oils

Surfactant

Co-surfactant

Natural oils

Synthetic oils

Tween 80

Poloxamer 407

Kolliphor RH 40

Cremophore RH 40

Solutol HS15

Labrasol

Span 80

Transcutol HP

Ethanol

Propylene Glycol

PEG 4000

Imwitor 988

Capmul MCM

Ethylene Glycol

Castor oil

Olive oil

Sesame oil

Coconut oil

Corn oil

Soyabean oil

Captex 355PG

Captex 300

Labrafac

Isopropyl- myristate

Miglyol 812 N

Self-Nanoemulsifying Drug Delivery Systems (SNEDDS):

In recent years, the researcher’s interest in the SNEDDS method has been raised drastically, it is due to its capability to solubilize and improve the bioavailability of poorly water-soluble drugs. Fundamentally, SNEDDS are isotropic mixtures consisting of oil, surfactant, co-surfactant, and drug that produce fine oil in water (o/w) nanoemulsion when it comes in contact with aqueous phase under mild agitation [13]. Usually, the globule size of the SNEDDS formulation lies below 200nm [16]. Some of the important features of SNEDDS formulation are; [18,19,9]

ⅰ) It can exhibit the drug in a solubilized form within the gastrointestinal (GI) lumen.

ⅱ) It increases drug absorption by providing a larger interfacial area.

ⅲ) It also provides good chemical and enzymatic stability.

ⅳ) Inhibits p-gp mediated drug efflux.

ⅴ) It enhances lymphatic transport and prevents the drug from first-pass metabolism.

ⅵ) Lesser inter and intra-subject variability.

ⅶ) Quick onset of action.

ⅷ) Reduced level of drug dose.

ⅸ) Easy to manufacture.

Moreover, the liquid SNEDDS (L-SNEDDS) have a great initial absorption rate when compared to its solid form, this may be due to the presence of L-SNEDDS in the solution form [20]. The SNEDDS which consists of a higher fraction of shorter chain lipids gets absorbed into the systemic circulation, whereas the SNEDSS consisting of long-chain and medium-chain fatty acids achieve entry to intestinal lymph [21].

Characterization of SNEDDS:

Visual observation and emulsification time:

SNEDDS is visually observed beside powerful light, to identify the transparency of the solution. The transparent form denotes the formation of clear nanoemulsion. It is also done to identify the existence of an undissolved drug [22]. The SNEDDS is said to be stable if it forms emulsification within 1 minute having clear solution form and it is said to be unstable if it forms an unclear solution. SNEDDS formulation is classified into different grades depending upon the time required for self-emulsification and visual appearance (given in table 2) [23].

Effectiveness of drug loading:

The drug loading efficiency is tested to determine the fraction of drug-loaded into the solvents. By increasing the concentration of the oily phase, it may reduce the loading capacity of the drug [24,25].

Initial Drug Load – Amount of Drug in Filtrate

Drug Loading = ------------------------------------------ × 100

efficiency Initial Drug Load

Viscosity:

The viscosity of SNEDDS can be determined using Brookfield-Dv-Ⅱ+pro viscometer. The viscosity of the formulation completely depends on the concentrations of oils, surfactants, and co-surfactants. Moreover, SNEDDS which have low viscosity tend to produce o/w type of nanoemulsion system [26,17].

Droplet size:

The measurement of droplet size can be done by Dynamic light scattering (DLS) with the use of zetasizer (Nano ZS). The droplet size plays a critical role in determining the rate and extent of drug release and drug absorption. Oils (LCT) possess greater viscosity will influence the emulsification process, which causes a significant effect on the droplet size of the globules. The droplet size must be less than 200 nm. Smaller the size of the droplets provides a larger interfacial area for drug absorption [25,27,28].

Polydispersity index (PDI):

The polydispersity is the ratio of standard deviation to the mean droplet size uniformity, the larger the polydispersity, the lesser the droplet size uniformity [29].

