A Review on Nanoemulsion in Improving the Bioavailability of Poorly Soluble Drugs

Abstract

Nanoemulsions are innovative drug delivery systems that significantly enhance the bioavailability of poorly water-soluble pharmacological compounds, which constitute approximately 40% of newly discovered drugs. These submicron-sized carriers, also known as ultrafine or miniemulsions, are composed of surfactant-lipid formulations capable of interacting with natural biological barriers to facilitate drug absorption. Their small droplet size, transparency, and thermodynamic stability make nanoemulsions suitable for various routes of administration, including oral, topical, and intravenous. They improve drug stability, reduce adverse effects, and enable targeted and controlled delivery, thereby increasing therapeutic efficacy. Nanoemulsions can be classified into three types based on composition: oil-in-water, water-in-oil, and bi-continuous systems, each stabilized by specific surfactants or co-surfactants. Several preparation methods exist, such as high-energy techniques like high-pressure homogenization, microfluidization, ultrasonic emulsification, and low-energy approaches like phase inversion temperature and spontaneous emulsification. Critical factors influencing stability include surfactant selection, concentration, and environmental conditions like pH and temperature. Characterization techniques such as zeta potential, particle size analysis, and polydispersity index are essential for quality control. Despite their advantages, nanoemulsions face challenges related to stability under extreme conditions and economic concerns due to high production costs. Their applications extend across pharmaceuticals, cosmetics, food, and agriculture, with future prospects focusing on improving bioavailability and targeted delivery of bioactive compounds, especially herbal medicines, through lipid-based nanocarriers...

Keywords

Introduction

About 40% of newly discovered pharmacological compounds are poorly water-soluble, and nano-sized carriers are known to be effective drug delivery vehicles for these medications. Nanoemulsions have surfaced as a viable substitute medication carrier among the innovative strategies [1]. Because of its composition and mechanism, this kind of surfactant-lipid-based formulation can interact with the body's natural barriers to facilitate medication absorption. Oil-in-water nanoemulsions improve bioavailability, increase medication stability, and reduce adverse effects, they may be able to overcome the disadvantage of those pharmaceuticals' limited solubility, offering a variety of uses [2]. Other names for the nanoemulsions are submicron emulsions, ultrafine emulsions, and miniemulsions. Phase behavior experiments have demonstrated that the surfactant phase structure (bicontinuous microemulsion or lamellar) at the inversion point, which is caused by either composition or temperature, controls the droplet size. Regardless of whether the initial phase equilibrium is single or multiphase, research on nanoemulsion production using the phase inversion temperature approach has demonstrated a relationship between the minimal droplet size and full solubilization of the oil in a microemulsion bicontinuous phase.[3] Making nanoemulsions for a variety of drug delivery techniques offers a number of notable benefits, significantly increasing the effectiveness and adaptability of pharmaceutical formulations. Examples of nonnanoemulsion formulations that significantly increase medication bioavailability as compared to formulations based on nanoemulsions are transdermal gel formulations. Known for theirnanoscale droplets, nanoemulsions provide a high interfacial area for drug dissolution and enhanced solubility for drugs with low water solubility.[4] A greater range of therapeutic drugs can be delivered thanks to higher drug-loading capacities brought about by this benefit. In the case of transdermal gels, nanoemulsions can improve drug penetration through the skin, leading to a speedier onset of action and superior therapeutic outcomes. Furthermore, there is considerable flexibility in the way that nanoemulsions can be applied topically, intravenously, or orally. They can satisfy different patient needs and are helpful in a range of drug delivery applications because of their versatility.[5]

1.1 Nanoemulsion Types

Depending on the composition, three different kinds of nanoemulsions are most likely to form:

• Water with oil in it nanoemulsions in which the continuous aqueous phase contains scattered     oil droplets;
• Water in oil nanoemulsions in which the continuous oil phase contains water droplets;
• Bi-continuous nanoemulsions, in which water and oil microdomains are distributed throughout the system.[6]

A proper combination of surfactants and/or co-surfactants stabilizes the interface in all three forms of nanoemulsions. The primary distinction between emulsions and nanoemulsions is that the former are essentially thermodynamically unstable and will eventually phase separate, even though they may show exceptional kinetic stability.[7] Another significant distinction is how they seem; emulsions are hazy, whereas nanoemulsions are transparent or clear. Additionally, there are evident variations in how they are prepared, since emulsions need a significant amount of energy, whilst nanoemulsions need not.[8]

