Emulsomes: An Advancing Nanotechnology for Targeted Drug Delivery Systems and Therapeutics

Abstract

Lipid-based drug delivery systems have been widely employed over the past few decades for efficient drug delivery. These systems offer several benefits, including protection of drugs from the biological environment, thereby improving their therapeutic efficacy. Various types of lipid-based drug delivery systems have been developed, such as solid lipid nanoparticles, liposomes, emulsions, emulsomes, pharmacosomes, lipospheres, Nano emulsions, niosomes, and transferosomes. Among these, emulsomes have garnered significant attention due to their unique properties, which overcome many limitations associated with other systems. This review emphasizes lipid-based drug delivery systems, with a particular focus on emulsomes. It explores the success of emulsomes as drug carriers, detailing their advantages, structure, and composition, which include a lipid core, antioxidants, phosphatidylcholine, negatively charged particles, surfactants, and cholesterol. Additionally, it outlines various preparation methods for emulsomes, such as lipid film hydration, reverse-phase evaporation, high-pressure extrusion technique, sonication, cast film method, ethanol injection method and detergent removal method, along with their diverse applications.

Keywords

Introduction

Emulsomes are lipid-based nanoparticles commonly used as drug delivery systems. Their structure can be described as a combination of liposomes and solid lipid nanoparticles, as they consist of an oil phase enclosed by a phospholipid bilayer. The phospholipid bilayer in emulsomes is formed by a head-to-tail arrangement, where the hydrophilic heads of the phospholipids face outward, and the hydrophobic tails face inward. This bilayer provides stability to the emulsomes and helps protect the encapsulated oil phase from degradation the structure and composition of emulsomes is shown in Figure 1 and Figure 2^[9].

Advantages Of Emulsomes

       
           
       
1. Lipid film hydration

2. Reverse-Phase Evaporation (REV) Technique:

       
           
       
Figure: 4

3. High-pressure extrusion technique

• This method is used to produce unilamellar vesicles by forcing multilamellar vesicles through a small orifice under high pressure.
• A filter membrane, typically made of polycarbonate with a pore size of 0.8 to 1.0 µm, is utilized in the process.
• After 5–10 passes through the membrane, unilamellar vesicles in the size range of 60–180 nm is obtained.
• Some researchers have used a microfluidizer to produce nanosized vesicles.
• A microfluidizer is an instrument that forces the feed material through a narrow orifice under high pressure.
• This process removes multiple layers of the phospholipid bilayer to create nanosized unilamellar vesicles.

4. Sonication method

• Solid lipids, cholesterol, and phosphatidylcholine were dissolved in chloroform with 3–4 drops of methanol in a round-bottom flask in varying molar ratios.
• A specific quantity of the drug was added to this solution.
• The organic solvent was evaporated under reduced pressure using a rotary evaporator until a thin lipid layer formed on the walls of the flask.
• The dry lipid film was hydrated with 10 mL of phosphate-buffered saline (pH 7.4).
• The resulting suspension was homogenized through ultrasonication for 15 minutes at 40% frequency to produce nano-sized emulsomes.

 5. Cast film method

• Emulsomes are prepared by mixing phospholipids with triglycerides (solid lipids).
• The mixture is suspended in an aqueous solution at a temperature below the solid-to-liquid transition temperature.
• The resulting emulsion consists of liquid particles with a diameter ranging from 10–250 nm.
• The particle size is preferably determined based on weight percentage rather than particle number.
• The solvent is removed under reduced pressure using a rotary evaporator or by a stream of inert gases.
• The resulting dry lipid film is hydrated by shaking it with an aqueous solution.
• The drug to be encapsulated can be added either to the aqueous solution or the organic solution, depending on the drug's properties.

6. Ethanol injection method

• A technique for creating small unilamellar vesicles (SUVs) has been described.
• An ethanol-surfactant solution is rapidly injected into excess saline or another aqueous environment using a small needle.
• Vesicles form spontaneously as the ethanol evaporates.
• Small liposomes (sub-100 nm) with a tight size distribution can be produced in a single step by infusing ethanolic lipid solution into water, without the need for extrusion or sonication.
• The ethanol injection method is an efficient way to create emulsomes with a small average radius.
• In this method, the lipid or lipid mixture is dissolved in an alcohol-based solvent.
• An aliquot of 200, 500, or 600 µL is quickly injected using a 1 mL syringe into the dispersant solution, containing:
  • 9.8 mL water/saline diluted to 1:50,
  • 9.5 mL water/saline diluted to 1:20, or
  • 9.8 mL water/saline diluted to 1:17.
• The solution is vigorously stirred by hand for 20–30 seconds.
• The ethanol solution is then rapidly pumped into a 5% glucose solution.
• The resulting vesicles have an average diameter of 60 nm and are expected to remain stable for at least one week.

