The nanoemulsion technique, a prominent aspect of nanotechnology, is specifically designed for measurable clinical and therapeutic applications. Currently, various nano-carrier-based nanoemulsion approaches are gaining widespread attention for effectively addressing diverse cancer types. This innovative therapy successfully tackles challenges like low solubility, multidrug resistance, and toxicity. Consequently, nanoemulsions emerge as a promising solution for achieving efficient and safe cancer treatment.
Nanoemulsions boast numerous advantages, including their nanometric size, straightforward preparation, site-specificity, drug encapsulation, non-immunogenicity, biocompatibility, biodegradability, sustained and controlled release, large surface area, and thermodynamic stability. Recent research extensively explores nanoemulsions as drug carriers to enhance the delivery of therapeutic agents or compounds. These nanoemulsions can be formulated into various forms such as liquids, sprays, foams, creams, ointments, and gels, utilizing mushroom bioactive components.
The development of these potential nanoemulsions holds great promise for the future of cosmetics, diagnostics, drug therapies, and biotechnologies.
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What is Nanoemulsion?
Nanoemulsions are emulsions characterized by droplets with sizes typically around 100 nm. They are composed of oil, water, and an emulsifier, with the emulsifier playing a critical role in reducing interfacial tension between the oil and water phases. This reduction in tension allows for the creation of small droplets. The emulsifier also contributes to the stability of nanoemulsions through mechanisms such as repulsive electrostatic interactions and steric hindrance. Surfactants, proteins, and lipids are commonly used as emulsifiers.
Nanoemulsions find applications in diverse fields, including drug delivery, food industry (e.g., flavored nanoemulsions), cosmetics (e.g., for skin hydration), and material synthesis. The distinction between nanoemulsions and thermodynamically stable microemulsions is clarified, emphasizing the kinetic stability and resilience of nanoemulsions to physical and chemical changes.
Formation of Nanoemulsion
Understanding the intricacies of nanoemulsion formation is crucial for fine-tuning droplet sizes. Nanoemulsions are typically crafted in a two-step process: starting with the formation of a macroemulsion, which is then refined into a nanoemulsion. Here, we explore various methods developed in the past decade to create nanoemulsions and discuss advancements in predicting and managing the size of these minuscule droplets.
Nanoemulsion Preparation Strategies
Nanoemulsions, known for their small droplet size and heightened stability, are crafted through a variety of methods, broadly categorized as high-energy and low-energy techniques. The precision in controlling droplet size is paramount for the successful preparation of nanoemulsions.
Control of Droplet Size
Achieving precise control over droplet size is crucial as it directly impacts the stability and performance of nanoemulsions. Factors such as residence time, relative viscosity, surfactant concentration, and surfactant length play pivotal roles in determining the final droplet size. Researchers have developed scaling relations that incorporate Weber and Ohnesorge numbers, providing valuable insights into the dynamics of droplet breakup under different conditions.
Scaling Relations for Droplet Size
The use of scaling relations, incorporating dimensionless numbers like Weber and Ohnesorge, aids in predicting and understanding the behavior of nanoemulsion droplets. This correlation proves valuable in explaining variations in droplet size observed in different experimental setups and methods.
While significant progress has been made in nanoemulsion preparation, several questions remain unanswered. Researchers are actively exploring the influence of process parameters, material properties, and surfactant kinetics on droplet size distribution. Future studies are expected to provide a more comprehensive understanding of the intricate mechanisms involved.
High-Energy Emulsification Methods
High-energy methods are instrumental in nanoemulsion preparation, leveraging mechanical devices to introduce disruptive forces. Initially dominated by high-energy stirring and ultrasonic emulsification, the field is now witnessing a shift towards exploring low-energy methods for their gentler approach.
- High Pressure Homogenization (HPH): Considered one of the most popular methods, HPH employs homogenizers or piston homogenizers. Operating at high pressures, this technique generates nanoemulsions through a combination of hydraulic shear, intense turbulence, and cavitation.
- High-Shear Stirring: Utilizing high-energy mixers and rotor-stator systems, high-shear stirring is effective in reducing droplet sizes. However, achieving emulsions with an average droplet size below 200-300 nm remains challenging.