1.2 Advantages of Nanoemulsion

Boost the absorption rate. removes absorption fluctuation. aids in the lipophilic drug's solubility. gives water-insoluble medications an aqueous dose form. makes it more bioavailable. Various routes like tropical, oral and intravenous can be used to deliver the product. quick and effective drug moiety penetration. beneficial for disguising flavor. Patient compliance is increased when using a liquid dose form.[9] Not as much energy is needed. The thermodynamic stability of nanoemulsions enables self-emulsification of the system, whose characteristics are independent of the procedure used. Both hydrophilic and lipophilic medications can be transported by the same nanoemulsions. By lowering the overall dosage and reducing adverse effects, the use of nanoemulsion as a delivery mechanism can increase a medication's effectiveness. [10]

1.3 Disadvantages of Nanoemulsion

Temperature and pH are two environmental factors that may have an impact on the stability of nanoemulsifiers. Due to their limited solubility, compounds with high melting points face difficulties. A higher concentration of surfactant and cosurfactant in nanoemulsifiers is necessary for nanodroplet stability.[11] In addition, environmental factors like pH and temperature can easily affect the stability of nanoemulsions, so controlling emulsifying conditions is crucial. Emulsifiers, which are necessary to stabilize micro droplets, must be carefully chosen because excessive concentrations of them might become toxic.[12]

2. Preparation Methods of Nanoemulsions

2.1 High Energy Emulsification Method

High-pressure equipment is the most efficient way to create nanoemulsions because of their extremely small particle size range.[13]

2.2 High Pressure Homogenizer

High-pressure homogenization is necessary for the creation of nanoemulsions. This method creates nanoemulsions with incredibly small particle sizes (up to 1 nm) by using a high-pressure homogenizer/piston homogenizer.[14] By forcing the mixture of two liquids (oily phase and aqueous phase) via a tiny inlet orifice at extremely high pressure (500 to 5000 psi), the product is subjected to strong turbulence and hydraulic shear, producing incredibly fine emulsion particles.[15] The resulting particles have a monomolecular layer of phospholipids that separates the liquid, lipophilic core from the surrounding aqueous phase. The only drawbacks to this method's high energy consumption and emulsion temperature rise during processing are its high efficiency.[16] If there is enough surfactant present to completely cover the oil-water interface formed and the adsorption kinetics are high enough to prevent droplet coalescence; this method can produce emulsion droplet diameters as small as 100 nm.[17]

2.3 Microfluidization

A device known as a microfluidizer is used in the high-energy process of microfluidization technology. It uses a displacement pump at high pressure (500–20,000 psi) to direct the flow stream through the interaction chamber's microchannels, which are tiny channels that produce extremely fine particles in the sub-micron range.[18] Although it is shown to be more effective than ultrasonography, this method is less feasible because of manufacturing expenses, equipment contamination, and aseptic processing.[19]

2.4 Ultrasonic Emulsification

An alternate technique for high pressure homogenization is ultrasonic emulsification. Ultrasonic cavitations, which create bubbles and reduce the particles to the nanoscale, cause strong shear forces. This technique is frequently employed in the small-scale manufacturing of nanoemulsions. Additionally, compared to traditional mechanical techniques, it requires less surfactant, uses less energy, and produces a more homogenous emulsion.[20]

2.5 Low energy emulsification method

2.5.1 Phase Inversion Temperature Method

Phase transitions brought forth by the emulsification process provide the substance life that causes fine scattering. Either altering the composition at a constant temperature or altering the temperature at a constant composition will provide the necessary stage improvements. The Phase Inversion Temperature (PIT) approach is based on the idea that temperature affects the solubility of surfactants of the polyoxyethylene type.[21] As the temperature rises, the dehydration of the polymer chain causes this surfactant to become lipophilic. The surfactant monolayer exhibits a strong positive spontaneous curvature at low temperatures, resulting in an oil-swollen micellar solution phase.[22]

