INTRODUCTION:

Inspite of the significant barriers to drug delivery system in the gastrointestinal tract (GIT), The interest in the oral route is well appreciated by considering its obvious advantages (e.g., ease of administration without requiring sophisticated sterile manufacturing facilities and/or the direct involvement of health care professionals and large patient acceptability)¹. The barriers to absorption via the gastrointestinal tract (GIT) are primarily chemical, enzymatic, as well as penetration related (e.g., mucus layer, intestinal epithelium). During the last few decades, several strategies have been used to overcome these barriers to increase the oral bioavailability of various low soluble drug substances².

These strategies include, enzyme inhibitors, absorption enhancers, chemical modifications, liposomes, micro emulsions, solid lipid nanoparticles, multifunctional polymers and various drug delivery systems In particular, SNEDDS have recently gained an extensive pharmaceutical attention as potential carriers for oral drug delivery³.

Nanotechnology has revolutionized the sphere of drugs delivery and has overcome the problems of medication insolubility, instability and impermeability⁴. Pharmaceutical nanotechnology has been the charming area and has captured a wider recent medical enchantment. Various nanocarriers were suggested to growth drugs healing efficacy via enhancing their solubility, permeability and balance^5,6. Lipid primarily based drug shipping structures including lipid nanoparticles, liposomes, SNEDDS and self-micro-emulsifying drug shipping structures (SMEDDS) are broadly used for increasing drugs oral bioavailability^7,8,9 SNEDDS and SMEDDS are isotropic combination of oil, surfactant and co-surfactant that spontaneously supply oil-in-water kind dispersion with mild agitation.¹⁰ SNEDDS are differentiated from SMEDDS in term of emulsion droplet length ensuing in transparent to opalescent emulsions with about 200 nm droplet length¹¹

SMEDDS give emulsions with droplet size 100nm. Furthermore, SMEDDS contain higher surfactant and co-surfactant content and decreased lipid content as compared to SNEDDS¹². Greater extent of hydrophilic surfactant results in decreased droplet size of SMEDDS due to greater reduction of the interfacial energy and better emulsification¹³. Furthermore, risk of drug precipitation in SMEDDS is higher due to increase in the proportion of hydrophilic surfactants, co-surfactants and co-solvents . The present article is mainly focusing on nanoemulsions and more specifically on the spontaneously forming nanoemulsions or self-nanoemulsifying systems for oral drug delivery.

Self nano emulsifying drug delivery system (.SNEDDS):

Self-nanoemulsifying drug delivery systems (SNEDDS) are isotropic mixtures of oil, surfactant and cosurfactant spontaneously forming an O/W nanoemulsion upon mixing with water. The formed nanoemulsion is a thermodynamically stable system with extremely small droplet size (i.e., 650nm). Following their oral administration, drug loaded SNEDDS can rapidly disperse in gastrointestinal fluids resulting in the formation of drug containing nanodroplets which could diffuse through the mucus gel layer

Advantages of SNEDDS¹⁴

· It facilitates s in inter & intra subject variability & food effects

· Quick action in case of inflammation, Angina can be obtained by SNEDDS which can facilitate oral absorption of the drug,

· The SNEDDS can improve oral bioavailability and therapeutic effect of various drugs, Protein & Peptides

· It can be used to enhance the bioavailability of various therapeutic natural phytochemicals

Formulation Consideration for SNEDDS.¹⁵

Successful fabrication of SNEDDS relies upon at the thorough expertise of the spontaneous Nano emulsification method and additionally at the physicochemical and biological nature of the components used for the fabrication of SNEDDS

The factors influencing the phenomenon of self-nano emulsification are:

· The physicochemical behaviour and concentration of oily phase, surfactant and co-emulsifier or cosurfactant or solubilizer

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

· The temperature and pH of the aqueous phase where nano emulsification would occur;

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

Figure 2: Methods used for formulation of SNEDDS

Drug solubility studies:

