Int J App Pharm, Vol 14, Issue 3, 2022, 16-33Review Article

A SYSTEMATIC REVIEW ON SUPERSATURABLE SELF-NANO EMULSIFYING DRUG DELIVERY SYSTEM: A POTENTIAL STRATEGY FOR DRUGS WITH POOR ORAL BIOAVAILABILITY

**MUTHADI RADHIKA REDDY^1*,2 , KUMAR SHIVA GUBBIYAPPA¹**

^1*GITAM Institute of Pharmacy (Deemed to Be University), Rushikonda, Visakhapatnam, Andhra Pradesh, India, ²Department of Pharmaceutics, Guru Nanak Institute of Technical Campus, Hyderabad, Telangana, India, ¹GITAM School of Pharmacy (Deemed to Be University), Hyderabad, Telangana, India
Email: muthadiradhika@gmail.com

Received: 19 Jan 2022, Revised and Accepted: 31 Mar 2022

ABSTRACT

The most fundamental important extensive constitutive of drug molecules to be available for systemic absorption is aqueous solubility; subsequently, that is the nature of GIT fluid. When the drug molecules become solubilized, it has to reach the systemic circulation via the biological membrane. The solubility problem of many effective pharmaceutical molecules is still one of the major challenges in the formulation of this molecule. Drug molecules that belong to class II have a problem in bioavailability mainly due to low aqueous solubility and the rate-limiting step is the dissolution process and so electing of suitable drug delivery and proper additives are decisive to overcome this major obstruction and promote the fraction that will reach the systemic circulation. Among the different lipid-based systems, the su-SNEDDSs have gained attention because the inclusion of precipitation inhibitors within su-SNEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This enhances the bioavailability of drugs and minimizes the variability of exposure. Nowadays, supersaturable self-nano emulsifying and nano lipid-based drug delivery systems have constrained a substantial concern from pharmaceutical scientists for managing the oral delivery of poorly water-soluble compounds. By following oral administration, self-nano emulsifying drug delivery systems show complex aqueous dispersion and digestion in the GIT and enduring intestinal lymphatic transport, exorbitant pre-absorptive metabolism by gut membrane-bound cytochrome enzymes and preventing P-gp mediated drug efflux.

Mostly these processes result in drug supersaturation, which leads to increased absorption or the high drug concentrations may cause precipitation with capricious and variable oral bioavailability. This procession review briefly summarized drug supersaturation obtained from self-nano emulsifying and other lipid-based formulations and this review also delineate the effects of numerous physiological factors and the probable interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SNEDDS and focuses on reviewing the application of su-SNEDDS in enhancing the solubility and bioavailability of anti-cancer drugs in cancer therapy.

Keywords: Su-SNEDDS, Supersaturation, Bioavailability, Precipitation inhibitors, Cancer, Poorly aqueous solubility, Nanotechnology

© 2022 The Authors.Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2022v14i3.44178. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

About two-thirds of new drugs in drug discovery reveal low aqueous solubility in water due to which it becomes turn into arduous for formulations to develop oral solid dosage forms with a pharmaceutically acceptable range of therapeutic activity. Drugs of Class II or IV, as per the Biopharmaceutical classification system exhibit poor aqueous solubility. The oral delivery of these drugs is affected by low bioavailability, erratic absorption, inter and intrasubject variability, and lack of dose solubility. Another important factor that affects oral bioavailability is poor gastrointestinal permeability. Several other techniques, including liposomes, cyclodextrin, SLN, complexation, micronization, microemulsions, solid dispersions, and lipid-based formulations, have been developed to overcome these concerns. Hence to enhance their solubility and to increase their oral bioavailability, lipid-based formulations have emerged as a boon. Many approaches were developed to overcome this issue with a variable degree of success, from these approaches, the self-emulsifying drug delivery system (SEDDS) is extensively tried.

Self-emulsifying drug delivery systems (SEDDSs) are a constitutive strategy to enhance the bioavailability of formulations of poorly water-soluble compounds. However, these formulations have some limitations, comprising of vivo drug precipitation, poor in vitro in vivo correlation due to an inadequacy of predictive in vitro tests, issues in the liquid formulation, and the physicochemical instability of the drug. To overcome these circumspections, the possible form of such systems is restricted, and the supersaturable SEDDSs (su-SEDDSs) have gained attention based on the certainty that they consist of the inclusion of precipitation inhibitors (PIs) within SEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This improves the therapeutic efficacy and bioavailability of drugs and reduced toxicity can be achieved by targeted drug delivery.

Supersaturable formulations promote a supersaturated drug concentration and through co-formulation with precipitation inhibitors and this type of synergic effect can be achieved through Pls and also maintain drugs in a supersaturated state when exposed to the aqueous environment of the gastrointestinal tract.

SEDS

Self-emulsifying drug delivery system (SEDS) is an isotropic mixture of oils, surfactants, cosurfactants, and at times cosolvents, which emulsify extemporaneously to produce oil-in-water or water-in-oil emulsion when introduced into the gastrointestinal tract [1]. Based on the droplet size after emulsification, they are classified into two broad classes, namely self-emulsifying drug delivery systems (SEDDS) with a droplet size range varying between 100-300 nm and self-micro emulsifying drug delivery systems (SMEDDS) with a droplet size range<50 nm [2]. As a result of the lower globule size, the micro/nano emulsified drug can be taken up efficiently through lymphatic pathways, where it bypasses the hepatic first-pass effect [3]. Larger lipid droplet which represents SMEDDS or microemulsions, is converted into smaller micelles on encountering bile salts and lipases and on absorption through intestinal villi help enhance the absorption of the drug [4].

Fig. 1: Absorption mechanism of lipid-based systems (Reprinted from [25] with permission (AJP 2019)

Furthermore, the miniscule globule size, micro-emulsified drugs are easily absorbed through lymphatic pathways, bypassing the hepatic first pass effect. Predominantly, the drug absorption across the intestinal epithelium enhances substantially for highly permeable (BCS) class II and class IV drug molecules when formulated as SEDDSs [5]. These conventional solubilized SEDDSs have several advantages in absorption, there are certain limitations [6], like the drug precipitation in vivo, and another limitation of a conventional solubilized SEDDS is toxicity.