7. Detergent removal technique

In this method, lipids are combined with a detergent to form a micelle mixture. The detergent is then removed through various techniques, resulting in the formation of micelles. These micelles attract phospholipid molecules from the bulk solution, causing additional lipid molecules to aggregate and form a bilayer. Detergent removal can be achieved using methods such as dialysis, column chromatography, or adsorption. Detergents with a high critical micelle concentration (CMC), such as sodium cholate, sodium deoxycholate, and octyl glycoside, are commonly used in this process.

Stability Ascepts of Emulsomes

In nanoparticle-mediated drug delivery systems (DDSs), stability refers to the nanocarrier's ability to maintain its biophysical properties such as size, zeta potential, and drug retention over time. Emulsomes, with their high absolute zeta potential values, are expected to exhibit significant physical stability, minimizing the risk of coalescence. Compared to other lipid-based formulations like liposomes, emulsomes are more stable in suspensions, a property that holds great potential for clinical applications ^[19,20]. Emulsomes are formed by combining two key components: a phospholipid layer surrounding the lipidic core, which provides vesicular steric stability. This allows for the development of pharmaceutically stable emulsomal formulations without the need for additional solubilizers or surfactants. Furthermore, PEGylation of the emulsome surface enhances steric stabilization and prolongs circulation time in the body. The stability of the nanocarrier is significantly influenced by the physicochemical properties of the lipids used and the storage temperature ^[21].

These characteristics make emulsomes particularly suitable for developing sustained-release formulations for oral administration. The zeta potential measurement of electrostatically stabilized vesicles is a critical parameter for evaluating storage stability, as it helps understand dispersion and aggregation behaviour. High-energy input during sonication reduces particle size and zeta potential, resulting in stable, dense emulsomes ^[22].

Characterization Of Emulsomes

Characterizing the prepared emulsomes is essential for ensuring their effectiveness and consistency in application. Monitoring both physical and chemical properties is necessary to guarantee that the emulsomes preparation is reproducible and meets its intended purpose. Key properties of emulsomes include average size, size distribution, shape, polydispersity index, surface charge, and encapsulation efficiency.

Transmission electron microscopy (TEM) confirms that emulsomes are spherical in shape, similar in size and morphology to empty emulsomes. These biocompatible vesicular structures consist of a solid lipid core surrounded by multiple layers of phospholipids. The solid core enables emulsomes to encapsulate more lipophilic therapeutic molecules and provides a longer half-life compared to emulsion formulations with a liquid core. Due to their lipid composition, emulsomes are biocompatible and offer promising potential for delivering poorly water-soluble drugs like curcumin and silybin. Recent studies have demonstrated that a dehydration-rehydration technique, followed by temperature-controlled extrusion, can be used to combine phospholipids and triglycerides, resulting in stable, dispersed emulsomes ^[13].

Application Of Emulsomes ^{[4,5,7,12,13,27,28,29,30,31]}

1. Anti-fungal therapy

Amphotericin B (AmB) is a polyene macrolide antifungal antibiotic with limited oral bioavailability. Its use is associated with adverse effects such as fever, chills, nausea, vomiting, headache, renal failure, anemia, hypokalaemia, and hypomagnesemia. Lipid-based formulations of AmB offer significant advantages over conventional formulations, particularly in reducing renal toxicity.

2. Anti-inflammatory action

Lornoxicam is a novel non-steroidal anti-inflammatory drug (NSAID) belonging to the oxicam family, with a plasma half-life of approximately 3 hours. It is commonly used for relieving musculoskeletal and joint pain and is administered through the skin using soya lecithin-based emulsomal nanoparticles. Lornoxicam is effective in treating conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

 3. Drug targeting

One of the key advantages of emulsomes is the ability to modify or tailor their phospholipid bilayer, making them ideal for surface coating with specific ligands. These ligands possess free ends that specifically bind to surface overexpressed receptors, enabling targeted delivery. By coating emulsomes with ligands such as O-Palmitoyl Amylopectin or O-Palmitoyl Mannan, they can be directed for tissue-specific targeting.

Once administered in the body, emulsomes become coated with serum factors known as opsonin’s, which are recognized by the reticuloendothelial system and subsequently taken up. This process, called opsonization, facilitates the clearance of opsonin-coated particles. This unique property makes emulsomes particularly useful for treating tumours and infections in the liver and spleen.

