INTRODUCTION:

NE's are micro colloidal molecular structures in the micron arrangement acting as carriers of drug particles. Their size ranges between 10 to 1,000 nm. They are negative charged solid sphere-shaped carriers with an amorphous surface and lipophilic nature. Specific site targeting can be progressed by using magnetic nanoparticles. Antagonistic effects and toxic reactions are reduced and increased therapeutic value is observed in this type of DDS. The most important applications include cancer treatment, reticuloendothelial system (RES) treatment during infections, and vaccination. The combination of two phases one in another in the form of micro sphere-shaped particles of diameter ranging between 0.1 - 100nm is known as an emulsion.

An emulsifying agent (emulgent or emulsifier) can stabilize the thermodynamically unstable emulsions. The dispersed phase (DP) is also termed as the internal phase or the discontinuous phase while the outer phase is called the dispersion medium, external phase, or continuous phase¹. The emulsifier is also termed as interphase or intermediate. The NEs are transparent because of their minute size particles dispersed hence, called mini emulsions, another reason for the transparency of NEs is due to their decreased globule size which is less than 25% of visible light². According to the composition NEs are classified as: (a) oil in water NEs, (b) water in oil NEs, and (c) bi-continuous NEs¹.

NEs are clear isotropic dispersions and have thermodynamic stability consists of two immiscible liquids (oil and water) stabilized by interfacial surfactant component^2,3. A NE is considered to have both thermodynamic and kinetic stability due to the presence of surfactant (interface) between two immiscible mixtures of the liquid formulation⁴. The DP is typically made up of small particles or droplets, with a size range of 50 nm–500 nm, and has very low oil/water interfacial tension. The NEs sometimes without the requirement of high energy are formed easily and impulsively. In many cases, the emulsions consist of co-solvent or co-surfactant for enhancing stability⁵. They are having long-term physical stability as they are kinetically stable systems. Brown motion is abundant to resist gravity due to the gravitational force acting NE is very low as this type of formulation contains minute to micron-sized droplets in it, which is a significant feature of NE to reduce flocculation and coalescence effect on it^6,7. Creaming or sedimentation will also not occur during its storage. It has also been proposed that NE formulations are a smart substitute to DDS types having poorly water-soluble drugs^8,⁹. The nanoscale particle sizes mark NEs with a special and acceptable type of DDS with long-term stability^{10, 11}.

Advantages of NEs:

The merits of NEs are^{12,13,14,15,16,17.}

· Liposomes and vesicles can be substituted.

· The bioavailability is improved with these formulations.

· It has non-hazardous and non-irritant properties.

· They have more physical stability.

· Small-sized droplets having a higher surface area can provide maximum absorption.

· Many more varieties of formulations are formed.

· It offers an improved application of cell culture technology for the intake of lipid-soluble forms.

· Solubilization of Lipophilic medications enhanced.

· masking the taste of the API is easy.

· Very low consumption of energy.

Fig.1: Showing the process of formulation of Nanoemulsions by using an ultra sonicator.

Factorial Design:

Factorial design (FD) is the analyzing, planning, performing the experiment, and interpreting the information received from the experiment through a mathematical approach ¹⁸. It belongs to applied statistics study which is helpful for scientific investigation in the experiment to be performed. Sir Ronald Fisher is the pioneer of this FD study¹⁹. The quality of the product and consistency was gradually improved by the practice of FD in pharmaceutical formulations in, last two decades. This process is used in computer simulation models and physical methodologies^20,
21.

Some of the following experimental designs are^22,23:

· Full FD

· Fractional FD

· Plackett‐Burman designs (PBD)

· Box‐Behnken designs/model (BBD)

· Central composite designs/model (CCD)

· Optimal designs/model (D‐criterion)

· Definitive screening designs/model (DSD).

The assets of using FDs is because of its multipurpose means that can be useful in numerous conditions for identification of chief input factors (independent variable) and how they are associated to the outputs (dependent variable). Generally preferred FD types are the following:

1. Comparison ‒ this is one factor among multiple comparisons to select the best option that uses t-test, Z‒test, or F‒test.

2. Variable screening ‒ two-level FDs used to select variables

3. Transfer function identification (TFI) ‒ relation between dependent and independent can be established

4. System Optimization ‒ the TFI can be utilized for optimization by taking the experiment to the optimum setting of the variables

5. Robust design ‒ a decrease of difference in the system, which consists of environmental/external and internal factors.

Table 1: Independent and Dependent variables in preparations of NEs. (Articles published from 2020 to 2015).

