A Review on: Nanoemulsions as Advanced Drug Delivery Systems, Formulation Strategies, Mechanisms, Applications, and Future Perspectives

Abstract

Nanoemulsions have been widely recognized as mart, versatile system to deliver drugs effectively natural products and nutraceuticals mainly due to their unique physicochemical properties and application potential in pharmaceutical development. They represent kinetically stable colloidal dispersions made of oil, water, surfactant, and co-surfactant with the droplet sizes usually being in the nanometre range. The small droplet size and the large interfacial surface of nanoemulsions that enhance drug solubility, improve bioavailability accelerate drug release, and provide better therapeutic efficacy are especially useful for drugs with very low water solubility. Nanoemulsions have been very promising for a wider range of administration routes such as oral, topical, transdermal ocular, nasal, pulmonary, and parenteral delivery methods. Different preparation techniques, including high-energy and low-energy can be employed to achieve desired formulations, while thorough characterization ensures their stability, safety, and effectiveness. Recently, the frontiers of nanoemulsions' applications have been; targeted, stimuli-responsive, herbal, and brain-targeted drug delivery systems. However, issues of surfactant toxicity, long-term stability large-scale production, and regulatory approval continue to be the stumbling blocks for the technology. This article takes an in-depth look at nanoemulsions their components, methods of preparation, drug absorption mechanisms pharmaceutical applications, toxicity and safety issues recent advances and future directions, thereby underlining their potentiality as next-generation platform of drug delivery.

Keywords

Nanoemulsions, Drug delivery systems; Bioavailability enhancement; High-pressure homogenization; Phase inversion method; Droplet size characterization; Targeted drug delivery; Pharmaceutical nanotechnology

Introduction

Owing to the gradual increase in molecular complexity of drugs along with the rising need for highly efficient and patient-friendly therapies, research on advanced drug delivery systems has intensified (Allen & Cullis, 2004). Conventional dosage forms often fail to deliver expected therapeutic benefits due to poor aqueous solubility, low permeability, rapid metabolism, and limited bioavailability of many active pharmaceutical ingredients (Lipinski, 2002). Approximately 40–70% of newly developed drug candidates exhibit poor water solubility, which significantly restricts their therapeutic application and commercial success (Savjani et al., 2012). These limitations have encouraged the exploration of innovative formulation strategies to improve drug solubility, stability, and therapeutic performance (Kalepu& Nekkanti, 2015).

Nanotechnology has emerged as a powerful tool in pharmaceutical sciences, offering novel approaches to overcome challenges associated with conventional drug delivery systems. Nanoparticles, liposomes, solid lipid nanoparticles, and nanoemulsions have demonstrated significant promise in enhancing drug delivery efficiency (Panyam &Labhasetwar, 2003; Torchilin, 2006).

Among these systems, nanoemulsions have attracted considerable attention as versatile drug delivery platforms (Solans et al., 2005). Nanoemulsions are defined as kinetically stable, transparent or translucent dispersions of two immiscible liquids, typically oil and water, stabilized by surfactants and co-surfactants, with droplet sizes generally ranging from 20 to 200 nm (Tadros et al., 2004). Their ultra-fine droplets provide a large interfacial surface area, enhancing drug dissolution and membrane penetration, thereby improving drug absorption and bioavailability (Anton & Vandamme, 2011). Furthermore, nanoemulsions exhibit high physical stability with minimal creaming or sedimentation, contributing to prolonged shelf life and uniform drug distribution (McClements, 2012).

One of the major advantages of nanoemulsion systems is their ability to solubilize lipophilic drugs while protecting them from chemical and enzymatic degradation (Lawrence & Rees, 2000). Drug encapsulation within nanoemulsion droplets reduces exposure to harsh physiological environments, enhancing drug stability and therapeutic efficacy (Shakeel et al., 2007). Additionally, nanoemulsions may facilitate lymphatic transport following oral administration, thereby bypassing first-pass hepatic metabolism and improving systemic bioavailability (Porter et al., 2007).

Nanoemulsions have been extensively investigated for multiple routes of administration, including oral, topical, transdermal, ocular, nasal, pulmonary, and parenteral delivery (Alany et al., 2006). In oral drug delivery, nanoemulsions significantly enhance dissolution rate and absorption of poorly water-soluble drugs, resulting in improved pharmacokinetic profiles (Date et al., 2010).

For topical and transdermal applications, nanoemulsions improve skin penetration and drug accumulation at the target site while minimizing systemic side effects (Kreilgaard, 2002). Their low irritation potential and favorable sensory characteristics enhance patient compliance (Aqil et al., 2007).

In ocular and nasal drug delivery, nanoemulsions provide prolonged residence time, enhanced permeability, and improved bioavailability compared to conventional formulations (Abdelkader et al., 2011). They have also shown promising potential in cancer therapy, vaccine delivery, gene delivery, and brain targeting due to their ability to cross biological barriers and provide controlled drug release (Shah et al., 2017). Surface modification and ligand attachment strategies further enhance site-specific drug delivery (Torchilin, 2007).

Recently, nanoemulsions have gained attention for the delivery of herbal medicines and nutraceuticals that suffer from poor solubility and low bioavailability (Ahmad et al., 2016). Incorporation of phytoconstituents into nanoemulsion systems has been shown to enhance stability, cellular uptake, and therapeutic efficacy (Ganesan & Narayanasamy, 2017). This approach supports the development of safer and more effective natural product-based therapies (Singh et al., 2017).

Despite numerous advantages, nanoemulsion systems face certain challenges, including the need for high surfactant concentrations, potential toxicity concerns, and stability issues such as Ostwald ripening (Higuchi & Misra, 1962). Additionally, large-scale manufacturing and regulatory approval remain significant barriers to widespread clinical translation (Tadros, 2016). Therefore, successful development of nanoemulsions requires comprehensive understanding of formulation components, preparation techniques, characterization methods, and safety considerations (Kumar et al., 2019).