- Ultrasonic Emulsification: This method utilizes acoustic fields and cavitation to create nanoemulsions cost-effectively. However, concerns exist regarding potential denaturation, depolymerization, and lipid oxidation during the ultrasonic process.
- Microfluidization: Widely embraced in the pharmaceutical industry, microfluidization employs devices like microfluidizers. High pressure propels macroemulsions through microchannels, ensuring the production of nanoemulsions with uniform droplet sizes.
Low-Energy Emulsification Methods
Low-energy methods are gaining attention for their ability to produce small, uniform droplets. Techniques such as phase inversion temperature and phase inversion component leverage physicochemical properties for nanoemulsion production.
- Spontaneous Nanoemulsification: This method relies on the release of chemical energy during the dilution process, occurring at constant temperatures. Requiring no special devices, spontaneous nanoemulsification finds application in the pharmaceutical industry, termed as self-emulsifying drug-delivery systems (SEDDS) or self-nano-emulsifying drug-delivery systems (SNEDDS).
Nanoemulsion preparation involves a diverse array of techniques, each presenting unique advantages and considerations. The choice of a specific method depends on the desired characteristics of the nanoemulsion and its intended applications across various industries. Ongoing research aims to refine these methods, addressing current challenges and expanding the scope of nanoemulsion applications.
Nanoemulsion Stability
Nanoemulsions, characterized by their small droplet size and heightened stability, undergo destabilization mechanisms over time. This section delves into the fundamental aspects of emulsion destabilization, highlighting the key mechanisms and exploring research endeavors focused on controlling nanoemulsion stability.
Destabilization Mechanisms
Nanoemulsions exhibit kinetic stability, with eventual separation into distinct phases if given enough time. Four primary destabilization mechanisms include:
- Flocculation: Attractive interactions bring droplets closer, causing them to move collectively.
- Coalescence: Droplets merge, forming larger drops, often challenging to differentiate from flocculation.
- Ostwald Ripening: Driven by differences in chemical potential, smaller droplets transfer material to larger ones, leading to droplet size variation
- Creaming/Sedimentation: Droplets rise or settle due to buoyancy, causing phase separation.
Control Strategies for Nanoemulsion Stability
Efforts to maintain nanoemulsion stability involve understanding and manipulating influencing factors. These factors and their impact on destabilization rates are explored:
Temperature Dependence: Ostwald ripening rates follow an Arrhenius behavior, influenced by solubility and diffusivity changes with temperature.
Ionic Strength: Significant impact on repulsive barriers between droplets; higher ionic strength reduces repulsive barriers, enhancing flocculation/coalescence probability.
Polydispersity: Affects Ostwald ripening rate; higher polydispersity increases the difference in chemical potential between droplets.
Emulsifier Choice and Concentration: Type and concentration alter properties like interfacial tension, droplet elasticity, and interaction potential between droplets.
Research studies demonstrate the effectiveness of various methods in controlling destabilization:
Surfactant Concentration Influence: Higher surfactant concentrations accelerate Ostwald ripening, impacting nanoemulsion stability.
Addition of Insoluble Emulsifier: Controlling stability by varying the concentration of insoluble emulsifier in the continuous phase, offering a method akin to the trapped species approach.
Comparison of Preparation Methods: Stability comparison between nanoemulsions prepared through phase inversion temperature (PIT) and high-pressure homogenization (HPH) reveals lower destabilization rates in HPH-prepared nanoemulsions.