Drug	Polymer	Independent variables	Dependent variables	References
Bromocriptine	Propylene Glycol Monocaprylate, diethylene glycol monoethyl ether, Cremophor EL, T80(polyoxyethylene sorbitan monooleate), Propylene Glycol, triethylamine, Carbopol 974P NF	Oil, Surfactant, Co-surfactant, Co-solvent	Particle size (PS), stability, solubility. %transmitance.	24
Pyridoclax	Caprylic/capric acid triglycerides, caprylocaproyl Macrogol-8 glycerides, Kolliphor HS15 (70% PEG 660 hydroxy stearate and 30% free PEG 660).	Quantity of Pyridoclax,	Drug retention time, polydispersity index (PDI), Zeta potential index (ZPI), encapsulation eﬃciency, Pharmacokinetic parameters: Cmax [ng/mL], Tmax [min], AUC _0-α and Confidence Interval (CI), AUC_0-last and CI, MTT (Mean Transit Time).	25
Daidzein	Ethyl oleate, T80, Lipoid S100, isopropyl alcohol, RPMI 1640, Methanol HPLC grade.	The concentration of drug and polymers.	Stability, Rheological analysis, Droplet size (DS) and size distribution, ZPI, pH	26
Fucoxanthin	High-oleic sunflower oil, ABTS+.	Amplitude, temperature, sonication time, and duty cycle.	DS, PDI, ZPI, viscosity, antioxidant, FX content, encapsulation efficiency.	27
Thyme oil, cyclodextrins	PVA, chitosan, T80.	pH, the composition of thyme oil.	Entrapment efficiency, (PS), Swelling ratio, pH.	28
Ceftriaxone Sodium	T20, T80, propylene glycol, polyethylene glycol(PEG) 400, PEG 200, and transcutol.	Combination of drugs with various surfactants and cosurfactants.	DS, PDI, ZPI, shape determination, Thermodynamic stability, Percent transmittance.	29
Captopril	HPMC, T80, Span(S) 85, oleic acid, PEG.	The concentration of T80.	PS, PDI, ZPI, adhesion, film burst(FB), youngsmoudli(YM), disintegration time, permeability,	30
Nimodipine	Transcutol HP, Transcutol P, Capryol 90, Labrafil M 1944, Labrasol, Peceol, Maisine 35-1, PEG400, PEG200, Brij L23 (ethoxylated natural fatty alcohol), Captex 200, Campul MCM, Cremphor EL, Cremphor RH40, T80, Tween 40 (T40), S 120-LQ, S 80-NV-LQ, S 85- NV-LQ, Glycerol.	Concentration and combination of polymers.	Droplet Z-average size, PDI, ZPI, viscosity, emulsification percentage after 20 min, emulsification rate (%/min), emulsification lag time (min), the concentration of fatty acids produced (m·mole), percentage of lipolysis (%), rate of Lipolysis (m·mole/min), percentage drug in the aqueous phase (%), percentage drug in residue, and oily phase (%).	31
Eplerenone	T80, Poloxamer 407, Polyglyceryl-3 methyl glucose distearate.	Constituents (%), encapsulation eﬃciency (EE), and loading capacity (LC) of the NE formulations.	DS, PDI, ZPI, physical stability.	32
eugenol oil	Gum Arabic, lecithin, ethanol.	The concentration of gum Arabica, Drying and Re-dissolution,	Optimization of Aqueous Phase, Optimization of the oil phase, Stability of NE, Drying and re-dissolution of nanoemulsion,	33
Mebudipine	S 80, T20, T80, Propylene glycol, Isopropyl Alcohol and PEG 400.	% w/w of different components.	DS and size distribution, emulsion stability, concentration.	34
Efavirenz	Labrafil M 2125 CS, Labrafil 1944, Labrafac, Peceol, Labrasol, Transcutol P, Lauroglycol, Caproyl 90, and Caproyl P, Capmul, Captex, and Caproyl PGE	The concentration of polymers.	Solubility, Visual Assessment, DS, In Vitro Dissolution	35
Piplartine	T80 PEG 400, solutol HS and trichloroacetic acid.	Plasma concentration of the drug.	Solubility, stability, DS, Caco-2 permeability.	36
Avanafil	T80, Labrafil M, Labrafac, Transcutol, CremophorEL, Miglyol 812 N (triglyceride ester of saturated coconut/palm kernel oil).	Combination of the drug in different oils.	PS, in-vitro dissolution, in vitro drug release, drug bioavailability, PS, surface area, drug solubility, dispersion of drug.	37
olmesartan medoxomil	Sefsol 218 (propylene glycol caprylate), solutol HS 15, soybean oil.	Olmesartan concentration in host body systems.	Molecular weight, Run time (min), mass Fragments, Declustering potential (DP), Collision energy (CE), Entrance potential (EP), Collision cell exit potential (CXP).	38
Daptomycin	Dermofeel MCT, Capmul MCM, Cremophor EL, Cremophor RH40.	The concentration of surfactant and cosurfactants.	DS, PDI, and ZPI	39
Clindamycin	PEG sorbitan monooleate (T 80), sorbitan monolaurate (S 20), methylparaben.	Composition of pre-formulation.	DS, Liquefaction, Color, Phase Separation, Viscosity, pH Determination.	40
betulinic acid	Soybean lecithin, x-3 fatty acids, olive oil.	Fatty acid composition (mol%) in x-3 fatty acid concentrate, medium-chain oil and olive oil.	Saponification, Immobilization of phospholipase A1, acidolysis, stability,	41
Itraconazole	Glyceryl Monocaprylate (Capmul MCM C8) Cremophore EL, Pluronic F127 (Poloxamer 407), Pluronic F68 (Poloxamer 188) and Soya Lecithin.	The solubility of itraconazole in different oils.	drug entrapment, PS, drug concentration.	42
Vitamin E	PEG-40 hydrogenated castor oil, sorbitan monooleate (Mw = 428.61) (S801).	Drug concentration(mg/ml).	Partition coefficient, stability, encapsulation efficiency, drug loading, concentration.	43

Table 2: Independent and Dependent variables in preparations of NEs. Articles published from (2014 to 2010)