Table: 2 Grades of SNEDDS

Grade	Reason
Grade A	Quickly forms nanoemulsion (less than 1min), and appears to be clear and bluish form.
Grade B	Quickly forms emulsion but less clear, and appears to be bluish-white form.
Grade C	Forms emulsion within 2 mins, with milky appearance.
Grade D	Emulsion formed is slow, with grayish-white and a little oily appearance.
Grade E	Produces lesser emulsion, forms larger oil globules on the surface.

Supersaturable-SNEDDS (S-SNEDDS):

Although SNEDDS has several benefits, it also undergoes certain disadvantages such as ⅰ) More number of dosing frequency due to its low drug loading capacity which affects the patient’s compliance in a negative way, ⅱ) The drug precipitation in the GI tract leads to low drug bioavailability [30,31]. These drawbacks can be overcome by including the supersaturation process into the SNEDDS formulation. The ability of the drug to exist in solution state even when its concentration is increased above its saturation solubility, without getting precipitated is known as supersaturation. It is a thermodynamically unstable system, consists of a water-soluble polymeric precipitation inhibitor (PPI) and a low quantity of surfactant. The PPI is used to inhibit drug precipitation in the GI tract [32,33]. Also, the supersaturated form (greatly dispersed and dissolved) of a drug have the ability to improve Caco-2 cell permeation of poorly soluble drug [34]. The supersaturating based drug delivery system consists of drugs in high energy form which affords a potential method to increase the oral bioavailability of poorly water-soluble drugs [35,36]. Since the absorption of the drug takes place in the intestine (not in the stomach), to obtain maximum absorption the supersaturation state in the gastric phase should be retained until it is transferred to the intestine. So, it is important to understand the kinetics of precipitation in the stomach surrounding to estimate the in-vivo performance of the supersaturation based drug delivery system [37]. The mechanism behind the supersaturation is explained simply through the “spring and parachute” theory by Guzman et al. Here, “spring” is given as the high energy supersaturated form (in comparison to the crystalline powder) which is thermodynamically unstable and has a tendency to precipitate and forms crystals. But to increase the oral bioavailability and drug absorption, the supersaturated state should be maintained in the GIT for a long period. Therefore “parachutes” (Precipitation inhibitors) are used to inhibit the precipitation of drugs and also maintains the high concentration for a long period [38].

Evaluation of S-SNEDDS:

As already mentioned the secretion of pancreatin in the intestine is the important reason for precipitation of SNEDDS in GIT. When S-SNEDDS is diluted, the drug may exist in three distinct states: free drug molecules (state 1), solubilized globules into nanoemulsion (state 2), precipitated form (state 3). Hence the concentration of drug can be measured by adding the state 1 and 2 excluding the precipitated form of the drug. In-vitro drug supersaturation test is one of the commonly used studies to identify the level of supersaturation and response of the drug towards precipitation during the release study of S-SNEDDS formulation [30,8].

Precipitation Inhibition (PI):

When the solubilization ability of the drug’s formulation has decreased, it causes the drug to precipitate in the stomach. There are some factors which credit to this process are, ⅰ) severe change in pH, ⅱ) The ability of the body fluid to dilute the formulation (or) the solubilizing agents get digested before the drug is absorbed. Hence the drug bioavailability and efficacy are affected due to precipitation. To inhibit the precipitation of drug, polymeric precipitation inhibitors (PPI) incorporated into the SNEDDS actual formulation, the PPI blocks the nucleation process that is required for formation and growth of crystal, this retards the precipitation of drug out of the solution and maintains a metastable supersaturated state for a certain period. Some of the commonly used PPI in S-SNEDDS formulation are Methylcellulose, PVP, HPMC, sodium CMC, HPMC phthalate which maintains the supersaturated state by preventing the drug precipitation [1,8]. To estimate the precipitation activity of the drug, the precipitated drug should be taken apart from the dispersion system, this can be done using two methods (ⅰ) Syringe filters method and ⅱ) Centrifugation method). In the syringe filter method, the precipitated drug can be separated from the solution by filtration. In the centrifugation method the precipitated drug can be separated from the solution [43,44,45]. When comparing both of the above methods, the centrifugation method seemed to have greater recovery and repeatability than the filtration method [32]. Some of the other hydrophilic and amphiphilic polymers used as the function of PPI are Kollicoat MAE, Kollidon 90 and Soluplus. From these polymers, soluplus have a major effect on inhibiting the precipitation of a drug (dutasteride) [40]. Moreover, HPMC (small amount) significantly retards the precipitation of trans-resveratrol and maintains the metastable supersaturation state for a sufficient period [46]. There are two mechanisms (ⅰ) thermodynamic inhibition and ⅱ) kinetic inhibition) to achieve the inhibition of drug precipitation. Thermodynamic inhibition is the process where inhibition of drug precipitation is attained through increasing the solubility of the drug, therefore brings down the amount of supersaturation and also minimize the nucleation and crystal growth (by inclusion of solubilizing agents). Kinetic inhibition is the process where inhibition of drug precipitation is done through retarding or inhibiting the drug in supersaturated form (inclusion of polymers which act as PPI) [47,48].