The objective of this article is to provide a comprehensive overview of nanoemulsions, including their fundamental principles, formulation aspects, preparation methods, characterization techniques, advantages, limitations, and pharmaceutical applications. Particular emphasis is placed on their potential as versatile and promising drug delivery systems capable of addressing current and future challenges in pharmaceutical development (Acosta, 2009).

COMPOSITION OF NANOEMULSIONS

Nanoemulsions are thermodynamically unstable but kinetically stable colloidal systems composed of oil, water, surfactant, and often co-surfactant. The careful selection and optimization of these components are essential for achieving desired droplet size, stability, drug loading efficiency, and therapeutic performance (Tadros et al., 2004; McClements, 2012).

1. Oil Phase

The oil phase plays a crucial role in solubilizing lipophilic drugs and influencing drug release characteristics. The type of oil selected affects drug loading capacity, droplet size, and overall stability of the nanoemulsion (Porter et al., 2007). Commonly used oils include medium-chain triglycerides, long-chain triglycerides, fatty acids, and semi-synthetic oils.

Medium-chain triglycerides are frequently preferred due to their excellent solubilizing capacity and enhanced lymphatic transport potential, which can improve oral bioavailability (Porter et al., 2007). Oils such as caprylic/capric triglycerides and isopropyl myristate are widely utilized in pharmaceutical nanoemulsions because of their biocompatibility and formulation versatility (Shakeel et al., 2007).

The viscosity of the oil phase significantly influences droplet size during emulsification. Lower-viscosity oils facilitate the formation of smaller droplets under high-energy methods (Mason et al., 2006).

2. Aqueous Phase

The aqueous phase typically consists of purified water and may contain hydrophilic additives such as preservatives, buffering agents, and tonicity modifiers. The pH and ionic strength of the aqueous phase can affect nanoemulsion stability and drug release behavior (McClements, 2012).

For parenteral and ophthalmic applications, sterility and isotonicity of the aqueous phase are critical to ensure patient safety and regulatory compliance (Gupta et al., 2016).

3. Surfactants

Surfactants are essential components that reduce interfacial tension between oil and water, enabling the formation of nano-sized droplets. They stabilize the dispersed droplets by forming a protective interfacial film and preventing coalescence (Tadros et al., 2004).

Non-ionic surfactants such as polysorbates (Tween), sorbitan esters (Span), and polyethylene glycol derivatives are commonly used due to their low toxicity and good biocompatibility (Shah et al., 2010). The hydrophilic–lipophilic balance (HLB) value of the surfactant determines whether an oil-in-water (O/W) or water-in-oil (W/O) nanoemulsion will form. Surfactants with higher HLB values generally favor O/W nanoemulsions, while lower HLB values favor W/O systems (Komaiko& McClements, 2016).

Appropriate surfactant concentration is critical; insufficient surfactant may lead to instability, whereas excessive surfactant may cause toxicity concerns (Tadros, 2016).

4. Co-Surfactants

Co-surfactants such as short-chain alcohols (e.g., ethanol), propylene glycol, and polyethylene glycol are often added to further reduce interfacial tension and increase interfacial film flexibility (Mason et al., 2006). They facilitate spontaneous nanoemulsion formation and improve physical stability.

The use of co-surfactants also expands the nanoemulsion region in pseudo-ternary phase diagrams, simplifying formulation optimization (Shakeel et al., 2007).

5. Drug Incorporation

Drug incorporation depends on the physicochemical properties of the drug, including solubility, partition coefficient, and stability. Lipophilic drugs are typically dissolved in the oil phase, while hydrophilic drugs may be incorporated in the aqueous phase or at the oil–water interface (Torchilin, 2006).

Encapsulation of drugs within nanoemulsion droplets protects them from degradation and enhances membrane permeation, thereby improving bioavailability and therapeutic effectiveness (Panyam &Labhasetwar, 2003).

PREPARATION METHODS OF NANOEMULSIONS

The preparation method significantly influences droplet size, stability, scalability, and drug delivery performance of nanoemulsions. Broadly, nanoemulsion preparation techniques are classified into high-energy methods and low-energy methods (Solans et al., 2005; Tadros et al., 2004).

1. High-Energy Methods

High-energy methods utilize mechanical devices to generate intense disruptive forces that break coarse emulsions into nano-sized droplets (Mason et al., 2006).

1.1 High-Pressure Homogenization

High-pressure homogenization involves forcing a coarse emulsion through a narrow gap under extremely high pressure (500–5000 psi). The intense shear stress, turbulence, and cavitation forces reduce droplet size to the nanometer range (Jafari et al., 2008).

This method is widely used in pharmaceutical and industrial applications due to its reproducibility and scalability. Multiple homogenization cycles are often required to achieve uniform droplet distribution (Gupta et al., 2016).

1.2 Ultrasonication

Ultrasonication employs ultrasonic waves to generate cavitation bubbles in the liquid medium. The collapse of these bubbles produces strong shock waves that break down droplets into nanoscale sizes (Mason et al., 2006).

This method is suitable for laboratory-scale production; however, scale-up may be challenging due to equipment limitations and potential heat generation (Jafari et al., 2008).

1.3 Microfluidization

Microfluidization forces the emulsion through microchannels at high velocity, where impingement of fluid streams reduces droplet size (Gupta et al., 2016). This technique produces uniform nanoemulsions with narrow size distribution and high stability.

2. Low-Energy Methods

Low-energy methods rely on the intrinsic physicochemical properties of the system rather than mechanical energy input (Solans et al., 2005).

2.1 Phase Inversion Temperature (PIT) Method

The phase inversion temperature method is based on temperature-induced changes in surfactant solubility. Non-ionic surfactants become more lipophilic at higher temperatures, leading to phase inversion and nanoemulsion formation upon cooling (Tadros et al., 2004).

This method produces fine droplets with low energy input but is limited to temperature-sensitive surfactants.

