INTRODUCTION:

In the pharmaceutical sciences, nanotechnology has become a buzzword, and efforts are being made to broaden its applications in a variety of fields. Nanotechnology has had a significant impact on drug delivery research over the last two decades, with several nanoscale technologies/carriers being investigated for improving drug therapeutic performance. The four broad categories of nanoscale technologies are lipid-based nanocarriers, polymeric nanocarriers, inorganic nanocarriers, and drug nanoparticles or nanosuspensions¹. Class IV drugs of the Biopharmaceutical Classification System (BCS) present a significant challenge in oral formulations due to their low solubility and permeability, as solubility enhancement approaches alone may not be sufficient to improve oral bioavailability of these drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel, diclofenac)².

The Self-Nanoemulsifying Drug Delivery System (SNEDDS) is an oil or fat-based nanoparticle formulation made up of an isotropic mixture of the oil phase, surfactant, and co-surfactant that, when mixed with water, forms a spontaneous nanoemulsion O/W. (oil in water)³. When creating SNEDDS, drug molecules can be incorporated into dispersed oil droplets and solubilized in the carrier system. The drug in SNEDDS consistently acts on the target without causing any food-related side effects, and it is rapidly released onto the specific target site⁴. Because the solubility of poorly water-soluble drugs with intermediate partition coefficients (2log P4) is typically low in natural lipids compared to high solubility in amphiphilic surfactants, co-surfactants, and co-solvents, increased drug loading capacity has been observed in SEDDS formulations. A poorly water-soluble compound is one that dissolves in less than one part per ten thousand parts of water^5,6.

Several potential advantages of SNEDDS were drug was presented in a solubilized form inside the gastrointestinal (GI) lumen in a Nano sized globule thus providing greater interfacial area for drug dissolution there by enhancing absorption⁷, improving lymphatic transport, evading hepatic first-pass effect, providing greater chemical and enzymatic stability, and also by inhibiting P-glycoprotein (P-gp) mediated drug efflux. Components of SNEDDS and their concentrations have profound effect upon droplet size of the formed nanoemulsions which may affect its in-vitro and in-vivo performance^8,9.

Advantages and Disadvantages of SNEDDS¹⁰:

Advantages	Disadvantages
Ease of manufacture and scale – up	Drugs which are administered at very high dose are not suitable for SNEDDS
Protection of sensitive drug substances from the hostile environment in gut by providing a large interfacial area for partitioning of the drug between oil and water.	The drug exhibiting limited solubility in water and lipids are most difficult to administered as SNEEDS
Enhanced oral bioavailability by increasing w solubility and reducing the dose, thereby promoting efficient drug transport	The potential of XNEEDS in maintaining the drug in solubilized form is greatly influenced by the solubility of the drug in oily phase
Self nanoemulsifying drug delivery system (SNEDDS) has a much larger surface area and free energy than micro emulsion (SMEDDS)	If the surfactant orco-surfactant contributes to a greater degree for drugs solubilization, more would be the risk of precipitation
Reduction in inter-subject and intra-subject variability and food effects	The stability of self nanoemulsifying drug delivery system was affected by temperature and pH
When polymer is incorporated in composition of SNEDDS it gives prolonged release of medicament	Possibility of drug leakage and precipitation.
Fine oil droplets would pass rapidly and promotes wide distribution of the drug though out the GIT, hence minimizing the irritations encountered during extended contact of bulk drug substance and the gut wall	Lower drug incompatibility and stability

Components of SNEDDS:

Fig. 1. Components of SNEDDS

Oil phase:

One of the most important components of the SNEDDS formulation is the oil phase. The oil is important for selecting the oily phase for Nanoemulsion Formulation because it has the greatest solubilizing ability for the selected drug candidate. The choice of oily phase is determined by the ability of the solubilized drugs, and it is critical to obtain a nanoemulsions with the desired properties¹¹.

General class	Example	Commercial name	References
Fixed oil Medium chain triglycerides	Castor oil, soyabbean oil Triacetin	- Captex 500	12
Medium chain mono-and diglycerides	Mono-and diglycerides of Capric	Inwitor 747, capmol MCM	13
Long chain monoglycerides	Glyceryl monoleates	Campul GMO	14

Surfactant:

It can prevent interfacial voltages while also providing interfacial the term "surfactant" refers to molecules and ions that are adsorbed into the interface¹⁵.

Classification surfactant molecule:

Fig. 2. Classifiction surfactant molecule

Anionic Surfactants:

The negative charged group such as carboxyl (RCOO-), sulphonate (RSO₃ -) or sulphate (ROSO₃-). Examples- Potassium laurate, sodium lauryl sulphate.

Cationic surfactants:

The hydrophilic group carries a positive charge is known has cationic Surfactant. Example- quaternary ammonium halide.