Fig. 2: Schematic presentation of lipid digestion, drug solubilization, and absorption processes occurring in the stomach and small intestine. Reprinted from [7] with permission (Elsevier 2019). For this system, other limitations include a high surfactant concentration is usually required to sufficiently stabilize the high surface area of the lipid–water interface and during storage that the drug remains in a dissolved state and also upon oral administration. Subsequently, solubilized SEDDSs essentially contain high concentrations of surfactants [7]. These high doses of surfactants can lead to gastrointestinal side effects and the conventional dissolution techniques cannot be applied for self-Nano emulsifying drug delivery system as they are dependent on digestion former to dissolution, the in vitro-in vivo correlations of SNEDDS must be studied further [8, 9]

Supersaturated self-emulsifying drug delivery systems (Su-SEDDSs)

To conquer drawbacks of solubilised SEDDS, a new class of supersaturable formulation has been designed and developed as a thermodynamically stable self-emulsifying drug delivery system to resolve above limitations.

These su-SEDDS formulations contain a reduced amount of surfactant and a hydrophilic Polymeric Precipitation Inhibitor (PPI) for generating and maintaining a supersaturated state in vivo by preventing or minimizing the precipitation of the drug [10]. Many research groups have demonstrated that supersaturable formulations are a promising alternative to improve the oral bioavailability [11].

Theoretically, drugs at high concentrations have an increased driving force for flux across the GI membrane, and enhanced absorption could be achieved with a sufficient period [12]. The main designing of supersaturation is to increase the thermodynamic activity of the drug beyond its solubility limit and, hence, to create increase free drug concentrations with a stronger driving force for move into and across biological barriers, thus resulting in a more effect on the uptake flux.

Oils

The oil is used in SNEDDS formulation for solubilizing the lipophilic drug and ease self-emulsification to increase the amount of drug passing through the intestinal lymphatic system, thus, enhancing absorption. The long and medium-chain triglycerides with varying saturations are employe [13-16]. Hydrolysed vegetable oils are used due to the formation of superior emulsification systems; these systems are accepted for oral administration and semisynthetic medium-chain derivatives, such as, medium-chain triglycerides, e. g., caprylic/capric triglyceride, Miglyol®, and Captex® have also been highly developed. The edible oils are not chosen for SNEDDS formulation due to their ineptitude in solubilizing larger drug concentrations.

Table 1: Commonly employed oil components in the preparation for oral delivery

General class examples	Examples commercial name	Commercial name	References
Fatty acid esters	Ethyl oleate Crodamol EO	Crodamol EO	[196]
Fixed oils	Castor oil, Soyabean oil	-	[196]
Vitamins	Vitamins E	Aqua Gem-E	[197]
Medium chain triglycerides	Tryglycerides of capric/caprylic acids	Miglyol 812, Labrafac CC, Crodamol GTCC	[196]
	Triacetin	Captex 500	[196]
Medium-chain mono-diglycerides	Mono-and diglycerides of Imwitor 742, Capmul MCM diglycerides	Imwitor 742, Capmul MCM	[198]
Long chain monoglycerides	Glyceryl momooleate	Peceol, Capmul GMO	[198]
Fatty acids	Oleic acid Crossential O94 Caprylic acid	Crossential 094 -	[ 200]
Propylene glycol fatty acid esters	Propylene glycol monocaprylate Propylene glycol dicaprylate/caprate	Capryol 90, Capmul PG-8 Miglyol 840, Captex 200	[198]

Surfactants

The non-ionic surfactants are orally acceptable that possess a higher hydrophilic-lipophilic balance. Mostly employed emulsifiers include ethoxylated polyglycolyzed glycerides and polyoxyethylene oleate. Natural emulsifiers are considered safer than synthetic versions, but surfactants possess incomplete self-emulsifying ability. Non-ionic surfactants have lesser toxicity compared to ionic surfactants and direct to increase permeability through the intestinal lumen, and these can be used alone or in combination [17-20].

Table 2: Generally employed surfactants in preparation for oral delivery

General class	Examples	Commercial name
Polyoxyethylene hydrogenated castor oil	Polyoxyethylene 40 hydrogenated castor oil Polyoxyethylene 60 hydrogenated castor oil	Cremophor RH40, HCO-40
Polyoxyethylene stearate	Polyethylene glycol-660-12-hydroxysterate	Solutol HS 15
Polysorbates	Polyoxyethylene-20-sorbitan monooleate Tween 80 Polyoxyethylene-20-sorbitan monolaurate	Tween 80 Tween 20
Sorbitan esters	Sorbitan monooleate Sorbitan monolaurate	Span 80 Span 20
PEO-PPO-block copolymers	Poloxamer 188 Poloxamer 407	Pluronic F68 Pluronic F127
Polyglycolyzed glycerides	Oleoyl macrogol glycerides Caprylocaproyl macrogol glycerides Lauroyl macrogol glycerides	Labrafil 1944 CS Labrasol Gelucire 44/14
Polyoxyethylene vitamin E	Tocopheryl PEG 1000 succinate	Vitamin E TPGS
Polyoxyethylene castor oil	Polyoxyethylene 35 castor oil	Cremophor EL
Polyoxyethylene stearate	Polyethylene glycol-660-12-hydroxysterate	Solutol HS 15

Co-surfactant

The addition of co-surfactant along with surfactants lower the interfacial tension to–ve value, where it expands to form fine droplets that are consequently adsorbed larger quantities of surfactant and surfactant/co-surfactant till the interfacial tension turns+ve. This process is called “spontaneous emulsification” [21].

Active drug candidate

Preferentially those in BCS classes II and IV. The drug candidate should be a poorly water-soluble drug with an intermediate partition coefficient (log P between 2-4) [22-28].

PIs

Polymeric precipitation inhibitors employed in supersaturable SMEDDS formulation are mainly water-soluble cellulosic polymers like HPMC, PVP, Methyl cellulose, HPMC phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium CMC which can sustain the supersaturated state by preventing the precipitation of drug [29]. The precipitation inhibiting capacity of the three hydrophilic polymers has been found to be in the order PVP K174PEG 40004HPMC. PVP K17 (0.5%) has been found to efficiently retard precipitation [30-35]. PIs can inhibit crystal nucleation and/or growth through their interactions with the drug molecules. Conversely, the drug precipitation can also be prevented thermodynamically by increasing drug solubility. An increased drug solubility by various solubilizing agents such as surfactants, co-solvents, and CDs can reduce the degree of supersaturation, decreasing the nucleation rate. A phase diagram study is preferentially required to obtain an optimal formulation design. Optimized formulations should be selected (i) to achieve maximal drug loading; (ii) to achieve a minimal self-emulsification time and small uniform droplets in the GI fluid for maximal absorption; and (iii) to prevent/minimize drug degradation/metabolism under in vivo physiological conditions. Then, for su-SEDDSs, a PI is added to the pre-concentrate formulation. Finally, the liquid state su-SEDDS should be converted to a suitable dosage form [36]. Some of the Pls are given in table 3. Other mechanisms of precipitation include

i). Hydrogen bonding between drug and polymer

Hydrogen bonding interaction between drug and polymer could inhibit the growth of crystals as well as the nucleation process. It has been seen that if the drug has hydrogen bond donor sites (hydroxyl, amide group) is always interacted with acceptor site such as PVP, which inhibits the precipitation through the formation of hydrogen bond interaction between polymer-drug [37-40].