2.5.2 Spontaneous Emulsification

It has been observed that spontaneous emulsification happens when a solution containing a little amount of oil in a water-miscible solvent without surfactant is poured into water. The ratio of surplus oil to water-soluble solvent determines the width of the oil droplets that are created. This technique can be applied in place of high-shear and ultrasonic techniques. Its limited oil content that may be spread and the requirement that the solvent be soluble in water in all proportions are some of its drawbacks.[23]

2.5.3 Membrane Emulsification

This low-energy nanoemulsion method yields emulsions with a limited size distribution range and uses less surfactant. Using this technique, a dispersed phase is formed via a membrane. into an ongoing stage. However, a drawback of this approach is the scattered phase's low flux.

through the membrane, which presents a problem for scaling up.[24]

2.5.4 Emulsion Inversion Point

This technique involves changing the system's composition while maintaining a steady temperature. To produce kinetically stable nanoemulsions, the structures are created by gradually diluting them with water or oil.[25]

3. Factors to Be Considered During Preparation of Nanoemulsion

In order to achieve an ultra-low interfacial tension (< 10-3 mN/m) at the oil/water interface a crucial prerequisite for the production of nanoemulsions surfactants must be carefully selected. The concentration of surfactant must be high enough to supply the number of surfactant molecules required to stabilize the ultra-low interfacial tension-produced microdroplets. To encourage the creation of nanoemulsions, the contact needs to be sufficiently flexible or fluid.[26]

4. Characterization of Nanoemulsion

4.1 Zetapotential

A device known as Zeta PALS is used to assess zeta potential. It is employed in nanoemulsion to determine the droplet surface load. Emulsifiers create surface charges in addition to acting as a mechanical barrier. Coalescence is hampered by the repulsive electrical forces that can be produced by zeta potential between approaching oil droplets. The emulsion is more stable and has a higher net droplet charge when the zeta potential is more negative. Zeta potential readings below -30 mV often indicate a high level of physical stability. Zeta potential is measured by the Malvern Zetasizer, which is based on the dispersion of dynamic light.[27]

4.2 Polydispersity Index

Photon correlation spectroscopy is used to determine the samples' average diameters and polydispersity index. A He-Ne laser is used to conduct the measurements at 25°C [28].

4.3 Particle size analysis:

In the instance of nanoemulsion, particle size and distribution are often measured using the dynamic light scattering (DLS) method.[29]

4.4 Percent Drug Loading:

After dissolving the pre-weighted nanoemulsion in a suitable 25 ml solvent, the extract is extracted using spectrophotometric and HPLC analysis. in opposition to the typical medication solution. Several columns with the right porosity are used in the reverse phase HPLC procedure to determine the drug content.[30]

4.5 Analysis of nanoemulsion droplet size.

Using a Zetasizer 1000 HS (Malvern Instruments, UK), photon correlation spectroscopy, which examines variations in light scattering caused by Brownian motion of the particles, was used to evaluate the droplet size distribution of the nanoemulsion. At a 90° angle and 25 °C, light scattering was observed. Studies of droplet size distribution were conducted using the corresponding formulation at a given refractive index.[31]

5. Limitations and Challenges of Nanoemulsions

5.1 Nanoemulsion Stability

To completely comprehend the relationship between the chemical composition and properties of nanoemulsions, lab- and pilot-scale research is still necessary in the new techniques, such as in the oil and gas sectors. Since nanoemulsions are kinetically stable (although slowly), phase separation will occur. This instability can happen during on-site storage, ground transportation, or even on-site transit in the reservoir when utilized in long-term field applications. The effects of extreme reservoir conditions, such as high salinity, high temperature, and intricate chemical interactions, on nanoemulsion stability are still unknown. On the one hand, ex situ research could clarify the mechanics of phase separation of nanoemulsions in reservoir-like conditions and look into desirable tactics.[32]