2.2 Phase Inversion Composition (PIC) Method

In the PIC method, nanoemulsions are formed by gradually changing the composition of the system, such as by adding water to an oil–surfactant mixture (Solans et al., 2005). Spontaneous nanoemulsification occurs due to interfacial tension reduction.

2.3 Spontaneous Emulsification

Spontaneous emulsification involves mixing oil, surfactant, co-surfactant, and aqueous phase under mild stirring conditions, resulting in the formation of nano-sized droplets without significant external energy (Shakeel et al., 2007).

This method is simple and cost-effective but requires careful optimization of component ratios.

3. Factors Affecting Preparation

Several formulation and process variables influence nanoemulsion characteristics:

• Surfactant concentration (Tadros, 2016)
• Oil-to-water ratio (McClements, 2012)
• Homogenization pressure and cycles (Jafari et al., 2008)
• Temperature during preparation (Solans et al., 2005)

Proper optimization of these parameters ensures smaller droplet size, enhanced stability, and improved drug delivery efficiency.

Advantages and Limitations of Preparation Techniques

High-energy methods provide better control over droplet size and are suitable for large-scale production but require expensive equipment and high energy consumption (Mason et al., 2006).

Low-energy methods are energy-efficient and cost-effective but may be limited by formulation constraints and surfactant selection (Solans et al., 2005).

CHARACTERIZATION OF NANOEMULSIONS

Characterization is essential to evaluate physical stability, droplet size, drug loading, and performance of nanoemulsions (McClements, 2012).

1. Droplet Size and Polydispersity Index (PDI)

Droplet size is typically measured using dynamic light scattering (DLS). Nanoemulsions generally exhibit droplet sizes between 20–200 nm (Tadros et al., 2004).

Polydispersity index (PDI) indicates size distribution uniformity. A PDI value below 0.3 suggests a narrow size distribution and good stability (Jafari et al., 2008).

2. Zeta Potential

Zeta potential measures surface charge and predicts physical stability. Higher absolute zeta potential values (±30 mV or above) indicate improved electrostatic stabilization and reduced aggregation (McClements, 2012).

3. Morphological Evaluation

Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) are used to observe droplet shape and surface characteristics (Gupta et al., 2016).

4. Viscosity and Rheological Studies

Viscosity influences stability and drug release behavior. Rheological analysis helps determine whether the nanoemulsion exhibits Newtonian or non-Newtonian flow behavior (Tadros, 2016).

5. Drug Content and Entrapment Efficiency

Drug content is determined using analytical methods such as UV spectroscopy or HPLC. Entrapment efficiency indicates the percentage of drug successfully incorporated within the nanoemulsion system (Panyam &Labhasetwar, 2003).

6. Stability Studies

Stability evaluation includes centrifugation, heating–cooling cycles, freeze–thaw cycles, and long-term storage studies to assess physical and chemical stability (Shakeel et al., 2007).

Ostwald ripening is a major destabilization phenomenon in nanoemulsions and must be carefully monitored (Higuchi & Misra, 1962).

7. In Vitro Drug Release Studies

Drug release studies are conducted using dialysis membrane methods to evaluate release kinetics and predict in vivo performance (Date et al., 2010).

APPLICATIONS OF NANOEMULSIONS IN DRUG DELIVERY

Nanoemulsions have emerged as versatile drug delivery systems due to their ability to enhance solubility, improve bioavailability, provide controlled release, and enable targeted delivery (Solans et al., 2005; McClements, 2012). Their small droplet size and large interfacial surface area make them suitable for multiple routes of administration.

1. Oral Drug Delivery

Oral administration remains the most preferred route due to patient compliance and convenience. However, poor aqueous solubility and low permeability limit the effectiveness of many drugs. Nanoemulsions enhance dissolution rate and intestinal absorption of poorly water-soluble drugs (Porter et al., 2007).

Nanoemulsions can facilitate lymphatic transport, thereby bypassing first-pass hepatic metabolism and improving systemic bioavailability (Porter et al., 2007). Improved pharmacokinetic profiles have been reported for several lipophilic drugs formulated as nanoemulsions (Date et al., 2010).

2. Topical and Transdermal Delivery

Nanoemulsions are widely used for dermal and transdermal drug delivery due to their enhanced skin penetration ability. Their nanoscale droplet size improves drug permeation across the stratum corneum (Kreilgaard, 2002).

They provide uniform drug distribution, increased hydration of the skin, and reduced irritation potential compared to conventional creams or ointments (Aqil et al., 2007). Controlled drug release from nanoemulsions also minimizes systemic side effects.

3. Ocular Drug Delivery

Ocular drug delivery is challenging due to rapid tear turnover and limited corneal permeability. Nanoemulsions enhance ocular residence time and improve corneal penetration (Alany et al., 2006).

They provide better bioavailability and prolonged therapeutic action compared to conventional eye drops (Abdelkader et al., 2011).

4. Nasal and Pulmonary Delivery

Nanoemulsions are effective for nasal and pulmonary drug delivery due to their ability to enhance mucosal absorption. The nasal route provides rapid systemic absorption and potential brain targeting via the olfactory pathway (Shah et al., 2017).

Pulmonary nanoemulsions improve drug deposition and absorption in the lungs, offering potential treatment strategies for respiratory diseases.

5. Parenteral Drug Delivery

Nanoemulsions are used in injectable formulations to solubilize hydrophobic drugs and reduce irritation at the injection site (Gupta et al., 2016).

Their small droplet size ensures safe intravenous administration with minimal risk of embolism. Lipid-based nanoemulsions have been successfully used in parenteral nutrition and anesthetic delivery systems.

6. Targeted Drug Delivery

Surface modification of nanoemulsions with ligands, antibodies, or polymers enables site-specific drug delivery (Torchilin, 2007).

Targeted nanoemulsions have demonstrated significant potential in cancer therapy by improving tumor accumulation and reducing systemic toxicity (Shah et al., 2017). Their ability to cross biological barriers, including the blood–brain barrier, enhances their application in neurological disorders.