ii). Hydrophobicity and rigidity

Hydrophobicity and rigidity of polymer are affecting the precipitation process. Generally, that moderate hydrophobic polymer are more effective than highly hydrophobic polymer or highly hydrophilic polymer due to weak adsorption of polymer to the drug crystal surface [41].

iii). Molecular weight and steric hinderance

Polymer adsorption capacity depends on the molecular weight of polymer. It has been investigated that high molecular weight polymer are the efficient choice for supersaturated solution [42, 43].

It was shown that PVP 2000 seen less crystal inhibiting capacity than PVP due to low molecular weight and the PVPK90 has a better inhibiting effect than PVP K12, PVPK29 and PVPK32 [44].

Table 3: Various precipitation inhibitors and their performance with active drug

Drug/Active compound	Precipitation inhibitor	Intent	Reference
Piroxicam	HPMC	Investigation of rate of in vitro penetration across silicon membrane and full thickness human skin.	[187]
Ricobendazole	HPβCD	Sheep PK study showed 2.2-fold increase in Cmax and 1.6-fold increase in AUC	[186]
Felodipine	HPMC	Evaluating the impact of HPMC on the crystal growth and nucleation kinetic of supersaturated solution.	[197]
Paclitaxel	CD, HPβCD	Higher than 80% oral bioavailability achieved	[195]
Saquinavir	HPβCD	Saquinavir precipitation avoided in seminal fluid simulant with 12% PEG 1000+2.5% HPβCD	[103]
Griseofulvin	Polooxamer and HPMC	Design and investigation of exvivo intestinal permeability study of griseofulvin	[199]
Indirubin	PVP K17	Rat PK study showed1.3 times higher bioavailability	[42]
Carbamazepine	PVP	Dog PK study showed 5-fold increase in bioavailability compared with the commercial tablet	[126]
Econazole nitrate	HPMC	Improvement of bioavailability by designing ocular supersaturated SNEDDS for improving bioavailability.	[58]
Fenofibrate	Soluplus	Improvement of bioavailability and investigation of precipitation assays of supersaturated formulation.	[199]
Butyl paraben	HPMCAS	At least 0.6 mg/ml of butyl paraben was maintained in the supersaturated condition for 72 h	[127]
PNU-91325	HPMC	A 5-fold higher bioavailability was observed from an S-cosolvent formulation containing PEG+20 mg/g HPMC compared with a neat PEG 400 formulation	[164]
Silybin	HPMC	Enhancement of oral bioavailability of silybin by ss-sedds.	[15]
Cyclosporin A	PVP	For improvement of dissolution rate of cyclosporin A by using PVP as precipitation inhibitor.	[194]
Tacrolimus	HPMC	Dog PK study showed a 10-fold increase in Cmax and AUC compared with crystalline powder	[125]
Paclitaxel	HPMC	Rat PK study showed 10-fold higher maximum concentration and 5-fold higher oral bioavailability.	[163]
Danazol	PVP, HPMC, HPMCAS	Characterization of phase behavior aswell as the degree of supersaturation	[192]
AMG 009	HPMC	17.5-fold increase in dissolution	[132]
Pazopanib	HPMC	Investigation of the phase behaviour of supersaturated solution from low PH followed by higher PH by phase diagram.	[198]

Cyclodextrin complexation

Cyclodextrin have the ability to form inclusion complexes with a variety of hydrophobic drug to increase solubility. The two well-known cyclodextrins which are used to improve the bioavailability of poorly soluble drug are 2-hydroxypropyl-β-cyclodextrin (HPβCD) and sulphobutylether-β-cyclodextrin [45].

Principles of drug precipitation for development su-SEDDSs

Supersaturation is a state in which drugs present above their saturation solubility in solution and are thermodynamically unstable [46]. The degree of supersaturation can be expressed with the relative ratio of the actual concentration of drug in solution to the saturated solubility of the drug as the supersaturation ratio S:

……. (1)

Where C_eq represents the saturation solubility and C is the experimentally measured actual drug concentration. The relative supersaturation index also can be used to express supersaturation and is defined as:

……. (2)

Based on the obtained S or a, the state of the drug solution is classified as follows:

1. S<1 (σ<0): unsaturated or subsaturated;

2. S = 1 (σ = 0): saturated;

3. S>1 (σ>0): supersaturated.

Compared with a stable, saturated solution (µ_eq), a supersaturated solution is characterized by an increased chemical potential (µ) or activity (a) of the drug in the solution. The thermodynamic driving force for drug precipitation can be formed by the difference in chemical potential (Δµ):

…… (3)

From the definition of chemical potential, it follows that:

……. (4)

where a and aeq refer to the activity of the drug in a supersaturated and saturated state, respectively, Rmis the universal gas constant, and T is the temperature of the solution system. Equation (4) can be transformed into Equation (5), assuming no difference between the activity coefficient of the drug in the supersaturated and saturated state:

……. (5)

Where C is the drug concentration in the supersaturated solution, is the equilibrium solubility of the drug in the saturated solution, and S is the supersaturation ratio, as defined in Equation (1). The drug solution is thermodynamically unstable in a supersaturated system; hence, it tends to return to a stable state through drug precipitation.

Compatibility studies

Various analytical methods have been used for characterizing polymer-drug interactions and crystallization process. The results can shed light on potential mechanisms of the inhibition process. Such methods include X-ray diffraction, differential scanning calorimetry, Raman spectroscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, microfluidic technology, polarized microscopy, scanning electron microscope and atomic force microscopy [47-54].

Enhance in absorption by supersaturation in the GIT

Drug absorption can be assessed by Fick’s First law; thus, the drug absorption via passive drug diffusion is driven by the maximum concentration in GIT [55]:

where the flux (J) of a drug through the GI barrier wall, which is defined as dM, the cumulative transport mass during dt, depends on the diffusion area (S), permeability coefficient (P) of the drug, and the drug concentration (C) in the GI lumen (assuming sink conditions). From this equation, it can be estimated that increasing the drug solubility can improve the absorption of a poorly water-soluble drug [56, 57].