Solid S-SNEDDS:

To improve the ⅰ) Stability, ⅱ) Effective manufacturing cost, ⅲ) Transportability, ⅳ) Patient compliance, the liquid formulation (SNEDDS or S-SNEDDS) is converted into solid dosage form [8]. Solidification is a technique where the liquid formulation or excipients is incorporated into the powder (solid carrier). Solid SNEDDS have a combined benefit of both SNEDDS and solid dosage form [49]. The proper selection of solid carrier is important to develop the effective solid formulation of the drug, the various characteristics of the solid carriers which affects the solidification process are, ⅰ) change in pore size, ⅱ) surface area, ⅲ) capacity to absorb oil, ⅳ) dissimilarity in particle size. The colloidal silica is one of the commonly used absorbents and a drug carrier in the pharmaceutical industry because it is porous material and its ability to avoid the chemical interaction when physically attached to the liquid substance [41]. Among the HPMC polymers, HPMC E-type (29% methyl substitution, hydrophobic) have good adsorbing property (on hydrophobic nuclei) and better precipitation inhibition than the HPMC K-type (22% methyl substitution, less hydrophobic). Also, the less viscous HPMC polymer grade (HPMC-E5) is more effective than the higher viscosity grades (HPMC-E50, HPMC-E15, and HPMC-E4 M). The HPMC-E5 (used as PPI) in the solid S-SNEDDS formulation completely dissolves the drug (ezetimibe) inside the pores of the formulation matrix [8,31,33]. Commonly used techniques to prepare the solid S-SNEDDS are, ⅰ) Adsorption into solid carrier [8], ⅱ) Spray drying [41]. Some of the solid carriers and their properties are given in Table 4 [50].

Table: 4 Solid carriers and its properties

Solid carrier	Properties
Neusilin US2, Florite PS-10, Sylysia 350 (used as silica-based adsorbents)	High surface area, high oil-absorption capacity, uniform pore size, and less particle size.
Hydroxypropyl cellulose L type (HPC), low substituted hydroxypropyl cellulose B1 (L-HPC) and Vivapur 105 (used as cellulose-based diluents)	Have hydrophilic and viscous properties.
Lactose monohydrate, Starch 1500 and maltodextrin (used as saccharide based diluents)	Have the ability to solubilize in water.

Characterization of Solid SNEDDS:

To identify the flow properties of the solid formulation, certain evaluation studies like Bulk density, Tapped density, Angle of repose, Compressibility index and Hausner’s ratio can be done [11]. Stability studies are conducted to identify whether the solidification process affects the mean droplet size and the self-emulsifying ability of the solid formulation for an estimated period [8]. It is important to identify the physical state of the drug in the solid S-SNEDDS because it has a huge effect on in-vitro and in-vivo properties. DSC studies are used to identify whether the drug is adsorbed properly onto the solid carrier and also the conversion of drug into the amorphous or molecularly dissolved condition. The powder shows good flow properties if the angle of repose value is less than 40°. The results obtained from these studies suggest ease of capsule filling procedures for the powdered form of solid S-SNEDDS [30].