Drug	Polymer	Independent variables	Dependent variables	References
Ibuprofen	Miglyol 840, Isopropyl myristate, Isopropyl Palmitate, Labrasol, Triton X 100 (Octylphenol Ethoxylates).	concentrations of ibuprofen (X1), anti-solvent volume (X2), and concentrations of surfactant cosurfactant combination (X3).	PS, Encapsulation, ZPI, Response surface, Permeation	44
Insulin	Soybean phospholipids, Miglyol 74 812N, Capmul1 MCM C10, Cremophor1 RH40.	Bioavailability of insulin, Association efficiency of insulin.	PDI, ZPI, plasma concentration of glucose.	45
Aceclofenac	Ethyl oleate, T80, S80, PEG 400, and Cremophore E.	Aceclofenac in different oils,surfactants: Cremophore , T80,S80,PEG 400.	lowest DS, lowest PDI, optimum, viscosity optimum, surfactant, cosurfactant concentration, highest skin permeation	46
Diazepam	Polysorbate 80, Glycerol, Potassium phosphate buffer.	Oil content (% w/w), Lecithin type, Model drug (DZM).	DS, ZPI, conductivity, viscosity.	47
Thymoquinone	Methanol, 2-propanol, Triolein (TR), T80.	Combination of drug and surfactant.	DS and PDI, ZPI, Refractive Index, stability	48
Tocopherol	Solutol HS15.	Volume of the external aqueous phase, time of coarse homogenization.	PS, density	49
Clotrimazole	Solutol HS 15, Capryol 90, Gelucire 44/14, Methocel E5.	The concentration of clotrimazole and oils.	Drug content, PS, pH, Dissolution, PDI	50
Amoxicillin	Chitosan, Liquid paraffin. T20, S 20, sodium acetate.	S 20/ T20 Mixture surfactant concentration (Wt. %).	Encapsulation efficiency, release profile, pH, H. pylori growth inhibition study.	51
Nystatin	Diethylene glycol monoethyl ethyl ether EP/NF (Transcutol PR), polyglyceryl-6-dioleate (PlurolR oleique), triglycerides medium-chain EP/NF/JPE (LabrafacR lipophile), Labrafac R PG, caprylocaproyl macrogol-polyoxyl-8-glyceride (LabrasolR), Caprylic/capric triglycerides (MiglyolR 812), Propylene glycol.	Mean Solubility Values of Nystatin in Different Oil.	DS, Stability Assays, Rheology.	52
Amlodipine besylate	Capmul MCM, Captex 100, Labrafil M 1944 CS, labrafac CC, labrasol, transcutol P, T80, propylene glycol, PEG, S 80.	Combination of Amlodipine besylate in different oils and surfactants and cosurfactants.	pH, viscosity, and percentage transmittance, PS, PDI, refractive index, ZPI, in-vitro drug release, Thermodynamic stability.	53
Caffeine	Caprylic/capric triglyceride PEG-4 complex (Labrafac), caprylo caproyl macrogol-8-glyceride (Labrasol), oleoyl macro glycerides EP (Labraﬁl), Lauroglycol90, Lauroglycol-FCC and diethylene glycol monoethyl ether.	Type of surfactant: Labrasol, chremopor-EL, tween80, tween 85, Transcutol, Plurol Oleique. The solubility of caffeine.	Screening of oils and water, cosurfactant, the solubility of caffeine.Smix ratio.	54
Indomethacin	Labrafil M1944CS, Tween-80, Transcutol-HP.	Composition of emulsions.	Skin permeation profile, lowest DS, and lowest viscosity. refractive index	55
Cetylpyridinium chloride.	Soybean oil, Triton X-100.	The concentration of drug and oils	Effect of treatments on demineralization, Effect of Nanoemulsion on biofilms, Transverse microradiography and image analysis,	56
Ezetimibe	Labrafac, Labrasol, Lauroglycol 90, Lauroglycol FCC, Maisine, Labrafil 1944 CS, Transcutol P, Sefsol 218, Cremophor EL, Triacetin, T80, T20, PEG 400.	Combinations of surfactants and cosurfactants.	Refractive index, viscosity, DS, Dispersion index, ZPI, drug release.	57

Table 3: Independent and Dependent variables in preparations of NEs. (Articles published from 2010 to 2000).