Factors affecting drug precipitation

The precipitation of drug from supersaturated solutions is a complex function of both nucleation and crystal growth, which in normally, is affected by various factors.

i). Degree of supersaturation: Increasing the degree of supersaturation of SMEDDS formulation favours drug precipitation by increasing nucleation rate. Supersaturation can occur through [58].

(a) Evaporation of solvent from the solution

(b) Cooling of the solution, if solute has positive heat of solution

(d) Addition of a substance which has higher solubility in the solvent than the solid to be crystallized and addition of solvent that lowers the solubility of the solute.

ii). Solubility: At constant supersaturation, increasing the solubility of SMEDDS increases the probability of intermolecular collision, which thereby increases nucleation rate [59].

iii). Impurities: Presence of impurities in solution stimulates the nucleation process. The presence of impurities decreases the energy barrier for the formation of nuclei which ultimately lead to crystal formation [60, 61].

iv). Temperature: Binding between drug and polymer is decreased at higher temperatures due to weakening of intermolecular interactions between the molecules and increased solubility of drug [62].

v). Solution viscosity: Low solution viscosity favors drug precipitation [63].

Mechanism to restrain drug precipitation

The key to designing and developing supersaturable formulations is to identify the optimal combination of “spring” and “parachute” [64-68]. Hence, the most common strategy to maintain supersaturation is to use Pls, such as polymers, surfactants, and/or cyclodextrins, which can produce a combination of “spring” and “parachute” functions [69].

A number of probable mechanisms are proposed, which include the following factors.

i). Spring and Parachute mechanism: Supersaturable formulations are thermodynamically stable formulations which could induce a supersaturated concentration in an aqueous environment of the gastrointestinal tract [70, 71]. The most common ways to initiate supersaturation is through salts which will rapidly dissolve amorphous solids, co-solvents and self-emulsifying formulations. All these formulations are referred to as springs and a formulation component which hinders nucleation or crystal growth acts a parachute to stabilize the metastable supersaturated formulations for a sufficient time period for absorption to take place. Parachute slowly settles down concentration to the saturation solubility given in fig. 3. The generation of a supersaturated state and subsequent inhibition of precipitation have been referred to as a ‘‘spring and parachute’’ approach [72, 73].

Fig. 3: Spring with parachute mechanism. Reprinted from [25] with permission (Elsevier 2015)

ii). Reticulate formation: Creation of a widely spaced cellulosic polymer network has been proposed to generate a supersaturated state of HPMC with supersaturable SMEDDS formulation.

iii). Hydrogen bonding: HPMC or the hydrophilic polymers can thus form both intramolecular and intermolecular hydrogen bonds with drug, which is likely to retard drug precipitation [74].

Kinetics drug supersaturation

The high drug solubilization of lipid-based formulations is a supersaturation effect; however, there is also a further increase in the solubility limit in the presence of lipids [75]. Fast dispersion occurs in parallel to rapid initial drug release for self-emulsifying systems. This initial increase in concentration beyond the thermodynamic solubility limit has been termed “spring”, whereas a “parachute” is the ability to sustain drug supersaturation, as given in fig. 4. The latter concept of supersaturation is often understood as a supersaturation ratio S, as given in below equation:

Where c is the (molar or mass) concentration of supersaturated drug and c* denotes the equilibrium solubility.

Pharmaceutical characterization and evaluation of Su-seddss

The final su-SEDDSs should be characterized for various parameters, including

Droplet size and polydispersity index

The droplet size (z-ave) and polydispersity index (PI value) can be determined by using a photon correlation spectroscopy technique and Dynamic light-scattering is the most widely used for routine evaluation of emulsion particle size and also small angle X-ray and coulter counter can be used for the droplet size analysis.

Fig. 4: Idealized concentration profiles of how lipid-based formulations (LBFs) can solubilize a poorly water-soluble drug in the gastrointestinal tract. Reprinted from (62) with permission

Conductivity and viscosity measurements

Conductivity measurements determine the point of aqueous phase addition at which the system changes from having an oil-continuous to a water-continuous phase. They can be applied to monitor the percolation and phase-inversion of emulsion [76]. The viscosity of liquid SNEDDS is generally known by a viscometer, such as, Brookfield cone and plate viscometer.

Self-emulsification properties

The free energy of emulsion formation is a direct function of the energy required to create a new surface between the two phases [77-79]. This self-emulsification process is defined by the equation below:

Where ΔG represents the free energy associated with the process, N is the number of droplets of radius r, and σ is the interfacial energy [80].

Zeta potential

The particle charge of formed nanoemulsions can be determined according to the Smoluchowski theory. Zeta potential indicates the stability of the colloidal dispersion. The formulation will remain stable if it has a high zeta potential, especially when the zeta potential value is more than±30 mV [81].

Morphology

The morphology of the nanoemulsion droplets can be determined by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) [82-85].

Phase separation method

The general method of knowing the stability of SEDDSs is the phase separation method.

Samples diluted with distilled water are centrifuged at a specified rpm for a specified amount of time and their phase separation is investigated. The determination of the cloud point is a crucial tool in the case of SEDDSs containing non-ionic surfactants. At the cloud point, irreversible phase separation occurs owing to an increase in temperature. The cloudiness of the preparation negatively influences the absorption of the incorporated drug because it indicates the dehydration of the SEDDS ingredients. Hence, the cloud point of self-emulsifying systems must be above 37 °C to avoid phase separation in the gastrointestinal tract [86].

Effectiveness of drug loading

The drug loading efficiency is tested and used to determine the fraction of drug-loaded into the solvents. By increasing the concentration of the oily phase, it reduces the loading capacity of the drug [87-90].

Self-nanoemulsification time

The efficiency of self-nano emulsification is assessed using a dissolution apparatus. In this method, 1 ml of the SNEDDS is dissolved in 250 ml of water at 37±0.5 °C. Gentle agitation is applied by paddle rotating at 50 rpm. SNEDDS are assessed visually according to the rate of emulsification and the final appearance of the emulsion. The time taken for the emulsification is noted and particle size is determined by photon electron microscope.

Refractive index

The RI of the system is measured using a refract meter by placing a drop of the solution on a slide and comparing with water, which has an RI of 1.333. If the RI of the system is similar to the RI of water, the formulation has a transparent nature.

