Formulation and Characterization of Multiple Emulsion for Enhanced Drug Delivery and Therapeutic Applications: A Review

Abstract

Many uses for emulsions have been suggested, such as improving bioavailability or acting as a sustained drug delivery method. However, before they can be used in pharmaceuticals, the system's essential instability must be resolved. Hydrophilic and hydrophobic surfactants are frequently used in combination to stabilise multiple emulsions. Achieving stable multiple emulsions depends on the ratio of these surfactants. was chosen as a model drug for studying the possibility of using several emulsions to increase bioavailability, with the idea that an improvement in the drug's release profile would correlate with an increase in its bioavailability. The aim of this research was to create many emulsions using two-step emulsification using various non ionic surfactants, Tweens and Spans, and assess stability, drug entrapment percentage, and in vitro drug release. The study arrived at the conclusion that a two-step emulsification approach combining Spans20,40, 60, and 80 as primary emulsifiers and Tween80 as secondary emulsifiers and cosurfectant like Peg400,use can produce stable multiple emulsions with good entrapment efficiency.

Keywords

Introduction

The unique look of multiple emulsions, which are complex colloidal systems, is that droplets of one liquid are enclosed in larger droplets of another immiscible liquid, which are then dispersed over a continuous exterior phase. Because of their layered structure, they are practically "emulsions of emulsions." Water-in-oil-in-water (W/O/W) and oil-in-water-in-oil (O/W/O) are the two main types of multiple emulsions.  Water droplets in a W/O/W system are enclosed by oil droplets, which are then released into an external aqueous phase.  On the other hand, water droplets dispersed across the outside oil phase enclose oil droplets in an O/W/O emulsion.  Due to their multi-phase nature, these systems are essentially more complex than simple emulsions, requiring a more advanced formulation and stabilisation technique.⁽¹⁾

Due to their flexibility and functional promise in a variety of industries, including food technology, cosmetics, and pharmaceuticals, multiple emulsions have drawn a lot of interest in recent decades.  Their ability to contain, barrier, and release active ingredients in a controlled and prolonged way is their most significant advantage.  Because of this, they are perfect for delivering complex substances like medicines, vitamins, enzymes, or flavours that could otherwise breakdown or cease to function when exposed to environmental factors like light, air, or enzymes

W/O/W emulsions can be used as hydrophilic drug carriers in pharmaceutical applications, allowing specific administration and prolonged drug release.  Multiple emulsions improve skin feel, moisturising effects, and active ingredient penetration in cosmetics, which improves product effectiveness.  Additionally, they enable the encapsulation of water- or oil-soluble active ingredients in a single formulation.  Similar to this, similar systems can be applied in food technology to reduce fat, disguise flavour, and release nutrients or functional substances in a regulated manner, all of which help create food items that are healthier and more effective.⁽²⁾

The helpful and concentration of emulsifiers, the preparation approach, and the physicochemical properties of the component phases are some of the most important factors that affect the successful production and stabilisation of multiple emulsions.  Multiple emulsions require a combination of hydrophilic and lipophilic surfactants to stabilise the internal and exterior surfaces, in contrast to simple emulsions, which usually only require one kind of emulsifier.  For example, in W/O/W emulsions, the water-in-oil interface of the main emulsion is stabilised by a lipophilic emulsifier, whereas the secondary oil-in-water dispersion needs to be stabilised by a hydrophilic emulsifier.

To prevent coalescence, creaming, or phase separation, other factors which have to be carefully regulated include the droplet size, viscosity, interfacial tension, and osmotic pressure between the internal and external aqueous phases.  To increase the stability and reproducibility of various emulsions, a number of methods have been developed, include membrane emulsification, two-step emulsification, and microfluidic technologies.  The multifunctional advantages of various emulsions make them highly desirable for contemporary product development across a wide range of sectors, notwithstanding the formulation constraints.  Their usefulness, scalability, and stability have been enhanced by ongoing research to increase their commercial and therapeutic uses.⁽³⁾

The benefits of multiple emulsions :-

1. Controlled Active Ingredient Release: The active ingredients in the inner phase can be encapsulated in multiple emulsions, allowing controlled and sustained release.⁽¹⁾
2. Protecting Sensitive Ingredients: They protect proteins, vitamins, and unstable medications from being dissolved down by outside factors like light, pH, enzymes, etc .⁽³⁾
3. Masking Taste: By protecting the active ingredients, certain emulsions help in the masking of bitter or uncomfortable tastes in medicines and nutraceuticals.⁽²⁾
4. Reduced Emulsifier: UsageThey may reduce the total emulsifier concentration, which is beneficial for reducing discomfort and expense in food and cosmetic compositions.⁽⁴⁾
5. Uses in Cosmetics: They offer improved skin feel, more effective moisturising properties, and controlled distribution of active ingredients (such as vitamins and anti-aging agents).⁽⁵⁾