Ampholytic surfactants/Zwitter or Zwitterionic surfactants:

The surfactant unit consist of both charges Positive as well as negative Charge. Example- sulfobetaines¹⁶.

Non-ionic surfactants:

The hydrophilic group carries no charge but derives its water solubility because it can contain strong polar functional groups such as hydroxyl or polyoxyethylene (OCH₂CH₂O). Examples- Sorbitan esters (Spans), polysorbates (Tween 20)¹⁷.

General class	Examples	Commercial name	References
Sorbitan esters	Sorbitan monooleate	Span 80	¹⁸
Polysorbates	Polyoxyethylene-20- Sorbitan monooleate	Tween 80	¹⁹
Polyglycolzyed glycerides	Oleoyl macrogol glycerides	Labrafil 1944 CS	²⁰

Co-surfactants:

A co-surfactant functions similarly to a surrogate unit. To increase surfactant capacity and improve the water solubility of water-soluble drugs, co-surfactant was combined with surfactant units or surfactant units. The primary function of co-surfactant in the nanoemulse drug administration system (SNEDDS) is to reduce interfacial tension at the oil-water interface²¹.

Mechanism of self-emulsification:

The SNEDDS on administration, followed by gentle agitation arising from gastric movements, forms oil in-water nanoemulsions immediately and impulsively with particles of nonmetric range (<200nm)²². These nanoparticles comprising the drug that is previously dissolved in the oil phase provides a superior interfacial surface to facilitate dispersion into GI fluids²³. This increased interfacial area enhances drug solubility and permeability by altering transport property²⁴. Nanosize droplets experience rapid digestion followed by quicker absorption of the drug into the GI tract²⁵. SNEDDS dosages range between 25mg and 2g²⁶. These are effectively encapsulated as single dosage forms which provide greater stability, palatability, and patient acceptance. They also possess higher drug loading capacity when compared to other lipid based formulations²⁷.

Fig 3. Mechanism of action of SNEDDS

Pseudo ternary Phase Diagram:

The self-emulsification process depends upon selection of individual excipients in the formulation³². From the ternary phase diagrams we can observe the self-nano emulsifying region which helps in selection of appropriate ratios of compounds³³. It also helps in selection of suitable excipients ratios for preparing formulation which forms spontaneous emulsion within GI condition upon mild agitation³⁴.The procedure consisted of preparing solutions containing oil and various surfactant-to-co-surfactant weight ratios such as 1:1, 2:1, 3:1, and so on³⁵. These solutions were then vortexed for 5 minutes and an isotropic mixture was obtained³⁶. This diagram corner can represent a % concentration of each phase content. The diagram is useful for providing information about a binary mixture of two components such as surfactant/cosurfactant, water/drug, or oil/drug³⁷.

Characterization of the SNEDDS:

Characterization of liquid SNEDDS:

Droplet size and polydispersity index:

The (SNEDDS) droplet size was determined using a Zetasizer 1000HS and photon correlation spectroscopy, which analyses fluctuations in light scattering caused by Brownian motion of the particle³⁸.

Thermodynamic stability studies:

The thermodynamic stability of the prepared SNEDDS formulations was investigated to determine the effect of centrifugation and temperature on the stability of nano emulsions.

Phase Separation:

The formulations were diluted and agitated with 20 mL distilled water at 37°C for 24 hours before being used. Visual assessment was used to determine the extent of phase separation and precipitation³⁹.

Transmission Electron Microscopy Analysis:

Transmission electron microscopy (TEM), samples were properly diluted with water. A drop of diluted sample was placed on 300 mesh carbon coated copper grid. Grid was left for 5 min to settle down the droplets. Then a drop of 1% phosphotungustic acid in water was added to the grid⁴⁰.

Viscosity:

Brookfield Viscometer was used to determine the consistency of nanoemulsions formulation by measuring the viscosity (rheological property) of the self-nanoemulsifying drug delivery system (SNEDDS)⁴¹.

pH Measurements:

The emulsion's clarity is determined by the percentage transmittance. The transmission rate of the nanoemulsion formulation (SNEDDS) was measured at 560nm with a UV Visible dual-beam or single-beam spectrophotometer while the distilled water was kept empty.

Characterization of S-SNEDDS:

Flow Properties of S-SNEDDS⁴²:

Angle of Repose:

Accurately weighed sample was allowed to flow through funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the equation:

tan θ = h/r

where h and r are height and radius of powder cone

The smaller the Angle of Repose is, the better the flowability of the powders.

Bulk density and tapped density:

The bulk density of a powder is the ratio of the mass of an untapped powder sample and its volume including the contribution of the interparticulate void volume. The bulking properties of a powder are dependent upon the preparation, treatment and storage of the sample, i.e. how it was handled. The tapped density is an increased bulk density attained after mechanically tapping a container containing the powder sample. The tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the powder sample.