Spectroscopic evaluation

For the qualitative and quantitative analysis of lipid-based formulations, spectroscopic techniques can be used as non-destructive methods [91]. Especially, low-frequency dielectric spectroscopy (LFDS) is based on the measurement of conductivity caused by the polarization of a material that occurs after the application of an electrical field. To analyze the intermolecular interactions and drug-excipient compatibilities, considering the structure and dynamics of microemulsions, Fourier-transform infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance are the most widely used [92-94].

Small-angle X-ray scattering

Small-angle X-ray scattering (SAXS) has been used for the determination of the microscale or nanoscale structure of particle systems, including the shape and size of macromolecules, characteristic distances of partially ordered materials, pore sizes, and other related data [95].

Biorelevant supersaturation testing

Many research scientists, promising progress has been made in the development of a biorelevant in vitro digestion model with good IVIVC for predicting the effects of various GI factors on the performance of supersaturable drug delivery systems, including in vivo supersaturation, drug precipitation, and absorption. More recently, improved computational models of the gastrointestinal environment using molecular dynamics showed a great potential to assist the complex process of drug formulation [96, 97].

Percentage transmittance

The percentage transmittance of the system is determined following the dilution of the formulation at 638 nm wavelength by a UV-spectrophotometer and using the water as blank. If the percentage transmittance value is closer to 100%, the formulation would indicate a clear and transparent nature.

In vitro dissolution study

The in vitro dissolution profile of the SNEDDS should be evaluated using a dissolution apparatus Type II in various dissolution media associated with the purposed route of administration, such as, pH 1.2 and pH 6.8 for oral application. The dissolved drug in the dissolution media would be collected during a set period of time and analysed by an appropriate analytical method. Cumulative amounts of drug dissolved against the times of the preparation would be plotted compared with the pure drug.

In vitro digestion model

There has been a development of a range of in vitro models simulating the digestion processes occurring in the GIT to evaluate su-SEDDSs. Many reviews have been reported, including detailed explanations [98].

Thermodynamic stability

To overcome the problem of metastable formulation, a thermodynamic stability test would be performed. The liquid Su-SNEDDS would be centrifuged at 3,500 rpm for 30 min. The formulation that does not show any phase separation would be subjected to the heating-cooling cycle. Six cycles between 4 °C and 45 °C for 48 h would be conducted. The formulation that is still stable would then be subjected to the freeze-thaw stress test by achieving three cycles between-21 °C and 25 °C for 48 h. The formulation that endures the thermodynamic stability test would be selected as the stable formulation for further studies.

Stability assessment

The stability study of nanomedicines including the Su-SNEDDS should be performed following the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). For the non-targeted nanomedicines, which are free from the regulations for biotechnological products, should follow the procedures of the ICH Q1A(R2) and Q1C guidelines. Meanwhile, the targeted nanomedicines, which are mostly incorporated with biotechnological products, should follow the procedures of the ICH Q5C guideline. Su-SNEDDS should also be evaluated under the storage conditions for their thermal stability and sensitivity to moisture. In general, the recommended long-term and accelerated storage conditions by the ICH guidelines are 25 °C±2 °C/60% RH±5% RH and 40 °C±2 °C/75% RH±5%RH, respectively. Appropriately, an intermediate storage condition (30 °C±2 °C/65% RH±5%RH) is recommended. In addition, if any drug products are intended for storage in a refrigerator, long-term and accelerated storage conditions are recommended at 5 °C±3 °C and 25 °C±2 °C/60% RH±5%RH, respectively [99].

HTP lipolysis model

To evaluate drug precipitation of a large pool of su-SEDDS formulations and select optimum PI, in vitro HTP lipolysis model has been required and developed. Presently, it was reported that the HTP lipolysis model become a useful tool to predicts drug dissolution and precipitation during the digestion of lipid-based formulations containing poorly water-soluble drugs in the same manner as pH-stat lipolysis models [100].

Digestion–permeation models

It may provide a better indication of various mechanisms critical to the negation of food effects and the enhancement of overall systemic drug exposure and recent research reported in vitro digestion-in vivo permeation model, which is called in situ perfusion [101, 102].

In vitro evaluation of solid su-SEDDSs

Whether the emulsion is formed as originally designed and has the desired properties after solidification should be evaluated [103]. After the re-emulsification evaluation mentioned below, evaluation using the emulsion characterization methods.

Re-emulsification and drug release from solid su-SEDDSs

Solid su-SEDDSs should maintain their self-emulsifying ability and should be able to be forming fine oil-in-water emulsions under the gentle agitation provided by GI motion. The drug is introduced in a dissolved state and has a huge interfacial area for absorption provided by the emulsion droplets, resulting in enhanced bioavailability. As the drug is transferred from solid su-SEDDSs into the dissolution medium and solubilized in the oil/surfactant emulsion droplets, the rate of release is expected to be controlled by the rate of re-emulsification and the completeness of reconstitution.

Stability assessment

The stability study of nanomedicines, including the SNEDDS should be performed following the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) For the non-targeted nanomedicines, which are free from the regulations for biotechnological products, these should follow the procedures of the ICH Q1A(R2) and Q1C guidelines and the targeted nanomedicines should follow the procedures of the ICH Q5C guideline [104].

Pharmaceutical excipient for solidification

The proper solid excipients for the solidification of su-SEDDSs should be adapted precisely because of their critical implications for not only the physicochemical properties of the su-SEDDS formulation but also in vivo drug absorption from the formulation. The water-insoluble mesoporous silica and Microcrystalline cellulose (MCC), water-soluble polysaccharide, or polymer or protein-based solid carriers are generally used as solidification excipients [105]. Eminently, some of the application cases in su-SEDDS have been reported, given in table 2. Many reviews have broadly discussed the properties of these excipients and in this review, only the summarised information about various solidification process for Su-SEDDS is mentioned in table 4 and an overview of approved anti-cancer nanodrugs are given in table 5.