Drug	Polymer	Independent variables	Dependent variables	References
Carvedilol	Polyoxyl-40 hydrogenated castor oil, HCO-40, MCT (Miglyol 812), Diethylene glycol monoethyl ether, Transcutol HP, HPMC 5cp, HPMC 15cp, methylcellulose 15cp, Microcrystalline cellulose.	Composition of Different Simple Liquisolid Powders (Lf=0.20-0.23, %composition of type A systems.	The angle of repose, bulk density, tapped density PS, Solubility, drug precipitation.	58
Ibuprofen	Methyl decanoate, isopropyl myristate, ethyl oleate, polyoxyethylene sorbitan Fatty acid esters (Tweens), sorbitan fatty acid esters (Ss), 1, 2-Octanediol.	Emulsifier concentration.	DS, interfacial tension, solubility, HLB values, emulsifier concentration	59
β-carotene	Medium-chain triglyceride, T20, T40, T60, T80	Concentration of b-carotene	DS, size distribution, emulsion stability, concentration,	60
Risperidone	Capmul MCM, Medium Chain Mono- and Diglycerides Medium Chain Mono- and Diglycerides Medium Chain Mono- and Diglycerides Medium Chain Mono- and Diglycerides), Tween 80, polyethylene glycol 400, Polycarbophil, Transcutol, Diethylene triamine penta acetic acid (DTPA)	Composition of surfactant and co-surfactant.	PS, ZP, PDI, viscosity, conductivity, radiolabelled complex.	61
Curcumin	Medium-chain triacylglycerols (Oil, MCT), T20.	The concentration of the drug.	Stability, Mean droplet diameter, Distribution parameter, Polydispersity, Viscosity.	62
Primaquine	Miglylol 812, Poloxamer 188.	Drug concentration	In vitro drug release, PS, Drug content, Stability,	63
Aspirin	Soybean oil, Polysorbate 80	Concentration of drug	Low diameter, %intensity,	64
Carbamazepine	Ethanol, acetone, medium-chain triglycerides, polysorbate80.	The oil phase composition, Lipophilic emulsiﬁer	PS analysis, ZPI, Viscosity, Drug content.	65
Cyclosporine	Mono and diglycerides of caprylic acid, Ethoxylated castor oil.	amount of Emulphor El-620 added (mg), amount of Capmul MCM (C8) added (mg), amount of oily phase added	PS, turbidity (NTU) 100, cumulative percent of CyA released after 5 min, cumulative percent of CyA released after 10 min, emulsification rate, lag time (min)	66
Poloxamer (emulsifier)	Pluronic P104 (polyoxyethylene), Pluronic L62, Pluronic L81, Transcutol HP, Lauroglykol 90.	Composition of preconcentrates examined in the Caco-2.	mean volume Particle diameter, PS, Evaluation of self-emulsifying.	67
Ramipril	Triglyceride, Caprylo caproyl macrogol-8-glyceride, Polyglyceryl-6-dioleate, Propylene glycol mono caprylic ester, Isopropyl myristate, Glycerol triacetate, T20, T80, Diethylene glycol monoethyl ether (Carbitol).	Oil, surfactants, and cosurfactants are grouped in diﬀerent combinations.	drug release, optimum globule Minimum PDI, lower viscosity, lower surfactant concentration, higher solubility, higher bioavailability.	68
Cefpodoxime proxetil (CFP	Solutol HS-15 (SHS-15), Cremophore-EL (Cr-EL), Poloxamer 188, Poloxamer 407, Transcutol, Plurol Oleique, Capryol 90 (CAE), Lauroglycol 90, Labrafac CC, Labrasol, PEG 400, propylene glycol, T80 and T20.	Surfactant and cosurfactant combinations, Emulsification efficiency of various non-ionic surfactants. T20, T80, Cremphore EL, Solutol HS 15, Labrasol, Poloxamer 407, Poloxamer 188.	PS, pH, solubility, PDI, %transmitance	69
Paclitaxel	Polyoxyl 35, castor oil NF, 49.7% (v/v) dehydrated alcohol, ethyl alcohol.	Plasma drug concentration of Paclitaxel.	PS, ZPI, absorption, distribution of the drug.	70
clotrimazole, econazole	Chitosan, polyvinyl alcohol, Polylactide-co-glycolide	The concentration of the drug.	Sensitivity, Linearity, Range, Regression equation, Correlation co-efficient, Correlation co-efficient.	71
Ubiquinone	Coenzyme Q10, Polyoxyl 35 castor oil (Cremophor EL), copolyvidone, Capmul MCM-C8, Maltodextrin, MCC.	Amount of copolyvidone added Amount of maltodextrin added, Amount of microcrystalline cellulose added.	Weight (mg), Flow ability index ( Carr's flow index point), Tensile strength (MPa), Friability (%),Disintegration time (min), Cumulative % of CoQ10 released after 45 min (%).	72
Benzathine penicillin G	Miglyol 812, poly (D, L-lactic-acid-co-glycolic Acid) polymer (PLGA), soya phosphatidylcholine, poloxamer (Synperonic F-68).	The concentration of penG.	Macroscopic aspects, Microscopicaspects, pH, Diameter mean size (nm) PenG content%, PenG 8.50, Accelerated stability, Centrifugation.	73

CONCLUSION:

NEs are periodically gaining prominence in pharmaceutical formulations and it will be the area of exploration and progress. Anyhow, there are numerous hurdles to move over in terms of extensive energy use. The production of NEs requires more concentration at the laboratory scale to the industrial scale and market in different areas even though they are having price complications. This issue is surpassed by using low energy formulation techniques as a choice. NEs give a cosmetic appearance due to their transparent look, they can resist the destabilizing mechanism due to their thermodynamic stability, and the rise of oral bioavailability for highly lipophilic drugs can be achieved by this type of formulations. Their size makes them most special for all routes of the formulation. NEs are assumed to be the best formulations in DDS which needs more progressive research work in it so most of the drawbacks of conventional DDS can be achieved.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech. 2015 Apr 1;5(2):123-7, DOI: 10.1007/s13205-014-0214-0.

2. Abdul AH, Bala AG, Chintaginjala H, Manchikanti SP, Kamsali AK, Dasari RR. Equator Assessment of Nanoparticles Using the Design-Expert Software. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31;13(1):4766-72. DOI : 10.37285/ijpsn

3. Chaudhari Pm, Kuchekar Ma. Development And Evaluation Of Nanoemulsion As A Carrier For Topical Delivery System By Box-Behnken Design. Development. 2018;11(8), 286-93, DOI:10.22159/ajpcr.2018.v11i8.26359.