Advantages and Disadvantages of High-Energy Method
| High Energy Method | Advantages | Disadvantages |
| High-pressure homogenizer | – High stability nanoemulsion production | – Utilizes a lot of energy, elevates temperature |
| – Simple production method | – May cause damage to thermolabile substances | |
| – Applicable to thermolabile materials | – Powerful breaking forces may affect sensitive components | |
| Microfluidization | – Can produce submicron emulsions | – Inappropriate for large-scale emulsion concentrations |
| – Even at lower emulsifier concentration | – Not suitable for high pressure and extended emulsification times | |
| Ultrasonication | – High energy efficacy, good stability | – Not suitable for heat-sensitive components |
| – Produces kinetically stable nanoemulsions | – Low mixing efficiency | |
| Jet disperser method | – Provides extremely fine nanoemulsions | – Difficult to operate, clean, and scale-up |
| Rotor-Stator emulsification | – Feasible for higher disperse phase ratio | – Challenging for droplet sizes below 200/300 nm |
| – Better performance with delayed adsorption kinetics | – Difficult to obtain homogenized nanoemulsions |
Advantages and Disadvantages of Low energy method
| Low Energy Method | Advantages | Disadvantages |
| Self-nanoemulsification | – No extra equipment needed | – Spontaneous emulsification occurs under specific conditions |
| – High efficacy, potential for large-scale sizes | – Limited to specific conditions | |
| Phase inversion nanoemulsification | – Efficient in forming nanoemulsions | – Complex, requires accuracy, use of surfactants |
| – Avoids intermediate phases | – Very high temperatures required | |
| D phase emulsification | – Forms emulsions even at low surfactant concentrations | – No need for well-balanced surfactant systems |
| – No specific solvents required | ||
| Membrane emulsification | – Low droplet size distribution, longer shelf life | – Limited to low viscosity liquids |
| – Minimal energy use, low running costs | ||
| Microemulsion dilution | – Low energy consumption, no temperature changes | – Requires specific controlled porous glass membranes |
| Solvent displacement | – Room temperature emulsification | – High solvent to oil ratio for droplet size control |
| – High lipophilic drug encapsulation efficiency | – Decreased encapsulation effectiveness due to water removal |
Nanoemulsion Properties
Nanoemulsions, boasting precise droplet dimensions, enduring stability, and a spectrum of customizable rheological responses, emerge as foundational components with vast technical applications. Their integration across diverse industries is accompanied by ongoing research, unraveling intricate rheological nuances for groundbreaking materials and product development.
Droplet Dimensions and Robustness
Nanoemulsions, characterized by their sub-100 nm droplets, offer a meticulous visual spectrum manipulation from optical transparency to controlled opaqueness. Their robust stability, resilient against dilution, temperature fluctuations, and pH variations, positions them as pivotal players in the dynamic landscapes of food and cosmetics.
Tailored Rheology
Nanoemulsions showcase intricate rheological behaviors, subject to sophisticated customization through diverse methodologies:
- Dispersed Phase Control: Precise adjustments in volume and droplet size enable the nuanced tailoring of nanoemulsion physical characteristics.
- Salt and Depletion Agent Integration: The introduction of these elements serves as a catalyst for inducing gel-like behavior in nanoemulsion droplets, expanding the system’s rheological repertoire.
- Polymer Integration Strategies: Polymers, especially those capable of intricate associations with nanoemulsion droplets, play a pivotal role in sculpting the nuanced rheological response. For example, the addition of a polymer gelator with hydrophobic end groups leads to the formation of thermoreversible gels.
- Flow-Induced Elastification: The controlled manipulation of passes in high-pressure homogenization induces irreversible flow-induced elastification, transforming nanoemulsions from a fluidic state to a gel-like configuration.
- Gelation Dynamics and Temperature Responsiveness: Polymer inclusion triggers reversible gelation, with the process intricately linked to temperature variations. The relative value of interaction length to droplet size serves as a critical parameter influencing the formation of resilient gels.
Continued research into the complex rheological intricacies of nanoemulsion-based gels is imperative, encompassing in-depth investigations into rupture mechanisms and the intricate dynamics governing the association-disassociation of bridging gelators. The exploration of the healing characteristics of these systems holds significant promise for advancing the technical understanding.
Application of Nanoemulsions
Nanoemulsion in Drug Delivery
Nanoemulsions have emerged as versatile carriers in various modes of drug delivery, offering unique advantages in terms of solubilizing hydrophobic drugs and improving bioavailability. The following are key applications of nanoemulsions in drug delivery:
Topical Drug Delivery: Nanoemulsions formulated for topical medication offer enhanced solubility of lipophilic drugs in the oil phase. The dispersed phase of oil-in-water (O/W) nanoemulsions provides a suitable environment for dissolving biopolymers like alginate, allowing adjustment of formulation rheology and texture. The mild, skin-friendly continuous phase facilitates the application of drugs through the skin barrier. Studies have demonstrated the effectiveness of nanoemulsions in permeation tests, with hydrophobic drugs being delivered more efficiently compared to suspensions.