Table 4: List of drugs that have been formulated into supersaturable self-emulsifying drug delivery system (Su-SEDDS)

Drug (BCS class)	Preconcentrate	PI		Dosage form (Solidification method)	Result/Outcome	Ref.
	Formulation (Drug Conc.)	Substance (Conc.)	PI Addition method
Resveratrol (BCS II)	Lauroglycol FCC, Transcutol P (100 mg/450 mg)	HPMC-E15LV(5%w/w)	Suspending ine pre-concentrate by vortexing (Suspension)	Liquid	-In vivo in Wister rats at a dose of 20 mg/Kg, 1.33-fold increase AUC of the su-SEDDS than conventional SEDDS without PI.	[146]
Silybin (BCS II)	Labrafac CC, Cremophor RH40, Labrasol (40 mg/1090 mg)	HPMC-E50LV (5% w/w)	Suspended in preconcentrate by vortexing (Suspension)	Liquid	-In vivoin SD rats at a dose of 533 mg/kg, three-fold increased AUC than those of the t conventional SEDDS without HPMC	[147]
Siliymarine (BCS II)	Labrafil M 1944 CS, Kolliphor® RH 40, Transcutol HP (15.6% as milk thristle powder, w/w)	Poloxamer 407 (10%w/w)	Dissolving in pre-concentraate by heating and magnetic stirring (Poloxamer 407: Clear solution). Suspending in pre-concentrate by milling (Other Pls: Suspension)	Liquid	-PI effect: Poloxamer 407>HPβCD, HPMCP, Eudragit L100. -In vivo in Rabbits at a dose of 28 mg/kg as silybin, 760% BA of su-SEDDS vs Legalon®, commercial products.	[148]
Tacrolimus (BCS II)	Capmul MCM, Cremophor EL, and Transcutol P (5.9%,w/w)	Soluplus (5.9%, w/w)	Suspended in preconcentrate by vortexing using a magnetic stirrer (Suspension)	Liquid	-PI effect: Soluplus>HPMC, PVP. -Concentration-dependent PI effect -In vivo in SD rats at a dose of 5 mg/kg. Similar or higher AUC and Cmax of su-SEDDS containing one-quarter the amount of vehicle compared to conventional SEDDS.	[149]
Valsartan (BCS III)	Capmul MCM, Tween 80, Gelucire 44/14, water (80 mg/190 mg)	Poloxamer 407 (5.3 %,w/w)	Adding in pre-concentrate	Solid su-SEDDS (Kneading and granulation by sieving, HPC and Florite® PS-10)	-Concentration-dependent PI effect -In vivo in SD rats at a dose of 10 mg/kg. Approximately 177%-198% AUC versus raw drug and Diovan®, commercial product.	[150]

Table 4 cont

Drug (BCS class)	Preconcentrate	PI		Dosage form (Solidification method)	Result/Outcome	Ref.
	Formulation (Drug conc.)	Substance (Conc.)	PI Addition method
Dutasteride (BCS II)	Capryol 90, Cremophor EL, Transcutol HP (100 mg/20.1 g)	HPMC, Solupus(1:1 w/w ratio compared to pre-concentrate)	Mixing with pre-concentrate (2.01 g) anad PI solution (2g in 400 ml EtOH) dispersed with solid carrier, Aerosil 200 (2g)	Solid su-SEDDS(Spray drying)	-In vivo in SD rats at a dose of 2 mg/kg, higher oral BA with 6.8 and 5.0-fold for C _max and AUC, respectively, compared to the physical mixture.	[118]
Dutasteride (BCS II)	Capryol 90, Cremophor EL, Transcutol HP (Drug: Vehicle=1:67.6,w/v)	Soluplus Vehicle=10:67.6(w/v)	Suspending in preconcentrate by vortexing (Suspension)	Liquid	-In vivo in SD rats at a dose of 2 mg/kg, 3.9-fold greater AUC than that of drug suspension.	[198]
Ellagic acid (BCS IV)	Ethyl oleate, Tween 80, polyethylene glycol (4 mg/g)	PVP K30 (0.5%, w/w)	Adding in preconcentrate by vortexing	Liquid	-Concentration-dependent on PI effect. -Good correlation between in vitro nucleation inhibition effect of PI and in vivo antioxidant ability.	[153]
Fenofibrate (BCS II)	Ethyl oleate, Cremophor RH40, Transcutol HP (15%w/w)	Soluplus: Drug=1:1(w/w)	Physical blending with solid su-SEDDS	Solid su-SEDDS(Solvent evaporation, mesoporous silica)	-In vivo in beagle dogs at a dose of 100 mg, 1.4-fold greater AUC than that without Soluplus.	[78]
Fenofibrate (BCS II)	Captex 300, Capmul MCM, Cremophor EL, Transcutol HP (40% or 85% of saturated solubility in formulation)	Lipid soluble: Eudragit RL100(5%,w/w), PPGAE(1%,w/w) Water soluble: HPMC E4M (5%,w/w)	Dissolving in pre-concentrate by vortexing (Lipid soluble: Clear solution, Water-soluble: Suspension)	Liquid	-Polymer specific stabilizing agent -In vitro-in situ model using SD rats, potential utility of PPIs in promoting drug absorption via stabilization of supersaturation.	[19]
Ezetimibe (BCS II)	Captex 355, Cremophor RH40, Imwitor 988(90% saturation solubility level of 90.62 mg/ml)	HPMC-E5 (5%, w/w)	Suspending in preconcentrate by Cyclo-mixer (Suspension	Solid su-SEDDS(Adsorption and granulation, MCC and talc))	In vitro release improved by 1.18-1.69, and 13.21-fold as compared to solid-SEDDS, commercial product, and the free drug, respectively.	[116]
Curumin (BCS IV)	Capryol 90, Labrafac PG, Cremophor EL, Labrasol (40 mg/940 mg)	Eudragit E PO (5% w/w)	Suspending in pre-concentrate by blending (Suspension)	Liquid filled in hard gelatin capsule	-In vivo in rabbits at a dose of 50 mg/kg, 1.22-and 53.14-fold increased absorption as compared to the conventional SEDDS without PI.	[155]