7. Vaccine and Gene Delivery

Nanoemulsions serve as effective adjuvants in vaccine delivery systems. They stimulate immune responses and enhance antigen stability (Shah et al., 2017).

In gene delivery, nanoemulsions protect nucleic acids from degradation and improve cellular uptake efficiency (Panyam & Labhasetwar, 2003).

8. Herbal and Nutraceutical Delivery

Many phytoconstituents exhibit poor aqueous solubility and low bioavailability. Nanoemulsions improve solubility, stability, and therapeutic efficacy of herbal drugs and nutraceuticals (Ahmad et al., 2016).

Encapsulation of plant-derived bioactive compounds enhances their absorption and biological activity (Ganesan & Narayanasamy, 2017; Singh et al., 2017).

ADVANTAGES OF NANOEMULSIONS

• Enhanced solubility of poorly water-soluble drugs (Lawrence & Rees, 2000)
• Improved bioavailability (Porter et al., 2007)
• Controlled and sustained drug release (Date et al., 2010)
• Reduced irritation and toxicity (Aqil et al., 2007)
• Enhanced stability and longer shelf life (McClements, 2012)
• Potential for targeted delivery (Torchilin, 2007)

LIMITATIONS OF NANOEMULSIONS

Despite numerous advantages, nanoemulsions have certain limitations:

• Requirement of high surfactant concentrations (Tadros, 2016)
• Potential toxicity of surfactants
• Risk of instability due to Ostwald ripening (Higuchi & Misra, 1962)
• Scale-up challenges in industrial production (Gupta et al., 2016)

Proper formulation optimization and regulatory evaluation are necessary to overcome these challenges.

FUTURE PERSPECTIVES

Nanoemulsions continue to gain significant attention in pharmaceutical research due to their versatility, safety profile, and ability to address challenges associated with poorly soluble drugs (McClements, 2012). With the increasing number of lipophilic drug candidates emerging from modern drug discovery pipelines, nanoemulsion-based delivery systems are expected to play an increasingly important role in future therapeutics (Kalepu& Nekkanti, 2015).

Recent advances in surface modification and ligand conjugation techniques have expanded the potential of nanoemulsions for targeted drug delivery applications (Torchilin, 2007). Functionalized nanoemulsions can selectively accumulate in diseased tissues, such as tumors, thereby improving therapeutic efficacy and minimizing systemic toxicity (Shah et al., 2017). This approach is particularly promising in oncology, where precision drug delivery is crucial.

In addition, nanoemulsions are being investigated for brain-targeted delivery via nasal administration and blood–brain barrier penetration strategies (Shah et al., 2017). Such developments may open new treatment avenues for neurodegenerative disorders and central nervous system diseases.

The integration of nanoemulsions with biotechnology-based therapeutics, including peptides, proteins, and nucleic acids, represents another promising research direction (Panyam &Labhasetwar, 2003). Nanoemulsion-based vaccine adjuvants have demonstrated enhanced immune responses, suggesting their potential role in next-generation immunization strategies (Shah et al., 2017).

Furthermore, the application of Quality by Design (QbD) principles and advanced analytical tools can improve formulation optimization, scalability, and regulatory acceptance (Gupta et al., 2016). Industrial translation will depend on improved manufacturing technologies, cost-effectiveness, and comprehensive safety evaluation (Tadros, 2016).

The growing interest in herbal and nutraceutical formulations also presents a valuable opportunity for nanoemulsion technology. Incorporation of phytoconstituents into nanoemulsion systems may enhance their stability, bioavailability, and therapeutic performance (Ahmad et al., 2016; Singh et al., 2017).

Despite these promising developments, further research is required to address long-term stability concerns, surfactant-related toxicity, and large-scale production challenges (Higuchi & Misra, 1962; Tadros, 2016). Collaborative efforts between academia, industry, and regulatory agencies will be essential to facilitate clinical translation.

CONCLUSION

Nanoemulsions represent an advanced and highly promising drug delivery system capable of overcoming major limitations associated with conventional dosage forms. Their ability to enhance solubility, improve bioavailability, provide controlled release, and enable targeted drug delivery makes them an attractive platform for modern pharmaceutical development (Solans et al., 2005; Porter et al., 2007).

The successful development of nanoemulsion formulations requires careful selection of formulation components, appropriate preparation methods, and comprehensive physicochemical characterization (Tadros et al., 2004; McClements, 2012). While challenges such as surfactant toxicity, stability issues, and scale-up limitations remain, ongoing technological advancements are steadily addressing these concerns (Tadros, 2016).

With continuous innovation and regulatory support, nanoemulsions are expected to contribute significantly to the future of drug delivery, particularly in areas such as oncology, neurology, vaccine development, and herbal therapeutics.