Multiple emulsions' limitations

The complex and delicate structure of multiple emulsions, which extends to their underlying thermodynamic instability, is one of the primary issues with them.  The high interfacial energy between the various layers causes this instability, which leaves them at risk for osmotic-driven swelling or shrinkage, phase separation, and coalescence.  Hence, maintaining their structural integrity over time develops into a major formulation problem.  Their practical utility decreases significantly in many areas where their usage could otherwise be very advantageous, such as pharmaceuticals, cosmetics, and food systems, due to their lack of long-term stability, which also making manufacture and storage more difficult.

Types of multiple emulsion

Water-in-oil-in-water (W/O/W) emulsions

These are complex structures in which small dispersed liquid droplets are contained within oil globules. Each internal water droplet is surrounded by an oil layer that protects it from the external aqueous phase.  At least two surfactants must be used to stabilise both interfaces: a hydrophilic surfactant for the outer oil-in-water interface and a lipophilic surfactant for the inside water-in-oil interface.

Oil-in- water- in-oil (O/W/O) emulsion

An external oil phase envelopes an internal oil phase that is distributed within a water phase in oil-in-water-in-oil (O/W/O) emulsions. An oil-in-water (O/W) emulsion is formed first, and it is further emulsified into an outer oil phase to create this kind of multiple emulsion. These systems are used in food formulations, cosmetics, and pharmaceuticals to protect sensitive oil-soluble components and allow for the controlled release of lipophilic chemicals. Hydrophilic and lipophilic surfactants are both necessary for stabilisation, as are accurate formulation methods that maintain emulsion integrity to prevent phase separation.^(6,7,8,9)

PREPARATION METHOD OF MULTIPLE EMULSION

1. Phase inversion technique or single-step technique

The increase in the dispersed phase volume can lead to the formation multiple emulsions by increasing the phase-volume ratio. The method includes mixing a liquid paraffin oil phase with a lipophilic emulsifier (Span 80) with an aqueous phase that has a hydrophilic emulsifier (Tween 80 sodium dodecyl sulphate). A precisely determined volume of the nil phase isp is put in a pin mixer container. Then, an aqueous cruelsifier solution is added to the oil phase in the container at a rate of 5 ml/min. At the same time, the pin mixer rotates at 88 rpm at room temperature.

2. Two step Emulsification technique

Usually, a two-step emulsification process using standard equipment like high-pressure valves homogenisers or rotor-stator mixers produces several emulsions. To make small uniform inner droplets, a primary emulsion—either water-in-oil (W/O) or oil-in-water (O/W)—is made in the first phase using powerful shear pressures. For good stability and effective encapsulation, this is essential. To prevent damaging the sensitive interfacial membrane between the inner and outer droplets, the primary emulsion is carefully distributed into the continuous phase of opposite polarity under low-shear ki factors in the second emulsification process. This stage frequently comes with a trade-off, though, since too little shear may result in the development of highly polydisperse outer droplets, which might risk the stability and homogeneity of the emulsion. However, high shear might break internal structures, decreasing encapsulation efficiency and causing the encapsulated material to leak too soon. Therefore, creating stable, efficient multiple emulsions requires optimising shear levels.

3. Multiple emulsion production by microfluidics technique

Benefits of multicomponent multiple emulsions include the ability to encapsulate hydrophilic and hydrophobic medications with flexibility and to allow controlled release. Accidental quick release is less probable thanks to their core-shell development. Weitz's team used a glass-capillary microfluidic system to demonstrate programmed release. The PEG(5000)-b-PLA(10000) copolymer was dissolved in a chloroform-hexane solvent system (5 mg/ml). The inner and outer phases were PVA (10 wt%) and aqueous PEG (Mw=6000, 10 wt%). Prior to producing multiple polymersomes using microfluidics, single polymersomes had been created.

shows optical pictures of many polymersomes produced via a double-emulsion technique. There are usually two to three distinct polymersomes in each ~200 µm droplet. PEG-b-PLA-only polymersomes broke down easily in a 1:1 water/ethanol mixture. Those that had PLA homopolymer added, however, stayed stable. The inner bilayer broke down over a few minutes, releasing its contents, while PLA homopolymer was only present in the outer membrane. This method worked well for creating triple polymersomes as well.

Using an O/W/O droplet system in a capillary-based microfluidic device, Weitz's group reported manufacturing QD barcode particles . The spectrum characteristics of these particles were similar. Drug delivery, bioimaging, and thermal/magnetic therapies may benefit from the encapsulation of nanoparticles including QDs, gold, and magnetic nanoparticles.