Table 4: Cont

Drug (BCS class)	Preconcentrate	PI		Dosage form (Solidification method)	Result/Outcome	Ref.
	Formulation (Drug Conc.)	Substance (Conc.)	PI Addition method
Cyclosporin A (BCS II)	Maisine 35-1, Kolliphor RH 40, ethanol, and propylene glycol (Drug: Vehicle=1:4.5 (w/v))	PVP: Vehicle = 0.3:4.5 (w/v)	Suspending (HPC) or dissolving (Kollidon VA64 and PVP in pre-concentrate by vortexing (Suspension)	Liquid	-PI effet: Without PI=HPC=PVPVA64<PVPK17 -In vitro dialysis test, equivalent concentration profile with that of conventional SEDDS prepared with two times more amount of lipid vehicle	[156]
Danazole (BCS II)	Captex 300, Capmul MCM, Cremophor EL, EtOH (40% or 80% of saturated solubility in formulation)	HPMC E4M (5% w/w)	Suspending in pre-concentrate (Suspension)	Liquid filled in hard gelatin capsule	-PI effect: Cellulosec PPI>Mesoporous silic, Eudragits, PVPs. -In vivo in beagle dogs, PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation), but not at higher drug loads (80%saturation).	[157]
Docetaxel (BCS II)	Labrafac, Cremophor RH40, Transcutol P (40 mg/640 mg)	HPMC K100 (2.5%,w/w)	Dispersing in pre-concentrate (ND)	Solid su-SEDDS(Spray drying, Lactose: pre-concentrates=6g: 8g in 100 ml water)	-In vivo in SD rate at a dose of 10 mf/kg, AUC increased by nearly 8.77-fold, 1.45-fold more than those of the powder drug than those of the powder drug and the conventional SEDDS without PI.	[158]
Dutasteride (BCS II)	Capryol 90, Cremophor EL, Transcutol HP(0.5 mg/170 kg)	Gelatin (44%,w/w)+Soluplus (14.7%, w/w0	Mixing with pre-concentrate and PI solution (Clear solution)	Solid su-SEDDS(Spray drying, Gelatin)	-PI effect on dissolution anad prolonged supersaturation state: Combination of gelatin with Soluplus>Gelucire 44/14, poloxamer 407, sodium lauryl sulfate, Soluplus, Solutol HS15 or TPGS.	[159]
AMG 517 (BCS II or IV)	Capmul MCM, Tween 80, PEG 400 (12.5 mg/450 mg)	HPMC-E5 (5% w/w)	Suspending in pre-concentrate by vortexing (Suspension)	Liquid filled in hard gelatin capsule	-PI effect: HPMC>PVP -Hydrophobicity dependent PI effect. -In vivo in Cynomolgus monkeys at a dose of 12.5 mg: -30% higher C_max and AUC, and short T_max as compared to an aqueous suspension.	[19]
Carbamazepine (BCS II)	Miglyol 812 N, Tween 80 Cremphor EL-35, PEG 400 (25 mg/830 mg)	PVP-K90 (2%w/w)	Dissolving in pre-concentrate by heating and stirring (Clear solution)	Liquid filled in soft gelatin capsule	-PI effect: PVP>HPMC -In vivo Beagle dog at a dose of 200 mg, 6.7 times higher C_max, 5.9 times higher AUC as compared to commercial tablet.	[161]
Celecoxib (BCS III)	PEG 400, EtOH, Tween 80, Oleic acid, Tromethamine, water (200 mg/g)	HPMC-E5(3.8%,w/w)+ PVP-12PF(4.7%w/w)	Suspending in pre-concentrate by vortexing (Suspension)	Liquid filled in hard gelatin capsule	-Highly supersaturated state in the aqueous, resultinh in high drug concentration in octanol for biphasic in vitro test dissolution method. -Good in vitro-in vivo correlations (IVIVC) with human PK as compared to solution and marketed capsule formulation.	[162]
Drug (BCS class)	Preconcentrate	PI		Dosage form (Solidification method)	Result/Outcome	Ref.
	Formulation (Drug conc.)	Substance (Conc.)	PI Addition method
Celecoxib (BCS III)	Caproyl 90, Tween 20, Transculatol HP (180 mg/ml)	Soluplus (4%, w/v)	Adding in pre-concentrate by vortexing (Suspension)	Solid su-SEDDS (Adsorption method, Sylysia 350 fcp)	-Physico-chemical properties (surface area, hydrophobicity) of solid carrier dependent drug dissolution. -In vivo in SD rats, 2.34-fold increase in C_max and 4.82 fold increase in AUC as compared to drug powder.	[163]
Celecoxib (BCS III)	Caproyl 90, Tween 20, Tetraglycerol (200 mg/ml)	Soluplus (4%, w/v)	Adding in pre-concentrate by vortexing (Suspension)	Liquiid	-In vivo in SD rats at a dose of 100 mg/kg, 1.32-fold increase in C_max and 1.35-fold increase in AUC and 0.49-fold decrease in T_max as compared to conventional SEDDS without PI. -Good correlation between in vitro dissolution, permeation and in vivo PK	[164]
Pacilitaxel (BCS IV)	EtOH, PEG 400, Cremophor EL, Glceryl dioleate (57 mg/g)	HPMC-ESLV (5% w/w)	Suspending in pre-concentrate by hand mixing (Suspension)	Liquid	-In vivo in SD rats at a dose of 10 mg/kg, 10-and 20-fold higher C_max and 5-and 10-fold higher AUC compared with those of Taxol® formulation and the conventional SEDDS, respectively.
PNU-91325 (BCS II or IV)	Cremophor EL, PEG 400, Dimethylacetamide, Pluronic L44, HPMC, Glycerol monooleate, Glycerol dioleate, water (4%, w/w)	HPMC-E50LV (20%w/w)	Suspending in pre-concentrate by vortexing (Suspension)	Liquid filled hard gelatin capsule	-In vivo in beagle dogs at a dose of 10 mg/kg. Oral BA of-76% compared to that of a PEG 400 (-12%) or tween(-68%) formulations.	[166]
Indirubin (BCS II or IV)	Maisine 35-1, Cremophor EL, Transcutol P	PVP-K17(0.5%,w/w)	Dispersing in pre-concentrate by vortexing	Liquid	-PI effect: PVP-K17>PEG 4000 and HPMC -In vivo in SD rats at a dose of 2.58 mg/kg, improved oral absorption and relative BA (129.5%) compared with conventional SEDDS, respectively.	[102]
Glipizide (BCS II)	Captex 355: SolutolHS15:Imwitor 988 (4%, w/v)	HPMC-ES (5%, w/w)	Suspending in pre-concentrate by Cyclo-mixer (Suspension)	Solid su-SEDDS (Adsorption, calcium carbonate and talc)	-In vivo in Himalayan rabbits at a dose of 1 mg/kg, increase in C_max (3.4-fold) and AUC (2.7-fold) from solid su-SEDDS as compared with pure drug.	[116]
Griseofulvin (BCS II)	Oleic acid, Labrafil, Tween 20, Labrafac PG (5 mg/16.545 g)	Poloxamer (0.48%)	Adding in preconcentrate	Liquid	-PI effect: Poloxamer>HPMC -In vivo permeability in Wister rats at a dose of 1 ml, with a concentration of 0.05 mg/ml, three-fold more permeability through the intestine, compared with conventional SEDDS.	[169]