Ocular Drug Delivery: Nanoemulsions have been explored for ocular drug delivery, presenting a promising approach for improving the bioavailability of drugs administered to the eyes. The small droplet size and tunable properties of nanoemulsions make them suitable for formulating ocular drug delivery systems.
Intravenous Drug Delivery: Nanoemulsions have been investigated for intravenous drug delivery, aiming to enhance the bioavailability and therapeutic efficacy of pharmaceutical drugs. This mode of delivery involves dissolving the drug in the dispersed phase of nanoemulsions, which are then evaluated for their delivery efficiency in conditions that mimic real physiological environments.
Intranasal Drug Delivery: Nanoemulsions have been applied in intranasal drug delivery, providing a non-invasive route for drug administration. This approach takes advantage of the unique properties of nanoemulsions to improve drug solubility and delivery efficiency in the nasal cavity.
Oral Drug Delivery: Nanoemulsions have been studied for oral drug delivery, with pharmaceutical drugs dissolved in the dispersed phase. Formulations are tested for bioavailability in environments simulating conditions similar to those of the small intestine walls. This application aims to enhance drug absorption and improve therapeutic outcomes.
Ultrasound Imaging Agents: Nanoemulsions have been utilized as ultrasound imaging agents, demonstrating their versatility in diagnostic applications. For example, nanoemulsions containing perfluorocarbons have been prepared for quantitative molecular imaging. These formulations can be engineered for multifunctionality, enabling imaging-guided therapies.
Multifunctional Nanoemulsion Platforms: Nanoemulsions can serve as multifunctional platforms for imaging-guided therapies. These platforms may incorporate various components, such as iron oxide nanocrystals for MRI, fluorescent dyes for near-infrared fluorescence (NIRF) imaging, and therapeutic agents for targeted treatments. This approach allows for a comprehensive assessment of the platform’s utility in both imaging and therapeutic applications.
Food Industry
Nanoemulsions play a pivotal role in designing smart foods, especially when dealing with challenging ingredients like β-carotene. In-depth studies dive into stability, size considerations, and bioaccessibility, addressing solubility challenges.
Nanoemulsions emerge as carriers for bioactive additives, showcasing anti-inflammatory responses, and demonstrating improved food digestibility compared to conventional consumption. Through low-energy methods, flavored nanoemulsions are crafted, presenting a versatile application in diverse food products.
Nanoemulsions in Material Synthesis
Nanoemulsions serve as foundational building blocks for crafting intricate materials. From compartmentalized silica nanospheres to self-assembled macromolecule-coated emulsions, they pave the way for diverse applications, including controlled release systems.
Pharmaceutical Crystal Production
A continuous, soft matter-inspired process is reshaping pharmaceutical crystal production, minimizing energy-intensive methods, and avoiding undesired polymorphic transitions.
The resulting composite hydrogel allows for controlled crystal size and loading. Achieving dissolution rates comparable to commercial formulations underscores the potential impact of nanoemulsion-based approaches in the pharmaceutical industry. This continuous process seamlessly extends to producing dried composite hydrogels, scalable for tablet formulation
Nanoemulsion in Cosmetic Industry
Nanoemulsions have gained significant attention and application in the field of cosmeceuticals due to their unique properties and benefits. The use of nanotechnology, specifically nanoemulsions, in cosmetic formulations has revolutionized the delivery of active ingredients and improved the overall efficacy of cosmetic products. Here are some key applications of nanoemulsions in cosmeceuticals:
Enhanced Stability of Active Ingredients: Nanoemulsions provide a stable platform for incorporating a variety of cosmetic ingredients, such as unsaturated fatty acids, vitamins, and antioxidants. The small droplet size and the presence of emulsifiers contribute to the improved stability of these active compounds, preventing degradation and ensuring a longer shelf life.
Improved Penetration Rate: The nano-sized droplets in nanoemulsions facilitate better penetration of active ingredients into the skin. This is particularly advantageous for substances like vitamins and antioxidants, which can now more effectively reach the deeper layers of the skin, providing enhanced benefits.
Aesthetic Improvement of Products: Nanoemulsions contribute to the aesthetic appeal of cosmetic products. The smaller droplet size leads to a more elegant and smoother texture, improving the overall feel and appearance of creams, lotions, and other formulations. This can positively influence consumer perception and satisfaction.