CONCLUSION:

The solid S-SNEDDS is the best approach in case of increasing drug release, improved stability, and oral bioavailability. Solid S-SNEDDS is a helpful method for increasing the solubility of the poorly water-soluble drugs, and it also inhibits precipitation with the help of polymeric precipitation inhibitor. Moreover, solid S-SNEDDS has the advantage of improved stability and low production cost when compared to SNEDDS. The screening of SNEDDS preconcentrate is the first and important step towards the formulation because the whole formulation depends on the ability of the SNEDDS preconcentrate to produce solubilizing and emulsifying properties. It is also important to select a proper polymer which can effectively prevent the nucleation. Bringing PPI into the formulation, surfactant concentration can be reduced which prevents the GI side effects like hypersensitivity, nephrotoxicity, and neurotoxicity. The solid formulation brings some extra advantages without reducing the benefits of liquid form. To obtain the maximum benefits of supersaturation, the gastric supersaturation should be maintained until transferred to the intestine (produces an increase in absorption). Therefore the combination of both S-SNEDDS and solid dosage form (solid S-SNEDDS) is a successful technique to improve the oral bioavailability of water-insoluble drugs.

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Received on 24.09.2019 Modified on 25.11.2019

Research J. Pharm. and Tech. 2020; 13(7): 3530-3535.

DOI: 10.5958/0974-360X.2020.00625.3

Type of delivery system	Drug	Oil: Surfactant: Co-surfactant	Development
Solid S-SNEDDS	Candesartan Cilexetil	Triacetin: Tween 80 and Cremophore EL: Tetraglycol	The solubility and oral bioavailability of poorly water-soluble drugs like Candesartan Cilexetil can be increased by using this approach.PPI (HPMC or PVP K 30 or both) used to retard the precipitation [1].
Solid S-SEDDS	Celecoxib	Capryol 90: Tween 20: Transcutol HP	A PPI (soluplus) used to retard the precipitation, Different solid carriers produced different drug release. Sylysia 350 fcp produced better drug release and improves oral bioavailability [39].
Solid S-SNEDDS	Ezetimibe	Captex 355: Cremophore RH40: Imwitor 988	A PPI (HPMC E5) incorporated into solid SNEDDS to maintain the supersaturated state. Hence, this supersaturable formulation has additional benefits of higher emulsifying ability which may be a useful oral dosage form for water-insoluble drug ezetimibe [8].
S-SEDDS	Dutasteride	Capryol 90: Cremophore EL: Transcutol HP	Adding a high amount of surfactant may cause side effects in GI, by adding a precipitation inhibitor (soluplus) into the SEDDS formulation prevents the GI side effects and also enhances the absorption of poorly water-soluble drugs like dutasteride [40].
Solid-SNEDDS	Tacrolimus	Capryol PGMC: Labrasol: Transcutol HP	Colloidal silica used as a solid carrier to formulate a solid form of SNEDDS. Further, this formulation enhances the dissolution rate and oral bioavailability of tacrolimus by forming rapid emulsion without chemical interaction and reduced droplet size [41].
S-SNEDDS	Silymarin	Labrafil: Kolliphor RH40: Transcutol HP	The co-polymer (Poloxamer 407) added as PPI significantly inhibited precipitation (promotes the formation of the compartment which consists of a large quantity of un-ionized free drug in the dissolution medium). This S-SNEDDS formulation has a significant enhancement in the bioavailability of the drug than the commercial product [42].
Solis S-SNEDDS	Rosuvastatin calcium	Olive oil: Tween 80: PEG 400	The secretion of pancreatin in the intestine is the important reason for the SNEDDS precipitation GIT (via the Lipolysis process). Microcrystalline cellulose 102 used as a solid carrier. The solid S-SNEDDS formulation of rosuvastatin calcium releases 100% of the drug with better oral bioavailability, which is 2.1 fold greater than the commercial product [30].