Core-shell drop production with microfluidic junctions The size of the drops in every phase can be accurately controlled because to microfluidic devices' ability to produce core-shell drops in one or two ordered emulsification steps. The most simple microfluidic structure for creating drops is the T-junction. Through the intake channel, which is perpendicular to the main channel carrying the continuous phase, the dispersed phase is injected into the continuous phase in a T-junction arrangement. At the T-junction, where the two liquids converge . ^{(10,11,12,13,14)}

4. The modified two-step emulsification technique

enhances traditional methods in two important ways. In order to produce a more uniform and stable water-in-oil (W/O) emulsion, it first uses both sonication and stirring. Second, in order to produce the water-in-oil-in-water (W/O/W) emulsion, the continuous phase is poured into the dispersed phase, as opposed to the conventional procedure that adds the dispersed phase to the continuous phase. It was discovered that the most stable emulsions were produced by an optimised phase ratio of 1:4:5 (internal aqueous phase: oil phase: external aqueous phase), which improved overall encapsulation efficiency and structural integrity.

Composition of Multiple Emulsions (W/O/W and O/W/O)

1. Aqueous Phase Internal (W?) Function: Generally carries hydrophilic drugs or active ingredients. Salts, water, buffers, and hydrophilic APIs are a few examples.⁽¹⁵⁾
2. Phase of Oil (0) Function: Acts as a middle phase and barrier; commonly delivers lipophilic drugs. Examples include olive oil, wer oil, isopropyl myristate, and light liquid naraffin.⁽¹⁶⁾
3. External Aqueous Phase (W?) Function: In W/O/W systems, it acts as the continuous                    Water or an aqueous solution containing stabilising agents are two examples.⁽¹⁷⁾
4. Surfactants: Principal W/O Emulsion Stabilising agents Lipophilic surfactants, such as Span60 and Span 80 (sorbitan monooleate). Low HLB Value (3–6). ⁽¹⁾
5. The o/w secondary emulsion stabilising agents: Hydrophilic surfactants include PEG-40 stearate, Tween 20, and Tween 80. High HLB Value (8–18). ⁽²⁾

APPLICATION OF MULTIPLE EMULSION

Pharmaceutical and drug delivery

Water-in-oil-in-water (W/O/W) emulsions, in particular, are important in pharmaceutical and drug delivery systems.  By sustaining doses over time, they improve therapeutic outcomes and are ideal for regulated and sustained drug release.  Peptides, proteins, and other sensitive active medicinal components are protected from degradation by the environment by these emulsions.  Additionally, they reduce systemic side effects by enhancing drug stability, bioavailability, and site-specific or targeted drug delivery.  They help in covering up unpleasant flavours and odours in oral formulations.  They are highly flexible carriers for modern drug delivery methods because they can encapsulate both hydrophilic and lipophilic drugs.^(18,19,20)

Cosmatic and personal care

Many emulsions, especially water-in-oil-in-water (W/O/W) types, are used widely in cosmetics and personal care because of their capacity to provide prolonged moisturization and improved skin feel. They enhance the stability and effectiveness of products by enabling the encapsulation and regulated release of active components such as vitamins, antioxidants, and UV filters. These emulsions can give delicate substances to the skin gradually while protecting them from degradation. They also have a light, non-greasy texture, which makes them perfect for anti-aging treatments, lotions, and creams. By regulating the amount of time active ingredients are exposed to the skin, multiple emulsions also help in minimising irritation while assuring gentle and effective application.^{(21,22,23,24)}

Textiles and coating

To allow regulated or sustained release during wear or washing, functional chemicals like dyes, perfumes, antimicrobial agents, or softeners are encapsulated in textiles and coatings using a variety of emulsions.  This improves the fabric’s utility without affecting its look or texture.  It is also possible to apply multiple emulsions as responsive or self-healing coatings, in which the encapsulated agents are released in response to external stimuli such as abrasion, heat, or moisture.  They help in enhancing textile coatings and finishes’ performance, durability, and effectiveness.  Additionally, their distinct structure enables improved stability and dispersion of active chemicals in environmentally friendly, water-based textile treatment formulations .^{(25,26,27,28)}

Food industry

In order to create low-fat and functional food items without sacrificing flavour or texture, the food industry uses a variety of emulsions, particularly water-in-oil-in-water (W/O/W) systems. They protect bioactive substances from deterioration during processing and storage by enabling their encapsulation and regulated release, including probiotics, vitamins, minerals, and flavours. These emulsions increase the bioavailability and stability of delicate substances. They are also employed for methods involving the reduction of salt or sugar, the masking of undesirable flavours, and the regulated delivery of nutrients that promote health. They are perfect for developing novel, healthier, and more effective food formulations because of their distinct structure. ^(29,30,)

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