REFERENCES

1. Allen TM, Cullis PR. Drug delivery systems: Entering the mainstream. Science. 2004;303(5665):1818–1822.
2. Lipinski CA. Poor aqueous solubility—an industry wide problem in drug discovery. Am Pharm Rev. 2002;5:82–85.
3. Savjani KT, Gajjar AK, Savjani JK. Drug solubility: Importance and enhancement techniques. ISRN Pharm. 2012;2012:195727.
4. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm Sin B. 2015;5(5):442–453.
5. Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 2003;55(3):329–347.
6. Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev. 2006;58(14):1532–1555.
7. Solans C, Izquierdo P, Nolla J, Azemar N, Garcia-Celma MJ. Nano-emulsions. Curr Opin Colloid Interface Sci. 2005;10(3–4):102–110.
8. Tadros T, Izquierdo P, Esquena J, Solans C. Formation and stability of nano-emulsions. Adv Colloid Interface Sci. 2004;108–109:303–318.
9. Anton N, Vandamme TF. Nano-emulsions and micro-emulsions: Clarifications of the critical differences. Pharm Res. 2011;28(5):978–985.
10. McClements DJ. Nanoemulsions versus microemulsions: Terminology, differences, and similarities. Soft Matter. 2012;8:1719–1729.
11. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev. 2000;45(1):89–121.
12. Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S. Nanoemulsions as vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech. 2007;8(4):E104.
13. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–248.
14. Alany RG, Rades T, Nicoll J, Tucker IG, Davies NM. W/O microemulsions for ocular delivery: Evaluation of ocular irritation and precorneal retention. J Control Release. 2006;111(1–2):145–152.
15. Date AA, Desai N, Dixit R, Nagarsenker M. Self-nanoemulsifying drug delivery systems: Formulation insights, applications and advances. Nanomedicine. 2010;5(10):1595–1616.
16. Kreilgaard M. Influence of microemulsions on cutaneous drug delivery. Adv Drug Deliv Rev. 2002;54(Suppl 1):S77–S98.
17. Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today. 2007;12(23–24):1061–1067.
18. Abdelkader H, Ismail S, Kamal A, Alany RG. Design and evaluation of controlled-release ocular nanoemulsions of brimonidine tartrate. Drug Deliv. 2011;18(6):385–397.
19. Shah MR, Imran M, Ullah S, et al. Lipid-based nanocarriers for cancer therapy. Colloids Surf B Biointerfaces. 2017;159:527–540.
20. Torchilin VP. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAPS J. 2007;9(2):E128–E147.
21. Ahmad J, Amin S, Rahman M, et al. Nanoemulsion formulation of phytoconstituents for improved oral bioavailability. Drug Deliv. 2016;23(3):998–1008.
22. Ganesan P, Narayanasamy D. Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers. Sustain Chem Pharm. 2017;6:37–56.
23. Singh Y, Meher JG, Raval K, et al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. 2017;252:28–49.
24. Higuchi WI, Misra J. Physical degradation of emulsions via the molecular diffusion route and possible prevention. J Pharm Sci. 1962;51(5):459–466.
25. Tadros TF. Emulsion formation, stability, and rheology. Colloids Surf A Physicochem Eng Asp. 2016;495:1–11.
26. Kumar M, Bishnoi RS, Shukla AK, Jain CP. Techniques for formulation of nanoemulsion drug delivery system: A review. Prev Nutr Food Sci. 2019;24(3):225–234.
27. Acosta E. Bioavailability of nanoparticles in drug delivery. Curr Opin Colloid Interface Sci. 2009;14(1):3–15.
28. Solans C, Solé I. Nano-emulsions: Formation by low-energy methods. Curr Opin Colloid Interface Sci. 2012;17(5):246–254.
29. Pouton CW. Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems. Eur J Pharm Sci. 2000;11(Suppl 2):S93–S98.
30. McClements DJ, Rao J. Food-grade nanoemulsions: Formulation, fabrication, properties, performance, biological fate, and potential toxicity. Crit Rev Food Sci Nutr. 2011;51(4):285–330.
31. Porter CJH, Charman WN. Uptake of drugs into the intestinal lymphatics after oral administration. Adv Drug Deliv Rev. 2001;50(1–2):61–80.
32. Date AA, Nagarsenker MS. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS). Int J Pharm. 2007;329(1–2):166–172.
33. Lawrence MJ. Surfactant systems: Microemulsions and vesicles as vehicles for drug delivery. Eur J Drug Metab Pharmacokinet. 1994;19(3):257–269.
34. Constantinides PP, Scalart JP, Lancaster C, et al. Formulation and intestinal absorption enhancement evaluation of water-in-oil microemulsions incorporating medium-chain glycerides. Pharm Res. 1994;11(10):1385–1390.
35. Alany RG, Rades T, Nicoll J, Tucker IG, Davies NM. Ocular delivery of drugs using microemulsions. Drug Dev Ind Pharm. 2006;32(3):247–255.
36. Tadros TF. Surfactants in nanoemulsions. In: Nanoemulsions: Formation, Applications and Characterization. London: Academic Press; 2014. p. 55–78.
37. Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 6th ed. London: Pharmaceutical Press; 2009.
38. Griffin WC. Classification of surface-active agents by HLB. J Soc Cosmet Chem. 1949;1:311–326.
39. Kabalnov AS. Ostwald ripening and related phenomena. J Dispers Sci Technol. 2001;22(1):1–12.
40. Fanun M. Microemulsions as delivery systems. Curr Opin Colloid Interface Sci. 2012;17(5):306–313.
41. Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm. 2007;66(2):227–243.
42. Izquierdo P, Feng J, Esquena J, et al. The influence of surfactant mixing ratio on nanoemulsion formation. Langmuir. 2004;20(16):6594–6598.
43. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: Formulation development and bioavailability assessment. Int J Pharm. 2001;212(2):233–246.