Drug solubility is an major parameter in SNEDDS formulation, the solubility of drug in diverse oils, surfactants and co-surfactants using shake flask technique. An excess amount of Drug is added to each oil, surfactants, and co-surfactants followed by vortex mixing for at least 15 min. The combination are shaken for 24 h at room temperature for facilitating the drug solubility. The mixtures were centrifuged at 5000rpm for 10 min and Samples were assayed by using UV–vis spectrophotometer (UV-240, Shimadzu, Japan)¹⁶

Selection of Oil phase¹⁷

The oil phase has great importance in the formulation of SNEDDS as physicochemical behaviour of oil (e.g., molecular volume, polarity and viscosity) extensively govern the spontaneity of the nanoemulsification technique, droplet size of the nanoemulsion, drug solubility and biological fate of nanoemulsions and drug. Usually, the oil, which has maximum solubilizing capability for the chosen drug candidate, is selected as an oily phase for the formulation of SNEDDS. This allows to attain the maximal drug loading inside SNEDDS. At the equal time, the chosen oil need to be able to yield nanoemulsions with small droplet size. Hence, the choice of the oily phase is mostly a compromise among its capability to solubilize the drug and its capacity to facilitate formation of nanoemulsion with desired traits.

Table :1 Various Oils used SNEDDS fabrication¹⁸

Oils	Examples	Acceptable Routes
Fixed oils	Sunflower oil, Soybean oil, arachis oil, Castor oil, cottonseed oil, maize (corn) oil, hydrolyzed corn oil, olive oil, sesame oil, sunflower oil, palm oil, peanut oil, triolein	oral/parenteral/ opthalmic/ topical
Fatty acid	Oleic acid (Crossential O94), Caprylic acid	oral/topical/mucosal
Long chain mono glycerides	Glyceryl monooleate (Peceol, Capmul GMO), glycerylmonolinoleate (Maisine ‑35)	oral/topical
Fatty acid esters	Ethyl Oleate (Crodamol EO), Ethyl butyrate, Isopropyl myristate, Isopropyl palmitate	oral/topical/mucosal
Caprylic/ capric/diglyceryl succinate	Miglyol 829	oral/topical

Selection of Surfactants:

The preference of surfactant is also essential for the method for the fabrication of SNEDDS. The properties of the surfactant, such as HLB (in oil), cloud point, viscosity and affinity for the oily segment, have impact on nanoemulsification technique, self nanoemulsification location and the droplet size of nanoemulsion The concentration of the surfactant within the SNEDDS has extensive have an impact on at the droplet size of nanoemulsions.

The acceptability of the chosen surfactant for the selected route of administration and its regulatory requirement (e.g., usually considered as safe [GRAS] status) should also be taken into consideration throughout surfactant selection. +

Table: 2 Various surfactants usedin SNEDDS fabrication

Surfactant	Examples	Acceptable Routes
Polysorbates	POE-20-sorbitan monooleate POE-20-sorbitan monolaurate	oral/parenteral/ opthalmic/topical
Sorbitan esters	Sorbitan monooleate, Sorbitan monolaurate, Sorbitanmonostearate	oral/topical/mucosal/Parenteral
PEO–PPO–block copolymers	Poloxamer 188 Poloxamer 407	oral/parenteral/opthalmic
POE castor oil	POE-35-castor oil	oral/topical/ mucosal/ Parenteral
Sucrose esters	Sucrose laurate Sucrose palmitate	oral/topical

Selection Co-surfactants¹⁹

Co-surfectants play major role in the fabrication of SNEDDS for pharmaceutical use. They can be included in SNEDDS for various purposes, for enhancing drug loading to SNEDDS; .To modulate self-nanoemulsification time of the SNEDDS; .To modulate droplet size of nanoemulsion .Hence, surfactants (hydrophilic or lipophilic) and/or amphiphilic solubilizers with pharmaceutical acceptability are used for this purpose. The incorporation of the co emulsifiers or solubilizers in SNEDDS may result in an expanding self-nanoemulsification region in the phase diagrams.