4. Birajdar GO, Kadam VS, Chintale AG, Halle PD, Nabde MK, Maske KS. A Comprehensive review on nanotechnology. Research Journal of Pharmacy and Technology. 2013 May 1;6(5):486-95, DOI: 10.52711/0974-360X.2021.00689.

5. Kaplan AB, Cetin M, Orgul D, Taghizadehghalehjoughi A, Hacımuftuoglu A, Hekimoglu S. Formulation and in vitro evaluation of topical nanoemulsion and nanoemulsion-based gels containing daidzein. Journal of Drug Delivery Science and Technology. 2019 Aug 1;52:189-203, Doi Number: 10.1016/j.jddst.2019.04.027.

6. Yamaguchi M, Yasueda SI, Isowaki A, Yamamoto M, Kimura M, Inada K, Ohtori A. Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate. International Journal of Pharmaceutics. 2005 Sep 14;301(1-2):121-8, DOI: 10.1016/j.ijpharm.2005.05.036.

7. Chinthaginjala H, Ahad HA, Pradeepkumar B, Gandhi KS, Sumala KK. Formulation and In Vitro Evaluation of Gastroretentive Ofloxacin Floating Tablets using Natural Polymers. Research Journal of Pharmacy and Technology. 2021 Feb 16;14(2):851-6, DOI: 10.5958/0974-360X.2021.00151.7.

8. Ahad HA, Haranath C, Vikas SS, Varam NJ, Ksheerasagare T, Gorantla SP. A Review on Enzyme Activated Drug Delivery System. Research Journal of Pharmacy and Technology. 2021 Jan 29;14(1):516-22, DOI: 10.5958/0974-360X.2021.00094.9.

9. Raman S. Formulation Development and In vitro Characterization of Solid Self Nano Emulsifying Drug Delivery System for Curcumin to Target Colon Adenocarcinoma. RJPT.;12(7), 247-9, DOI:10.22159/ajpcr.2019.v12i7.33231.

10. Subramanian B, Kuo F, Ada E, Kotyla T, Wilson T, Yoganathan S, Nicolosi R. Enhancement of anti-inflammatory property of aspirin in mice by a nano-emulsion preparation. International Immunopharmacology. 2008 Nov 1;8(11):1533-9, DOI: 10.1016/j.intimp.2008.06.009.

11. Bouchemal K, Briançon S, Perrier E, Fessi H. Nano-emulsion formulation using spontaneous emulsification: solvent, oil and surfactant optimization. International Journal of Pharmaceutics. 2004 Aug 6;280(1-2):241-51, DOI:10.1016/j.ijpharm.2004.05.016.

12. Raman S. Formulation Development and In vitro Characterization of Solid Self Nano Emulsifying Drug Delivery System for Curcumin to Target Colon Adenocarcinoma. RJPT.;12(7), DOI: 10.5958/0974-360X.2019.00563.8.

13. Kim CK, Cho YJ, Gao ZG. Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery. Journal of Controlled Release. 2001 Jan 29;70(1-2):149-55, DOI: 10.1016/s0168-3659(00)00343-6.

14. Kumar S. Asian Journal of Research in Pharmaceutical Sciences and Biotechnology. 2(1), 2014, 1 - 15. DOI: 10.1.1.1078.2789.

15. Rosso A, Lollo G, Chevalier Y, Troung N, Bordes C, Bourgeois S, Maniti O, Granjon T, Dugas PY, Urbaniak S, Briançon S. Development and structural characterization of a novel nanoemulsion for oral drug delivery. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2020 May 20;593:124614, DOI: 10.1016/j.colsurfa.2020.124614.

16. Ahad HA, Ksheerasagare T, Chelluru A, Haranath C, Reddy GS, Krishna JV. Herbal Mucilage attempted as a Super disintegrating agent in Oral Disintegrating Tablets. Research Journal of Pharmacy and Technology. 2020 Nov 1;13(11):5489-92, DOI: 10.5958/0974-360X.2020.00958.0.

17. Chinthaginjala H, Ahad HA, Pradeepkumar B, Gandhi KS, Sumala KK. Formulation and In Vitro Evaluation of Gastroretentive Ofloxacin Floating Tablets using Natural Polymers. Research Journal of Pharmacy and Technology. 2021 Feb 16;14(2):851-6, DOI: 10.5958/0974-360X.2021.00151.7.

18. Mandlik SK, Nandare DS, Joshi MM, Chudiwal PD, Jain KS. Statistical optimization of orodispersible tablets containing telmisartan using factorial design and response surface methodology. Optimization. 2009 Jul;15:30, DOI: 10.5958/0974-360X.

19. Fisher, R. A., The Design of Experiments, Oliver and Boyd, London, 1926, DOI: 10.2307/2682986.

20. B. Duraković and H. Bašić. Continuous Quality Improvement in Textile Processing by Statistical Process Control Tools: A Case Study of Medium-Sized Company. Periodicals of Engineering and Natural Sciences, vol. 1, no.1, pp. 36-46, 2013, DOI:10.21533/pen.v1i1.15.

21. Zalte AG, Saudagar RB. Preparation and Characterization of Etodolac Co-Crystals Using 3 2 Full Factorial Design. Research Journal of Pharmacy and Technology. 2018 Sep 1;11(9):3781-6, DOI: 10.5958/0974-360X.2018.00693.5.