44. Singh Y, Meher JG, Raval K, et al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. 2017;252:28–49.
45. Craig DQM, Barker SA, Banning D. An investigation into the use of pseudo-ternary phase diagrams for the formulation of emulsions. Int J Pharm. 1995;114(1):103–110.
46. Tadros TF. Emulsion stability and breakdown mechanisms. Adv Colloid Interface Sci. 2013;203:1–15.
47. Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: An advanced mode of drug delivery system. 3 Biotech. 2015;5(2):123–127.
48. Gupta A, Eral HB, Hatton TA, Doyle PS. Nanoemulsions: Formation, properties and applications. Soft Matter. 2016;12:2826–2841.
49. Salager JL. Emulsion properties and related know-how to attain them. Colloids Surf A Physicochem Eng Asp. 2006;272(1–2):1–10.
50. McClements DJ. Critical review of techniques and methodologies for characterization of emulsion stability. Crit Rev Food Sci Nutr. 2007;47(7):611–649.
51. Müller RH, Benita S, Böhm B. Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs. Stuttgart: Medpharm Scientific Publishers; 1998.
52. Scholz P, Keck CM. Nanoemulsions produced by rotor-stator high-speed stirring. Int J Pharm. 2015;482(1–2):144–150.
53. Tadros TF. Application of rheology for assessment and prediction of the long-term physical stability of emulsions. Adv Colloid Interface Sci. 2004;108–109:227–258.
54. Guttoff M, Saberi AH, McClements DJ. Formation of vitamin D nanoemulsion-based delivery systems by spontaneous emulsification. Food Chem. 2015;174:386–393.
55. Abismail B, Canselier JP, Wilhelm AM, Delmas H, Gourdon C. Emulsification by ultrasound: Drop size distribution and stability. Ultrason Sonochem. 1999;6(1–2):75–83.
56. Kentish S, Wooster TJ, Ashokkumar M, et al. The use of ultrasonics for nanoemulsion preparation. Innov Food Sci Emerg Technol. 2008;9(2):170–175.
57. Mason TJ, Lorimer JP. Applied Sonochemistry: Uses of Power Ultrasound in Chemistry and Processing. Weinheim: Wiley-VCH; 2002.
58. Solè I, Pey CM, Maestro A, González C, Solans C, Gutiérrez JM. Nano-emulsions prepared by the phase inversion composition method. Langmuir. 2010;26(8):5614–5620.
59. Shinoda K, Saito H. The stability of O/W type emulsions as functions of temperature and the HLB of emulsifiers. J Colloid Interface Sci. 1969;30(2):258–263.
60. Izquierdo P, Esquena J, Tadros TF, et al. Formation and stability of nano-emulsions prepared using the phase inversion temperature method. Langmuir. 2002;18(1):26–30.
61. Morales D, Gutiérrez JM, García-Celma MJ, Solans C. A study of the relation between bicontinuous microemulsions and oil/water nano-emulsion formation. Langmuir. 2003;19(18):7196–7200.
62. Forgiarini A, Esquena J, González C, Solans C. Formation of nano-emulsions by low-energy emulsification methods. Langmuir. 2001;17(7):2076–2083.
63. Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates. J Control Release. 2008;128(3):185–199.
64. Gutiérrez JM, González C, Maestro A, Solè I, Pey CM, Nolla J. Nano-emulsions: New applications and optimization of their preparation. Curr Opin Colloid Interface Sci. 2008;13(4):245–251.
65. Komaiko J, McClements DJ. Formation of food-grade nanoemulsions using spontaneous emulsification. Food Hydrocoll. 2016;54:1–11.
66. Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev. 1997;25(1):47–58.
67. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10. Int J Pharm. 2001;212(2):233–246.
68. Tadros TF. Formulation of nanoemulsions. In: Nanoemulsions. London: Academic Press; 2014. p. 1–32.
69. Jafari SM, He Y, Bhandari B. Nano-emulsion production by sonication and microfluidization. Food Hydrocoll. 2007;21(2):250–258.
70. Rao J, McClements DJ. Stabilization of phase inversion temperature nanoemulsions. Food Funct. 2010;1(1):42–48.
71. Patravale VB, Mandawgade SD. Novel cosmetic delivery systems: An application update. Int J Cosmet Sci. 2008;30(1):19–33.
72. Shah P, Bhalodia D, Shelat P. Nanoemulsion: A pharmaceutical review. Syst Rev Pharm. 2010;1(1):24–32.
73. McClements DJ. Emulsion characterization. In: Food Emulsions: Principles, Practices, and Techniques. 2nd ed. Boca Raton: CRC Press; 2005. p. 175–205.
74. Malvern Instruments Ltd. Dynamic Light Scattering: An Introduction in 30 Minutes. Worcestershire; 2012.
75. Danaei M, Dehghankhold M, Ataei S, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.
76. Müller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy. Adv Drug Deliv Rev. 2001;47(1):3–19.
77. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems. Trop J Pharm Res. 2013;12(2):255–264.
78. Hunter RJ. Zeta Potential in Colloid Science. London: Academic Press; 1981.
79. Date AA, Nagarsenker MS. Parenteral microemulsions: An overview. Int J Pharm. 2008;355(1–2):19–30.
80. Klang V, Matsko N, Raupach A, et al. Electron microscopy of nanoemulsions. Eur J Pharm Biopharm. 2012;80(3):631–636.
81. Tadros TF. Rheology of emulsions. Adv Colloid Interface Sci. 2013;198:1–11.
82. Barnes HA. A handbook of elementary rheology. University of Wales Institute of Non-Newtonian Fluid Mechanics. 2000.
83. Lawrence MJ. Microemulsions and nanoemulsions as drug delivery vehicles. Drug Dev Ind Pharm. 1994;20(9):1483–1496.
84. Sinko PJ. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
85. Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 3rd ed. Mumbai: Varghese Publishing House; 2009.
86. Shakeel F, Baboota S, Ahuja A, Ali J, Shafiq S. Stability evaluation of nanoemulsion formulations. AAPS PharmSciTech. 2008;9(3):938–945.
87. USP–NF. United States Pharmacopeia. Rockville: United States Pharmacopeial Convention; 2022.