Construction of ternary phase diagram²⁰

Construction of pseudoternary phase diagram is an important tool for screening of self-dispersible formulation components and to assess the effect of different component on in-vitro performance of formulation. Pseudo-ternary phase diagram of selected oil, surfactant and cosurfactant was plotted for identification of self-nanoemulsification region and optimization of concentration of oil, surfactant and cosurfactant each of whicrepresenting an apex of the triangle

Figure 3: Pseudoternary Phase diagram for SNEDDS

Characterization of drug loaded SNEDDS formulations²¹:

Morphological Characterization:

The morphology of SNEDDS is vary vital from drug delivery standpoint. transmission electron microscopy (TEM) (Hitachi transmission electron microscope H7650, Japan) is used to figure out the mophology SNEDDS formulationis diluted with distilled water and combined by barely shaking. One drop of diluted samples was deposited on a film-coated 200 mesh copper specimen grid and allowed to stand for 20 min, after which any excess fluid is eliminated with the filter paper. The grid was later stained with one drop of 2% phosphotungstic acid and dried for 15 min before examination with the transmission electron microscope.²²

Determination of Droplet Size and Zeta-Potential:

Droplet size and zeta potential of SNEDDS has an great impact on drug loading, Stability of formulation and delivery of drug from carrier molecule Dynamic light scattering with particle size apparatus (Malvern Zetasizer Nano ZS90, UK).is used for this pupose,

Thermodynamic stability:

To assess the thermodynamic stability of prepared SNEDDS formulations, it is exposed to various stress conditions including incubation at 4°C and 40°C (heating-cooling cycles) followed by incubation at −20 °C and 25°C (freeze-thaw cycles) for at least 48 h. For centrifugation stress, SNEDDS formulations are reconstituted to give 100 times dilution which are centrifuged at 12,000rpm for 15min and observed for any drug precipitation and phase separation

Percent transmittance:

Percent transmittance of SNEDDS formulation is measured by using UV–visible spectrophotometer considering distilled water as a blank, the formulation is diluted in water and visually observed for any turbidity.

Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA):

DSC and TG studies were performed for analyzing the qualitative property and thermal behavior of drug in the optimized SNEDDS formulations. Samples were analyzed using TA instruments SDT Q600 Differential scanning calorimeter. For DSC analysis, 5mg of each sample were heated up to 600°C under a nitrogen atmosphere at 50 kPa pressure at a rate of 10°C/min over a range of 30–600°C. For TGA analysis, each sample (6 mg)were analyzed using thermal ramp covering a temperature range of 25–600°C at a rate of 10°C/min under nitrogen atmosphere at 50 kPa pressure.

In vitro dissolution studies:

In vitro drug release was performed at pH 1.2, 4.6 and 6.8 by using dialysis bag of 12,000 kDa. Reconstituted CFT loaded SNEDDS equivalent to the 30 mg drug were filled in activated dialysis membrane. Formulation filled bags were dipped in separate beakers containing 30mL buffer of pH 6.8, 4.6 and 1.2 as dissolution medium at 37°C and subjected to shaking at 100rpm. Aliquots of 2mLwere taken out at specific time intervals and filled up with fresh medium to maintain sink condition. The drug content in samples was determined by spectrophotometer at specific nm and percent drug release was quantified.

SNEDDS IN VARIOUS RESEARCH AREA:

Supersaturated SNEDDS:

Thermodynamically stable s-SNEDDS inhibit and decrease the nucleation procedure and next drug precipitation in GIT by achieving and then sustaining the metastable supersaturated state.This Process includes incorporation of polymeric precipitation inhibitors (PPI’s) which are soluble in water and bring about longer precipitation time compared to mean absorption time

Solid SNEDDS:

Conventional liquid SNEDDS (L-SNEDDS) have some limitations such as liquid drug-drug interactions, drug-excipient interactions and reactions between pre-concentrate and capsule shell, precipitation at lower temperature, cost, palatability, formulation, handling and issues related to stability . Solidification of L-SNEDDS can fix these issues related to formulation, Combining the benefits of both traditional SNEDDS and the solid dosage forms. s- SNEDDS have the advantages of enhanced solubility and bioavailability, control over manufacturing process, less cost, reproducibility, increased stability.²³

Controlled release solid SNEDDS:

SNEDDS display the pharmacokinetic parameters which can be identical to traditional oral dosage forms. Normally SNEDDS show rapid absorption leading to maximum plasma concentration (Cmax) with shorter Tmax after which deep trough in between doses (peaks). This ends in high fluctuations in plasma drug concentration requiring close drug tracking specifically in case of drugs which can be potent and show intense adverse effects . Therefore, formulator are interested in developing SNEDDS with sustained or controlled release profile. For the enhancement in bioavailability.