22. Catarina P. Santos | Tiago J. Rato | Marco S. Reis, Design of Experiments: A comparison study from the non‐expert user's perspective, Journal of Chemometrics. 2019;33:e3087, DOI: 10.1002/cem.3087.

23. Hiral A. Makadia, Ami Y. Bhatt, Ramesh B. Parmar, Ms. Jalpa S. Paun, H.M. Tank, Self-nano Emulsifying Drug Delivery System (SNEDDS): Future Aspects, Asian J. Pharm. Res. 2013; Vol. 3: Issue 1, Pg 21-27, DOI: 10.5958/2231–5691.

24. Upasana K, Rathore KS, Saini S, Meenakshi B. Formulation and Evaluation of Ketorolac Tromethamine using 3 2 Factorial Design. EVALUATION. 2020 Jun 23;1:1-5, DOI: 10.5958/0974-360X.

25. Sita VG, Vavia P. Bromocriptine nanoemulsion-loaded transdermal gel: optimization using factorial design, in vitro and in vivo evaluation. AAPS PharmSciTech. 2020 Apr 1;21(3):80, DOI: 10.1208/s12249-020-1620-8.

26. Groo AC, Hedir S, Since M, Brotin E, Weiswald LB, Paysant H, Nee G, Coolzaet M, Goux D, Delépée R, Freret T. Pyridoclax-loaded nanoemulsion for enhanced anticancer effect on ovarian cancer. International Journal of Pharmaceutics. 2020 Sep 25;587:119655, DOI: 10.1016/j.ijpharm.2020.119655.

27. Kaplan AB, Cetin M, Orgul D, Taghizadehghalehjoughi A, Hacımuftuoglu A, Hekimoglu S. Formulation and in vitro evaluation of topical nanoemulsion and nanoemulsion-based gels containing daidzein. Journal of Drug Delivery Science and Technology. 2019 Aug 1;52:189-203, DOI: 10.1016/j.jddst.2019.04.027.

28. Saravana PS, Shanmugapriya K, Gereniu CR, Chae SJ, Kang HW, Woo HC, Chun BS. Ultrasound-mediated fucoxanthin rich oil nanoemulsions stabilized by κ-carrageenan: process optimization, bio-accessibility, and cytotoxicity. Ultrasonics Sonochemistry. 2019 Jul 1;55:105-16, DOI: 10.1016/j.ultsonch.2019.03.014.

29. Moradi S, Barati A, Salehi E, Tonelli AE, Hamedi H. Preparation and characterization of chitosan-based hydrogels containing cyclodextrin inclusion compounds or nanoemulsions of thyme oil. Polymer International. 2019 Nov;68(11):1891-902, DOI: 10.1002/pi.5899.

30. Kanwal T, Kawish M, Maharjan R, Ghaffar I, Ali HS, Imran M, Perveen S, Saifullah S, Simjee SU, Shah MR. Design and development of permeation enhancer containing self-nanoemulsifying drug delivery system (SNEDDS) for ceftriaxone sodium improved oral pharmacokinetics. Journal of Molecular Liquids. 2019 Sep 1;289:111098, DOI:10.1016/j.molliq.2019.111098.

31. Talekar SD, Haware RV, Dave RH. Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize the permeability of captopril oral films. European Journal of Pharmaceutical Sciences. 2019 Mar 15;130:215-24, DOI: 10.1016/j.ejps.2019.01.039.

32. Alayoubi A, Aqueel MS, Cruz CN, Ashraf M, Zidan AS. Application of in vitro lipolysis for the development of an oral self-emulsified delivery system of Nimodipine. International Journal of Pharmaceutics. 2018 Dec 20;553(1-2):441-53, DOI: 10.1016/j.ijpharm.2018.10.066.

33. Özdemir S, Celik B, Sümer E, Acar ET, Üner M. Eplerenone nanoemulsions for treatment of hypertension. Part II: Physical stability assessment and in vivo study. Journal of Drug Delivery Science and Technology. 2018 Jun 1;45:287-95, DOI: 10.1016/j.jddst.2018.03.014.

34. Hu Q, Gerhard H, Upadhyaya I, Venkitanarayanan K, Luo Y. Antimicrobial eugenol nanoemulsion prepared by gum arabic and lecithin and evaluation of drying technologies. International Journal of Biological Macromolecules. 2016 Jun 1;87:130-40, DOI: 10.1016/j.ijbiomac.2016.02.051.

35. Khani S, Keyhanfar F, Amani A. Design and evaluation of oral nanoemulsion drug delivery system of mebudipine. Drug Delivery. 2016 Jul 23;23(6):2035-43, DOI: 10.3109/10717544.2015.1088597.

36. Kamble RN, Mehta PP, Kumar A. Efavirenz self-nano-emulsifying drug delivery system: in vitro and in vivo evaluation. AAPS Pharm Sci Tech. 2016 Oct 1;17(5):1240-7, DOI: 10.1208/s12249-015-0446-2.

37. Fofaria NM, Qhattal HS, Liu X, Srivastava SK. Nanoemulsion formulations for anti-cancer agent piplartine—Characterization, toxicological, pharmacokinetics, and efficacy studies. International Journal of Pharmaceutics. 2016 Feb 10;498(1-2):12-22, doi: 10.1016/j.ijpharm.2015.11.045.

38. Soliman KA, Ibrahim HK, Ghorab MM. Formulation of avanafil in a solid self-nanoemulsifying drug delivery system for enhanced oral delivery. European Journal of Pharmaceutical Sciences. 2016 Oct 10;93:447-55,DOI:10.1016/j.ejps.2016.08.050.