88. Bala I, Hariharan S, Kumar MNVR. PLGA nanoparticles in drug delivery: The state of the art. Crit Rev Ther Drug Carrier Syst. 2004;21(5):387–422.
89. Snyder LR, Kirkland JJ, Dolan JW. Introduction to Modern Liquid Chromatography. 3rd ed. Hoboken: Wiley; 2010.
90. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–133.
91. Modi CD, Bharadia PD. A review on dialysis membrane technique for in vitro drug release. Asian J Pharm Sci. 2012;7(2):1–7.
92. Shah RM, Eldridge DS, Palombo EA, Harding IH. Controlled release of drugs from nanoemulsions. J Pharm Sci. 2015;104(3):934–945.
93. ICH Q1A(R2). Stability testing of new drug substances and products. International Conference on Harmonisation; 2003.
94. Shakeel F, Ramadan W, Ahmed MA. Investigation of nanoemulsion stability. J Mol Liq. 2015;204:289–296.
95. Mahajan HS, Tyagi VK. Stability evaluation of nanoemulsions. Int J Pharm Sci Res. 2014;5(8):3280–3292.
96. Gupta A, Eral HB, Hatton TA, Doyle PS. Nanoemulsions: Formation, properties, and applications. Soft Matter. 2016;12:2826–2841.
97. Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nanoemulsion templates. J Control Release. 2008;128(3):185–199.
98. Torchilin VP. Stimuli-sensitive nanocarriers for drug delivery. Nat Rev Drug Discov. 2014;13(11):813–827.
99. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12(11):991–1003.
100. Bae YH, Park K. Targeted drug delivery to tumors: Myths, reality, and possibility. J Control Release. 2011;153(3):198–205.
101. Torchilin VP. Targeted pharmaceutical nanocarriers. Pharm Res. 2007;24(1):1–16.
102. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment. J Control Release. 2010;148(2):135–146.
103. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect. J Control Release. 2000;65(1–2):271–284.
104. Fox CB. Squalene emulsions for vaccine adjuvants. Vaccine. 2009;27(34):4554–4561.
105. O’Hagan DT, De Gregorio E. The path to a successful vaccine adjuvant: MF59. Expert Rev Vaccines. 2009;8(3):293–304.
106. Bali V, Ali M, Ali J. Study of surfactant combinations for nanoemulsion-based gene delivery. Colloids Surf B Biointerfaces. 2010;76(2):410–420.
107. Ahmad J, Amin S, Rahman M, et al. Nanoemulsion formulation of phytoconstituents for improved oral bioavailability. Drug Deliv. 2016;23(3):998–1008.
108. Ganesan P, Narayanasamy D. Lipid-based nano delivery of nutraceuticals. Sustain Chem Pharm. 2017;6:37–56.
109. Yadav N, et al. Nanoemulsion-based delivery systems for chronic diseases. J Drug Deliv Sci Technol. 2020;56:101112.
110. Pardridge WM. The blood–brain barrier: Bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.
111. Kumar M, Pathak K, Misra A. Intranasal nanoemulsion drug delivery to the brain. Drug Deliv. 2008;15(7):471–484.
112. Patel MM, Patel BM. Crossing the blood–brain barrier: Nanotechnology-based strategies. Drug Discov Today. 2017;22(4):593–604.
113. Jafari SM, He Y, Bhandari B. Nano-emulsion production by microfluidization. Food Hydrocoll. 2007;21(2):250–258.
114. Tinkle S, McNeil SE, Mühlebach S, et al. Nanomedicines: Regulatory science challenges. Ann N Y Acad Sci. 2014;1313:35–56.
115. Desai N. Challenges in development of nanomedicines. Pharm Res. 2012;29(6):1423–1433.
116. Acosta E. Bioavailability of nanoparticles in drug delivery. Curr Opin Colloid Interface Sci. 2009;14(1):3–15.
117. Anton N, Vandamme TF. Nano-emulsions as drug delivery systems. Expert Opin Drug Deliv. 2011;8(6):701–714.
118. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–249.
119. Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration. Adv Drug Deliv Rev. 2008;60(6):625–637.
120. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: Optimizing oral drug delivery. Nat Rev Drug Discov. 2007;6(3):231–248.
121. Shakeel F, Baboota S, Ahuja A, Ali J, Shafiq S. Nanoemulsions for improving oral bioavailability of poorly soluble drugs. J Mol Liq. 2014;196:386–394.
122. Kreilgaard M. Influence of nanoemulsions on cutaneous drug delivery. Adv Drug Deliv Rev. 2002;54(Suppl 1):S77–S98.
123. Santos P, Watkinson AC, Hadgraft J, Lane ME. Enhancement of skin penetration by surfactants. Int J Pharm. 2008;354(1–2):124–134.
124. Puglia C, Bonina F. Lipid nanoparticles for dermal drug delivery. Expert Opin Drug Deliv. 2012;9(4):429–441.
125. Shakeel F, Baboota S, Ahuja A, Ali J. Nanoemulsions for transdermal drug delivery. Expert Opin Drug Deliv. 2008;5(9):1135–1148.
126. Gaudana R, Jwala J, Boddu SHS, Mitra AK. Ocular drug delivery systems. AAPS J. 2009;11(3):441–455.
127. Üstünda? Okur N, et al. Nanoemulsions for ocular drug delivery. Drug Dev Ind Pharm. 2014;40(2):159–170.
128. Vandamme TF. Microemulsions and nanoemulsions in ophthalmology. Prog Retin Eye Res. 2002;21(1):15–34.
129. Abdelkader H, Ismail S, Kamal A, Alany RG. Ocular nanoemulsions. Drug Deliv. 2011;18(6):385–397.
130. Illum L. Nasal drug delivery: Possibilities and challenges. J Control Release. 2003;87(1–3):187–198.
131. Kumar M, Pathak K, Misra A. Intranasal nanoemulsion drug delivery systems. Drug Deliv. 2008;15(7):471–484.
132. Pardridge WM. Drug delivery to the brain. J Cereb Blood Flow Metab. 2012;32(11):1959–1972.
133. Driscoll DF. Lipid injectable emulsions: Safety and pharmacopeial issues. Pharm Res. 2006;23(9):1959–1969.
134. Benita S, Levy MY. Submicron emulsions as colloidal drug carriers. J Pharm Sci. 1993;82(11):1069–1079.
135. Shah MR, Imran M, Ullah S, et al. Lipid-based nanocarriers for cancer therapy. Colloids Surf B Biointerfaces. 2017;159:527–540.