5.2 Economic Concerns about Nanoemulsion

Two factors need to be taken into account in order to address economic concerns: (1) nanoemulsion manufacturing and (2) necessary facilities. Many different chemicals are needed to produce a nanoemulsion in significant quantities. These substances consist of solvents, surfactants, and polymers. Emulsification, like other high-energy methods, uses extreme heat or pressure to disperse the droplets and break up the surfaces. Second, the formation of nanoemulsions requires a variety of facilities and equipment, which can greatly raise the cost. This is especially true when specific equipment is needed for large-scale mixing and homogenization procedures.[33] Due to their numerous health advantages, herbal bioactives have become more and more well-liked globally. Low solubility, permeability, and bioavailability are still drawbacks, though. Using high-throughput techniques, 40% of the active principle molecules are insoluble. These make creating effective natural treatments for medical therapy extremely difficult. To achieve the ideal blood concentration level in the body, research into new carriers for the transfer of herbal bioactive components is necessary.[34]

6. Applications of Nanoemulsion

Pharmaceutical preparations can be made using nanoemulsions that contain pharmaceutically active ingredients. The active ingredient in the nanoemulsion is combined with a solid or liquid vehicle that is appropriate for therapeutic delivery. The mixture can be given a unique galenic shape if required. In this regard, the following galenic administration methods may be taken into consideration: Ampoules, particularly sterile injection and infusion solutions; solutions, particularly oral liquids, eye drops, and nose drops, which may contain different auxiliary substances in addition to the nanoemulsion; aerosols without a metering feature, as well as dosing aerosols, which may contain propellant gas and stabilizers in addition to the nanoemulsion; gels and ointments that are hydrophilic and hydrophobic; o/w or w/o creams containing the nanoemulsion; lotions and pastes containing the nanoemulsion. [35]

6.1 Nanoemulsion for oral route

Because of their slow rate of dissolution, weakly water-soluble medications have limited bioavailability; consequently, o/w nanoemulsion increases the drugs' solubility, absorption, and bioavailability following oral administration.[36]

6.2 Nanoemulsion for ocular delivery

Lipophilic medications, such as erythromycin and pilocarpine, are delivered to the eye by nanoemulsion for improvement.[37]

6.3 Nanoemulsion for transdermal delivery

Hair follicles, sweat ducts, or the stratum corneum are the three ways the chemical substance might enter the skin layer, limit drug absorption and lowering its bioavailability. to enhance medication targeting and manage drug redistribution in lymphatic and blood arteries. The capacity of nano-sized emulsion to enter skin pores and deliver to the systemic level makes it a viable technology with advantages including minimal preparation costs, good storage stability, lack of organic solvents, and thermodynamic stability.[38]

6.4 Nanoemulsion in cosmetic

Nanoemulsions are thought to be effective delivery systems for regulated cosmetics and help active ingredients spread throughout the epidermis. Because nanoemulsion doesn't sediment, cream, or flocculate like microemulsion does, it is utilized in cosmetics.[39]

FUTURE PROSPECTS

The prospective applications of nanoemulsions in the food, cosmetics, healthcare, and agricultural sectors have sparked interest in them among scientists. They may contain phytochemicals and other bioactive substances used in the food and pesticide industries. The production of nanocarriers seeks to improve the pharmacokinetics and absorption of herbal bioactives that are only weakly accessible by means of size reduction, encapsulation, and stability. A high level of drug delivery is the only way to improve therapeutic efficacy at the target site. Large molecular size and lipid solubilization are the primary rate-limiting variables for biomembrane permeability in the case of herbal bioactives. One of the biggest challenges in making herbal medications is getting across the membrane with an improved pharmacokinetic profile. Lipid or oil-based nanocarriers may be the answer to these problems. They can improve bioavailability, reduce the impact of food on the rate of absorption of highly lipophilic compounds, and increase solubility, permeability, and gastrointestinal tract (GIT) absorption.

CONCLUSIONS

Nanoemulsions represent a significant advancement in drug delivery systems, especially for poorly soluble drugs. Their unique physicochemical properties, such as small droplet size, transparency, and thermodynamic stability, enable enhanced bioavailability, improved stability, and targeted delivery. The various types of nanoemulsions oil-in-water, water-in-oil, and bi-continuous offer versatile options tailored to specific therapeutic needs. The methods of preparation, including high-energy techniques like high-pressure homogenization, microfluidization, and ultrasonic emulsification, as well as low-energy approaches such as phase inversion temperature and spontaneous emulsification, provide flexible strategies for manufacturing nanoemulsions with desired characteristics. Critical factors like surfactant selection, concentration, and environmental conditions influence the stability and efficacy of these systems.

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