39. Gorain B, Choudhury H, Tekade RK, Karan S, Jaisankar P, Pal TK. Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion. Regulatory Toxicology and Pharmacology. 2016 Dec 1;82:20-31, DOI: 10.1016/j.yrtph.2016.10.020.

40. Zupančič O, Partenhauser A, Lam HT, Rohrer J, Bernkop-Schnürch A. Development and in vitro characterization of an oral self-emulsifying delivery system for daptomycin. European Journal of Pharmaceutical Sciences. 2016 Jan 1;81:129-36, DOI: 10.1016/j.ejps.2015.10.005.

41. Jiyauddin K, Fadli A, Wei JC, Jawad A, Samer AD, Kaleemullah M, Budiasih S, Rasha S, Rasny MR, Sung YK, Junainah AH. Formulation of clindamycin nano-emulsion. International Journal of Pharmaceutical Sciences and Research. 2015 May 1, DOI: 10.13040/IJPSR.0975-8232.6(5).1845-54.

42. Esquerdo VM, Dotto GL, de Almeida Pinto LA. Nanoemulsions containing unsaturated fatty acid concentrates. In Emulsions 2016 Jan 1 (pp. 71-106). Academic Pres, DOI:10.1002/ejlt.201700240.

43. Thakkar HP, Khunt A, Dhande RD, Patel AA. Formulation and evaluation of Itraconazole nanoemulsion for enhanced oral bioavailability. Journal of Microencapsulation. 2015 Aug 18;32(6):559-69, DOI: 10.3109/02652048.2015.1065917.

44. Diane JM, Burgess J. Vitamin E nanoemulsions characterization, and analysis. International Journal of Pharmaceutics. 2014 Apr 25;465(1-2):455-63, DOI: 10.1016/j.ijpharm.2014.02.034.

45. Salunkhe SS, Bhatia NM, Thorat JD, Choudhari PB, Bhatia MS. Formulation, development and evaluation of ibuprofen loaded nanoemulsion prepared by nanoprecipitation technique: use of factorial design approach as a tool of optimization methodology. Journal of Pharmaceutical Investigation. 2014 Aug 1;44(4):273-90, DOI:10.1007/s40005-014-0125-4.

46. Li P, Tan A, Prestidge CA, Nielsen HM, Müllertz A. Self-nanoemulsifying drug delivery systems for oral insulin delivery: in vitro and in vivo evaluations of enteric coating and drug loading. International Journal of Pharmaceutics. 2014 Dec 30;477(1-2):390-8, DOI: 10.1016/j.ijpharm.2014.10.039.

47. Dasgupta S, Dey S, Choudhury S, Mazumder B. Topical delivery of aceclofenac as nanoemulsion comprising excipients having optimum emulsification capabilities: preparation, characterization, and in vivo evaluation. Expert Opinion on Drug Delivery. 2013 Apr 1;10(4):411-20, DOI: 10.1517/17425247.2013.749234.

48. Ɖorɖević SM, Radulović TS, Cekić ND, Randelović DV, Savić MM, Krajišnik DR, Milić JR, Savić SD. Experimental design in the formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances. Journal of Pharmaceutical Sciences. 2013 Nov 1;102(11):4159-72, DOI: 10.1002/jps.23734.

49. Zaki Tubesha,1,2,3 Zuki Abu Bakar,1,4 and Maznah Ismail1,2, Characterization and Stability Evaluation of Thymoquinone Nanoemulsions Prepared by High-Pressure Homogenization, Journal of Nanomaterials. Volume 2013,1-6, DOI:10.1155/2013/453290.

50. Jordan M, Nayel A, Brownlow B, Elbayoumi T. Development and evaluation of tocopherol-rich argan oil-based nanoemulsions as vehicles possessing anticancer activity. Journal of Biomedical Nanotechnology. 2012 Dec 1;8(6):944-56, DOI: 10.1166/jbn.2012.1460.

51. Borhade V, Pathak S, Sharma S, Patravale V. Clotrimazole nanoemulsion for malaria chemotherapy. Part II: Stability assessment, in vivo pharmacodynamic evaluations, and toxicological studies. International Journal of Pharmaceutics. 2012 Jul 15;431(1-2):149-60, DOI: 10.1016/j.ijpharm.2011.12.031.

52. Lin YH, Chiou SF, Lai CH, Tsai SC, Chou CW, Peng SF, He ZS. Formulation and evaluation of water-in-oil amoxicillin-loaded nanoemulsions using for Helicobacter pylori eradication. Process Biochemistry. 2012 Oct 1;47(10):1469-78, DOI:10.1016/J.PROCBIO.2012.05.019.

53. Campos FF, Campmany AC, Delgado GR, Serrano OL, Naveros BC. Development and characterization of a novel nystatin‐loaded nanoemulsion for the buccal treatment of candidosis: Ultrastructural effects and release studies. Journal of Pharmaceutical Sciences. 2012 Oct 1;101(10):3739-52, DOI: 10.1002/jps.23249.

54. Chhabra G, Chuttani K, Mishra AK, Pathak K. Design and development of nanoemulsion drug delivery system of amlodipine besilate for improvement of oral bioavailability. Drug Development and Industrial Pharmacy. 2011 Aug 1;37(8):907-16, DOI:10.3109/03639045.2010.550050.