Efficient UV Filter Delivery: Nanoemulsions play a role in enhancing the performance and tolerance of UV filters on the skin surface. The formulation can be tailored to encapsulate UV-filtering agents, ensuring their even distribution and effective protection against harmful UV rays.
Hydration Effect and Skin Absorption: The water content in nanoemulsions plays a crucial role in improving percutaneous absorption of cosmeceuticals. Adequate hydration of the stratum corneum enhances the absorption of active ingredients, contributing to better skin hydration and overall health.
Colloidal Transdermal Carriers: Nanoemulsions, such as those based on hyaluronic acid and glycerol monostearate, serve as effective colloidal transdermal carriers. These formulations have applications in skin care and cosmetic products, offering a controlled and targeted delivery of active ingredients.
Factors Affecting Nanoemulsion Formulation
- The dispersed phase should be highly insoluble in the dispersed medium to prevent Oswald ripening.
- Surfactants play a crucial role, and they should not form lyotropic liquid crystalline “microemulsion” phases.
- Systems containing short chain alkanes, alcohols, water, and surfactants are commonly used with co-surfactants.
- Excess surfactants are essential to rapidly coat the new nanoscale surface area during emulsification, inhibiting induced coalescence.
- Extreme shear is necessary to rupture microscale droplets into nanoscale, with ultrasonication being a widely used laboratory method.
- Emphasis on reducing production costs and ensuring safety in the use of nanoemulsions in food applications.
- Exploration of the biological events and risks associated with nanoemulsion-based delivery systems in food products and packaging.
- Optimization of bioactivity of encapsulated components for scaled-up production.
- Comprehensive studies on the potential toxicological effects and biological fate of nanoparticles in nanoemulsion-based food systems.
Advantages of Nanoemulsion
- Nanoemulsions possess higher surface area and free energy, making them effective for transporting substances.
- They do not exhibit inherent issues like creaming, flocculation, coalescence, and sedimentation, enhancing their stability.
- Nanoemulsions can be formulated in various forms such as foams, creams, liquids, and sprays, providing versatility in applications.
- Non-toxic and non-irritant, making them suitable for easy application on skin and mucous membranes.
- Can be administered orally if the formulation contains biocompatible surfactants.
- Nanoemulsions do not cause damage to healthy human and animal cells, making them suitable for therapeutic purposes.
- Facilitates better uptake of oil-soluble supplements in cell cultures, aiding in the growth of cultured cells and enabling toxicity studies of oil-soluble drugs.
- Can be applied as a substitute for liposomes and vesicles, allowing the formation of lamellar liquid crystalline phases around nanoemulsion droplets.
- Due to their small size, nanoemulsions can penetrate through the rough skin surface, enhancing the penetration of active ingredients.
- Constitutes the primary step in the synthesis of nanocapsules and nanospheres using nano precipitation and interfacial polycondensation.
Disadvantages of Nanoemulsion
While nanoemulsions offer numerous advantages, it’s essential to acknowledge potential challenges:
- The production and formulation of nanoemulsions may involve higher costs compared to conventional formulations.
- Achieving the desired properties and stability in nanoemulsion formulations can be complex and may require specialized knowledge.
- Nanoemulsions heavily rely on surfactants, and the choice of surfactant is critical. Some surfactants may have limitations or undesirable effects.
- Maintaining long-term stability may be challenging, and nanoemulsions may require additional measures to prevent destabilization over time.
- Scaling up production from laboratory to industrial levels can present challenges, and the transition may impact the stability and properties of nanoemulsions.
References
- https://pubs.rsc.org/en/content/articlelanding/2016/sm/c5sm02958a
- https://www.intechopen.com/chapters/47116
- https://www.igi-global.com/dictionary/mushroom-derived-bioactive-based-nanoemulsion/105072
- https://doylegroup.mit.edu/wp-content/uploads/sites/68/2022/11/Nanoemulsions-Formation-Properties-and-Applications-1.pdf
- https://www.academia.edu/7313339/Nanoemulsion_Formation_Stability_and_Applications
- Nur Haziqah Che Marzuki, Roswanira Abdul Wahab & Mariani Abdul Hamid (2019) An overview of nanoemulsion: concepts of development and cosmeceutical applications, Biotechnology & Biotechnological Equipment, 33:1, 779-797, DOI: 10.1080/13102818.2019.1620124