136. Washington C. Stability of lipid emulsions for drug delivery. Adv Drug Deliv Rev. 1996;20(2–3):131–145.
137. Ahmad J, Amin S, Rahman M, et al. Nanoemulsion formulation of phytoconstituents. Drug Deliv. 2016;23(3):998–1008.
138. Ganesan P, Narayanasamy D. Lipid-based nano delivery systems for nutraceuticals. Sustain Chem Pharm. 2017;6:37–56.
139. Yadav N, et al. Nanoemulsion-based delivery systems for chronic diseases. J Drug Deliv Sci Technol. 2020;56:101112.
140. McClements DJ. Nanoemulsions: formulation, properties, and applications. Soft Matter. 2011;7:2297–316.
141. Tadros T, Izquierdo P, Esquena J, Solans C. Formation and stability of nano-emulsions. Adv Colloid Interface Sci. 2004;108–109:303–18.
142. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev. 2000;45(1):89–121.
143. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int J Pharm. 2001;212(2):233–46.
144. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–48.
145. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today. 2003;8(24):1112–20.
146. Shah B, Khunt D, Misra M, Padh H. Application of quality by design approach to optimize nanoemulsion formulation for nasal delivery. Int J Pharm. 2015;492(1-2): 137–47.
147. Mason TG, Wilking JN, Meleson K, Chang CB, Graves SM. Nanoemulsions: formation, structure, and physical properties. J Phys Condens Matter. 2006;18(41):R635–66.
148. Anton N, Vandamme TF. The universality of nanoemulsions. Expert Opin Drug Deliv. 2009;6(5):479–482.
149. McClements DJ, Decker EA, Park Y, Weiss J. Structural design principles for delivery of bioactive components. Crit Rev Food Sci Nutr. 2009;49(6):577–606.
150. Kaur IP, Garg A, Singla AK, Aggarwal D. Vesicular systems in ocular drug delivery: An overview. Int J Pharm. 2004;269(1):1–14.
151. Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 6th ed. London: Pharmaceutical Press; 2009.
152. Driscoll DF. Lipid injectable emulsions: Safety considerations. JPEN J Parenter Enteral Nutr. 2015;39(1 Suppl):41S–49S.
153. Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006;311(5761):622–627.
154. Donaldson K, Stone V, Tran CL, Kreyling W, Borm PJ. Nanotoxicology. Occup Environ Med. 2004;61(9):727–728.
155. Honary S, Zahir F. Effect of zeta potential on nano-drug delivery systems. Trop J Pharm Res. 2013;12(2):255–264.
156. Mahler GJ, Esch MB, Tako E, et al. Oral exposure to nanoparticles. Adv Drug Deliv Rev. 2012;64(7):624–632.
157. Shakeel F, Baboota S, Ahuja A, Ali J, Shafiq S. Skin safety evaluation of nanoemulsions. Drug Dev Ind Pharm. 2009;35(8):939–946.
158. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348–360.
159. Washington C. Stability and safety of lipid emulsions for drug delivery. Adv Drug Deliv Rev. 1996;20(2–3):131–145.
160. Fadeel B, Farcal L, Hardy B, et al. Advanced tools for nanotoxicology. Nat Nanotechnol. 2018;13(7):537–543.
161. ISO 10993-5. Biological evaluation of medical devices—Tests for in vitro cytotoxicity. Geneva: International Organization for Standardization; 2009.
162. Oberdörster G, Oberdörster E, Oberdörster J. Nanotoxicology. Environ Health Perspect. 2005;113(7):823–839.
163. Dobrovolskaia MA, McNeil SE. Immunological properties of engineered nanomaterials. Nat Nanotechnol. 2007;2(8):469–478.
164. Tinkle S, McNeil SE, Mühlebach S, et al. Nanomedicines and regulatory science. Ann N Y Acad Sci. 2014;1313:35–56.
165. EMA. Reflection paper on nanotechnology-based medicinal products. European Medicines Agency; 2011.
166. Desai N. Challenges in development of nanomedicines. Pharm Res. 2012;29(6):1423–1433.
167. Sutradhar KB, Amin ML. Nanoemulsions: increasing possibilities in drug delivery. Eur J Nanomed. 2013;5(2):97–110.
168. Shakeel F, Shafiq S, Haq N, Alanazi FK, Alsarra IA. Nanoemulsions as potential vehicles for transdermal delivery. J Drug Deliv Sci Technol. 2012;22(1):1–10.
169. Tadros TF. Emulsion formation and stability. Weinheim: Wiley-VCH; 2013.
170. Torchilin VP. Multifunctional nanocarriers. Nat Rev Drug Discov. 2014;13(11):813–827.
171. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers. Nat Mater. 2013;12(11):991–1003.
172. Danaei M, Dehghankhold M, Ataei S, et al. Impact of particle size and surface modification. Pharmaceutics. 2018;10(2):57.
173. Ventola CL. Progress in nanomedicine. P T. 2017;42(12):742–755.
174. Jafari SM, McClements DJ. Nanoemulsions: formation by low-energy methods. Food Hydrocoll. 2015;40:1–18.
175. Yu LX. Pharmaceutical quality by design. AAPS J. 2008;10(2):238–241.
176. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines. Nat Rev Drug Discov. 2018;17(4):261–279.
177. Pathak Y, Thassu D. Drug delivery nanoparticles. New York: CRC Press; 2009.
178. Mühlebach S, Borchard G, Yildiz S. Regulatory challenges of nanomedicines. Front Pharmacol. 2017;8:191.
179. Fadeel B. Safety assessment of nanomaterials. Nat Nanotechnol. 2019;14(3):208–216.
180. Solans C, Solé I. Nano-emulsions: formation by low-energy methods. Curr Opin Colloid Interface Sci. 2012;17(5):246–254.
181. Porter CJH, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilization. Adv Drug Deliv Rev. 2008;60(6):673–691.
182. Torchilin VP. Targeted pharmaceutical nanocarriers. Pharm Res. 2007;24(1):1–16.
183. Desai N. Challenges in development of nanomedicines. Pharm Res. 2012;29(6):1423–1433.
184. Mühlebach S, Borchard G. Regulatory challenges in nanomedicine. Adv Drug Deliv Rev. 2012;64(13):1329–1349.
185. McClements DJ. Delivery systems for nutraceuticals. Food Sci Technol. 2010;21(2):1–15.