SNEDDS: as mucus membrane permeation enhancing strategy:

Bioavailability of various drugs depends on its permeability through bio-membrane SNEDDS act as better mucus permeating nano lipoidal carrier. The importance of any mucus permeating method can be understood by knowing the reality that mucus barrier is found in buccal hollow space, nasal cavity, ocular cavity, gut, lungs and vagina Interaction of self-emulsified nano droplets with mucus is low because of hydrophobic surfaces and may cross the mucus layer without being entrapped. Hence easily it can cross the barrier and enhance the bioavailability

SNEDDS for the delivery of bio macromolecules:

Bio macromolecules (Lipids, proteins, genes and polysaccharides) have earned super interest nowadays as contemporary therapeutics because of their excessive selectivity, specificity and low toxic consequences. US-FDA has authorised lot of biopharmaceuticals mainly therapeutic proteins and many extra are within the pipeline which includes gene products for genetic disorders .More than 1800s clinical trials for gene therapeutics are on file and lots of are under different phases of clinical trial.

Site-specific SNEDDS²⁴:

Enhanced therapeutic efficacy and decreased toxicity may be done simultaneously through site-specific drug targeting . SNEDDS were given the capability to be considered for this technique. Surface functionalization of nanoparticulate systems had been tried successfully . Nanoemulsion droplets have higher biological half life stay in the plasma for a longer length of time escaping mononuclear phagocyte system(MPS). Cationic nanoemulsion droplets can be directed in the direction of anionic membrane boundaries . These lipid based structures are taken through the liver and spleen and it could be a clever manner to target those organs . Droplet surfaces may be tailored for stealth properties by way of linking hydrophilic polymers .PEGylation is one such method in which Poly Ethylene Glycol may be connected to the surface of the nano droplet through interaction with the surfactant molecules. As PEG is hydrophilic in nature it draws water making the floor of droplets slippery. This water layer inhibits the opsonins binding to the surface of nanocarriers offering stealth behaviour

CONCLUSION:

Innovative drug discovery programs yield a huge percentage of new chemical entities which might be lipophilic and poorly soluble. Self-nanoemulsifying formulations have proven extraordinary capacity in improving the oral bioavailability of such therapeutic entity with limited aqueous solubility. Enhanced dissolution and absorption is possible due to nanosize of droplets in SNEDDS. The lipophilic nature of these entity directs them towards lymphatic system. The amenability of changing SNEDDS into solid self-nanoemulsifyin structures enables development into solid dosage form. Thus, the self-nanoemulsifying system can serve as platform technology for delivering poorly soluble drugs

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Received on 17.09.2019 Modified on 02.11.2019

Research J. Pharm. and Tech 2020; 13(5):2516-2521.

DOI: 10.5958/0974-360X.2020.00448.5

Drug	Components	Therapeutic Application	*In-vitro* *& In-vivo* observation**	References
Glibenclamide	Capmul® MCM, Tween 20, Cremophor RH 40	Antidiabetic	Enhanced in vitro dissolution rate	25
Tamoxifen	peanut oil, corn oil, sesame oil, soyabean oil, sunflower oil,	Breast cancer	Enhanced in vitro dissolution and Bioavailability	26
Tadalafil	Capryol™ 90 , Labrafil® M 2125 Labrafac™ PG	Phosphodiesterase type 5 inhibitor	Increased dissolution	27
Dapagliflozin	eucalyptus oil, tween 80 and PEG 400	Antidiabetic	Enhanced in vitro dissolution	28
Embelin	Isopropyl myristate Oleic acid	Antibacterial,Antifertility	Enhanced in vitro dissolu	29
Cefatriaxone	soya bean oil, nutmeg oil, coconut oil, cinnamon oil, propylene glycol,	Antibiotics	Improved Bioavilability	30