Table 5: Overview of approved anti-cancer nanodrugs

Name	Formula	Advanced indication (s)	References
Mepact	Liposomal mifamurtide	Osteosarcoma	[180]
Onivyde	Liposomal irinotecan	Pancreas ca	[181]
DaunoXome	Liposomal daunorubicin	HIV-related Kaposi sa	[191]
Caclyx,, Doxil	Pegylated liposomal doxorubicin	Breast, Ovarian ca, Kaposi sa, Mulitple myeloma	[190]
Oncaspar	PEG asparaginase	Acute lymphoblastic leukemia	[183]
DepoCyte	Liposomal cytarabine	Lymphomatousmeningosis	[192]
Marqibo	Liposomal vincristin	Acute lymphoblastic leukemia	[192]
Genexol	Paclitaxel loaded polymeric micelle	Breast, Pancreas ca, NSCLC	[186]
Abraxane	Albumin-bound paclitaxel	Breast, Pancreas ca, NSCLC	[193]
Kadcyla	Trastuzumab linked to emtansine	HER2+breast ca	[194]
Gliadel wafer	Carmustine in poliferosan 20	High grade glial tumors-local therapy	[195]

Suitable solid dosage forms for su-SEDDSs

Tablets

Solid su-SEDDSs can be mixed with other suitable excipients for the tableting; then, the mixture is compressed to a tablet using a compression machine. It is important to select a suitable combination of mixing excipients for tableting to prevent liquid SEDDS escape from the solid carrier by tableting pressure. Eutectic-based self-emulsifying tablets inhibit the irreversible precipitation of the drug within the formulation [106].

Implant

Some authors were reported that 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic agent used to treat a malignant brain tumour, was formulated in SEDDS wafer implant to improve its effectiveness overcoming its short half-life and enhance its stability. These implants showed high in vitro antitumor activity and were less susceptible to hydrolysis as compared to that of PLGA [107].

Suppositories

A few papers demonstrated that solid SEDDS could enhance not only GI adsorption but also rectal/vaginal adsorption. For example, Glycyrrhizin, which barely achieves therapeutic plasma concentrations when administered via an oral route, can obtain satisfactory therapeutic levels for chronic hepatic diseases through either vaginal or rectal self-emulsifying suppositories [108].

Application of controlled-release technology in su-SEDDSs

The application of su-SEDDSs is mainly intended to improve the absorption of poorly water-soluble drugs, it would also be desirable to provide sustained-release action in the case of low-dose drugs with short biological half-lives that require frequent dosing [109, 110].

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 [111]. Their properties are given in table 6.

Table 6: Solid carriers and its properties

Solid carrier	Properties
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.
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
Lactose monohydrate, Starch 1500 and maltodextrin (used as saccharide based diluents)	Have the ability to solubilize in water.

Fig. 5: Probables of SNEDDS (Reprinted from (124) with permission)

Self-double nanoemulsifying drug delivery systems (SDEDDS)

SDEDDS are a promising technology that could resolve this problem. These are w/o/w spontaneous emulsions that consist of hydrophilic surfactant and w/o emulsions where the w/o/w emulsions were spontaneously formed during dilution with water at mild agitation. SDEDDS are applicable for peptides, proteins, and other macromolecular drugs, such as, insulin [112-120].

Targeted SNEDDS

Nanoemulsion droplets have the ability to be maintained in the circulation for a long duration of time. Cationic nanoemulsions can also directly attach to the anionic membrane barriers [121-135].

Perspectives and future trends i

To estimate the feasibility of developing a su-SNEDDS candidate as a final drug product, it is very important to evaluate the formulation using an in vitro digestion model with a good IVIVC. Early in vitro studies emphasized solubilization; however, recent research has shifted this interest to drug supersaturation, as it is triggered by the dispersion and/or lipolysis of lipids. The increasing awareness of the potential of supersaturation as an enabling formulation approach for drugs suffering from solubility-limited absorption has stimulated the need for in vivo predictive supersaturation/precipitation assays. However, intragastric lipolysis is still overlooked, as it is in conventional in vitro lipolysis models. With regard to gastric lipolysis accounting for 5%–35% of in vivo lipolysis and the pH shift due to movement in the gastrointestinal tract, a two-compartment in vitro lipolysis model should be considered a priority method to get a better IVIVC. The importance of the selection of solidification excipients and methods for converting liquid su-SEDDSs to solid dosage forms is also mentioned in this review. Since most solidification studies have been conducted on conventional SEDDSs, further studies about the effect of PIs addition should be performed through the application of more drugs in various aspects. We hope this review will help develop a desired su-SEDDS for a model drug. It should also be beneficial for efficient research based on fundamental and experimental understanding, facilitating the insightful perspective of the reader.

CONCLUSION

Supersaturable-SEDDSs are a promising approach for the formulation of poorly water-soluble drugs to enhance their bioavailability through the induction and stabilization by PIs of a supersaturated drug state in the GI fluid. This approach overcomes the main limitations associated with conventional solubilized SEDDSs.

Su-SNEDDSs in particular shows great potential in enhancing aqueous solubility, stability, oral absorption and in minimizing inter/intra-patient dose variability. SNEDDSs improve the absorption of drugs by several pathways, including increasing membrane fluidity, bypassing the first-pass effect, and inhibition of P-gp efflux. These Su-SNEDDSs dispersion in the GI tract, nano-emulsions are formed, which facilitate oil hydrolysis by lipases on the oil–water interface. Following this process, micelles along with other colloidal structures made of phospholipids, bile salt, and triglycerides are formed, which increase the transport of the drug through the intestinal barrier. The submicron size of the system with enhanced surface activity allows more robust drug transport through the GI boundary layer, conclusively ensuing in superior drug absorption and a rapid onset of action and ease of manufacture and scale-up is one of the most important advantages that make unique when compared with other novel drug delivery systems, such as solid dispersions, liposomes and nanoparticles. To use supersaturable-SNEDDS for a target drug, it is important to understand the in-depth mechanism of precipitation through the supersaturation of the drug. From this, it may be possible to inhibit this precipitation and prolong supersaturation by considering the various factors that influence precipitation, based on this mechanism. Many anti-cancer, anti-diabetic, and anti-viral drug solubility, stability, and bioavailability characteristics were improved via SNEDDSs formulations. In spite of the advancements and conversions in su-SNEDDSs, there are still areas that commitment to be consigned to make su-SNEDDSs commercially gorgeous. The precedence of prospect research should be based on the mechanisms of action of different SNEDDSs formulations and pharmacokinetic studies, especially on human subjects.

FUNDING

Nil

CONFLICTS OF INTERESTS

The authors declare no conflict of interest.

AUTHORS CONTRIBUTIONS

All authors are contributed equally.

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