Compressibility index and Hausner’s Ratio:

The Compressibility index and Hausner’s ratio are measures of the propensity of a powder to be compressed. They are measures of the powder ability to settle and they permit an assessment of the relative importance of interparticulate interactions.

Drug content:

S-SNEDDS were accurately weighed and dissolved in a sufficient amount of solvent. The solution was sonicated for 10 minutes to extract the drug in solvent before being filtered. The absorbance of the filtrate was measured using a UV-Visible Spectrophotometer⁴³.

In-Vitro drug release study:

The in-vitro dissolution study of S-SNEDDS filled into 0 size capsules, API, and marketed drug was performed in 500mL buffer of pH 1.2 containing 0.3 percent w/w SLS at 370.5^oC with 100rpm rotating speed using USP-Type II dissolution test apparatus. Samples were collected at 5, 10, 15, 30, 45, and 60 minute intervals and filtered through a 0.45 filter. To maintain constant volume, an equal volume of dissolution medium was replenished after each sampling. A double beam UV-Spectrophotometer set to 238.8nm was used to analyse the samples. The cumulative percentage of drug released was calculated and plotted against time on a graph⁴⁴.

Future Perspective:

The use of lipid-based formulations in general, and SNEDDS in particular, has the potential to significantly improve aqueous solubility, stability, oral absorption, and reduce inter/intrapatient dose variability. SNEDDS improve drug absorption via a number of mechanisms⁴⁵. The SNEDDS composition should be carefully determined. Because surfactants are typically used in relatively high concentrations in formulation, the toxicity of the surfactant should be considered. In SNEDDS, factors such as pH catalysed drug degradation and solution state drug degradation must be assessed. Although SNEDDS are commonly prepared in liquid dosage forms, solid SNEDDS are preferred due to their ease of handling, transportation, and improved stability. As a result, supersaturable SNEDDS are an effective method for improving the bioavailability of poorly water-soluble drugs via oral administration⁴⁶.

CONCLUSION:

The Self-Nanoemulsifying Drug Delivery System is a novel approach to the formulation of pharmacological molecules with low water solubility (SNEDDS). The Self Nanoemulsifying Drug Delivery System (SNEDDS) is a homogeneous mixture of oils, surfactants, cosurfactant, and co-solvents. SNEDDS improves drug dissolution by increasing the surface area of the dispersion and the rate of absorption of pharmacological molecules. SNEDDS enables the oral administration of lipophilic drugs, which is critical for improving oral bioavailability. The techniques and additives used to make SNEDDS are inexpensive and simple to use. This method, which involves the use of a polymer fuse in the synthesis, can be used to postpone the arrival of medication. It may be possible to develop controlled release SNEDDS by modifying the composition or manufacturing process of tablets or granules.

ACKNOWLEDGEMENT:

Authors would like to thanks Shri Ram Murti Smarak College of Engineering and Technology Department of Pharmacy, Bareilly, Uttar Pradesh, India for giving an idea to research and survey about Matrix tablet employed in this review.

CONFLICT OF INTEREST:

The authors declared no conflict of interest.

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Received on 09.11.2021 Modified on 05.01.2022

Research J. Pharm. and Tech 2023; 16(2):941-946.

DOI: 10.52711/0974-360X.2023.00158

S. No.	Method of preparation	Author	Result	Reference
1	High Pressure Homogenizer	Xiao-Lei Qiu et. al	High-pressure homogenization was used to create and characterize a heparin lipid microemulsion (HEP-LM). HEP-LM improves heparin absorption after oral administration, significantly prolongs activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and decreases fibrinogen (FIB) content. All of these findings suggest that HEP-LM has a lot of potential as an oral heparin formulation.	28
2	High energy approach	Manish Kumar et. Al	High energy method includes high pressure homogenization, microfluidization and ultrasonication whereas low energy methods include the phase inversion emulsification method and the self-nano emulsification method. Low energy methods should be preferred over high energy methods because they use less energy, are more efficient, and do not necessitate the use of sophisticated instruments. However, high energy methods are preferable for food grade emulsions because they require less surfactant than low energy methods.	29
3	Micro fluidization	Singh Dilpreet	In current study, The operating efficiency of a bench-top air-driven microfluidizer was compared to that of a bench-top high power ultrasound horn in the production of pharmaceutical grade nanoemulsions using aspirin as a model drug. Although these studies show that micro fluidizers have better physicochemical stability than ultrasound processors, ultrasound horns are more versatile, energy efficient, and capable of higher product throughput to meet industrial demands.	30
4	Sonication Method	Shah R.B. et. Al	As part of the overall Quality by Design (QbD) goal, a novel application of ultrasonic measurements is detailed to characterize nanoemulsions formulations. Correlation of ultrasonic data with formulation components revealed that increasing oil amount in the formulation, as well as surfactant-to-cosurfactant ratios, correlated negatively with ultrasonic velocity, whereas droplet diameter correlated positively with these formulation factor.	31