55. Shakeel F, Ramadan W. Transdermal delivery of anticancer drug caffeine from water-in-oil nanoemulsions. Colloids and Surfaces B: Biointerfaces. 2010 Jan 1;75(1):356-62, DOI: 10.1016/j.colsurfb.2009.09.010.

56. Shakeel F, Ramadan W, Gargum HM, Singh R. Preparation and in vivo evaluation of indomethacin loaded true nanoemulsions. Scientia Pharmaceutica. 2010 Mar;78(1):47-56, DOI: 10.3797/scipharm.0911-04.

57. Lee VA, Karthikeyan R, Rawls HR, Amaechi BT. Anti-cariogenic effect of a cetylpyridinium chloride-containing nanoemulsion. Journal of Dentistry. 2010 Sep 1;38(9):742-9, DOI: 10.1016/j.jdent.2010.06.001.

58. Bali V, Ali M, Ali J. Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids and Surfaces B: Biointerfaces. 2010 Apr 1;76(2):410-20, DOI: 10.1016/j.colsurfb.2009.11.021.

59. Mahmoud EA, Bendas ER, Mohamed MI. Preparation and evaluation of self-nanoemulsifying tablets of carvedilol. AAPS Pharmscitech. 2009 Mar 1;10(1):183-92, DOI: 10.1208/s12249-009-9192-7.

60. Wang L, Dong J, Chen J, Eastoe J, Li X. Design and optimization of a new self-nanoemulsifying drug delivery system. Journal of Colloid and Interface Science. 2009 Feb 15;330(2):443-8, DOI: 10.1016/j.jcis.2008.10.077.

61. Yuan Y, Gao Y, Zhao J, Mao L. Characterization and stability evaluation of β-carotene nanoemulsions prepared by high pressure homogenization under various emulsifying conditions. Food Research International. 2008 Jan 1;41(1):61-8, DOI: 10.1016/j.foodres.2007.09.006.

62. Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. International Journal of Pharmaceutics. 2008 Jun 24;358(1-2):285-91, DOI: 10.1016/j.ijpharm.2008.03.029.

63. Wang X, Jiang Y, Wang YW, Huang MT, Ho CT, Huang Q. Enhancing anti-inflammation activity of curcumin through O/W nanoemulsions. Food Chemistry. 2008 May 15;108(2):419-24, DOI: 10.1016/j.foodchem.2007.10.086.

64. Singh KK, Vingkar SK. Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. International Journal of Pharmaceutics. 2008 Jan 22;347(1-2):136-43, DOI: 10.1016/j.ijpharm.2007.06.035.

65. Subramanian B, Kuo F, Ada E, Kotyla T, Wilson T, Yoganathan S, Nicolosi R. Enhancement of anti-inflammatory property of aspirin in mice by a nano-emulsion preparation. International Immunopharmacology. 2008 Nov 1;8(11):1533-9, DOI: 10.1016/j.intimp.2008.06.009.

66. Kelmann RG, Kuminek G, Teixeira HF, Koester LS. Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process. International Journal of Pharmaceutics. 2007 Sep 5;342(1-2):231-9, DOI: 10.1016/j.ijpharm.2007.05.004.

67. Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: Understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box–Behnken design and desirability function. International Journal of Pharmaceutics. 2007 Mar 6;332(1-2):55-63, DOI: 10.1016/j.ijpharm.2006.09.060.

68. Brüsewitz C, Schendler A, Funke A, Wagner T, Lipp R. Novel poloxamer-based nanoemulsions to enhance the intestinal absorption of active compounds. International Journal of Pharmaceutics. 2007 Feb 1;329(1-2):173-81, DOI: 10.1016/j.ijpharm.2006.08.022.

69. Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. European Journal of Pharmaceutics and Biopharmaceutics. 2007 May 1;66(2):227-43, DOI: 10.5530/ijper.53.4s.148.

70. Date AA, Nagarsenker MS. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil. International Journal of Pharmaceutics. 2007 Feb 1;329(1-2):166-72, DOI: 10.1016/j.ijpharm.2006.08.038.

71. Tiwari SB, Amiji MM. Improved oral delivery of paclitaxel following administration in nanoemulsion formulations. Journal of Nanoscience and Nanotechnology. 2006 Sep 1;6(9-10):3215-21, DOI: 10.1166/jnn.2006.440.

72. Pandey R, Ahmad Z, Sharma S, Khuller GK. Nano-encapsulation of azole antifungals: potential applications to improve oral drug delivery. International Journal of Pharmaceutics. 2005 Sep 14;301(1-2):268-76, DOI: 10.1016/j.ijpharm.2005.05.027.

73. Nazzal S, Nutan M, Palamakula A, Shah R, Zaghloul AA, Khan MA. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients. International Journal of Pharmaceutics. 2002 Jun 20;240(1-2):103-14, DOI: 10.1208/s12249-009-9192-7.

74. Santos-Magalhaes NS, Pontes A, Pereira VM, Caetano MN. Colloidal carriers for benzathine penicillin G: nanoemulsions and nanocapsules. International Journal of Pharmaceutics. 2000 Nov 4;208(1-2):71-80, DOI: 10.1016/s0378-5173(00)00546-9.

Received on 26.02.2021 Modified on 14.09.2021

Research J. Pharm. and Tech. 2022; 15(8):3782-3789.

DOI: 10.52711/0974-360X.2022.00635