 4. Auto-Immunity

 Emulsomes can serve as adjuvants in mucosal vaccines. When combined with anti-CD3 monoclonal antibodies (mAb), emulsomes reduce antibody production against type II collagen and alleviate joint disease severity by lowering inflammatory cytokines in the joints. Anti-CD3 therapy, administered nasally or orally, enhances the Th2 response and activates LAP+ (latency-associated peptide) regulatory T cells, contributing to arthritis suppression.

Vaccines composed of the following components can benefit from emulsomes:

1. Protein or peptide antigens.
2. Hydrophobic compounds, if necessary, to enhance the formulation.
3. An immune-potentiating membranous carrier, such as emulsomes, which helps preserve the antigenic integrity of protein or peptide epitopes and enhances the vaccine’s immunogenicity.

This approach has been demonstrated to be a safe and effective mucosal and non-invasive therapy for rheumatoid arthritis.

5. Cancer treatment 

Emulsome formulations encapsulating the anti-cancer drugs methotrexate and curcumin have demonstrated effectiveness in cancer treatment, highlighting the potential of emulsomes as a powerful carrier for antineoplastic drugs.

6. Dermal therapy

Dithranol, also known as anthralin, has long been used to treat psoriasis, a non-contagious autoimmune skin disorder. However, its use has declined due to side effects such as skin irritation, erythema, peeling, and discoloration. Encapsulating dithranol in the lipidic core of emulsomes significantly enhances its skin permeability, increasing drug retention in skin tissues and reducing adverse effects. The formulation by design (FbD) approach has been applied to develop various compritol-based emulsomes. Formulations containing 63–75% compritol and 25–37% phospholipids (PL) demonstrated the highest entrapment efficiency. However, increasing the PL content reduced skin permeation due to the formation of multilamellar barriers. In a mouse-tail model antipsoriatic study, emulsome formulations showed superior pharmacodynamic performance compared to commercial products, with no signs of erythema or wrinkles on the mice's skin. These findings indicate that emulsomes can enhance dithranol's therapeutic efficacy while minimizing its side effect.

7. AIDS Treatment

Zidovudine is approved drug for AIDS treatment. Due to high lipophilicity, drug shows some serious side effects with altered pharmacokinetics. By incorporating zidovudine in emulsomes, problem of low bioavailability and other side effects have been overcome.

8. Ophthalmic delivery

Sparfloxacin, classified as a Biopharmaceutical Classification System (BCS) Class II drug, exhibits low solubility in aqueous media, with its therapeutic effect limited by its dissolution rate. It is a third-generation fluoroquinolone derivative commonly prescribed for external eye infections such as conjunctivitis and bacterial keratitis. Sparfloxacin demonstrates in vitro antibacterial activity against both gram-negative and gram-positive bacteria and is available as a 0.3% (w/v) ophthalmic solution. The standard dosage is 1–2 drops every 4 hours, or hourly for severe infections. To address the limitations of traditional sparfloxacin formulations, such as short residence time, drug drainage, and frequent administration, sparfloxacin emulsomes can be incorporated into an in-situ gelling system. This innovative delivery system provides controlled drug release on the ocular surface. The lipid bilayer of the emulsomes, combined with their slow diffusion within the hydrogel, ensures prolonged drug release and improved trans-corneal penetration. This thermosensitive in-situ emulsomal gel enhances patient compliance and has shown promising antibacterial activity in both in vivo and in vitro studies, demonstrating its potential as an effective ocular drug delivery system. As a result, emulsomal in-situ gels offer a viable alternative to conventional eye drops for sparfloxacin administration.

9. Hepatoprotective activity

Silybin (SIL) is a natural compound derived from milk thistle plants, commonly used to treat hepatitis, cirrhosis, and protect the liver from toxic substances. It also prevents hepatic lipid peroxidation and ischemia. However, its therapeutic potential is limited due to its low aqueous solubility (0.43 mg/mL in water), low oral bioavailability, and poor intestinal absorption.

Incorporating SIL into emulsomes significantly enhances its bioavailability. SIL is encapsulated within the solid lipid core of the emulsome, providing a sustained-release profile both in vitro and in vivo, unlike a standard SIL solution. Emulsomes are recommended for SIL delivery in the treatment of liver diseases due to their enhanced stability and reduced risk of coalescence, attributed to the high absolute zeta potential.

10. Increase bioavailability of lipophilic drugs

Emulsomes have been shown to be effective drug delivery carriers for lipophilic drugs that have poor aqueous solubility in biological fluids, which often limits their absorption and bioavailability. The core of emulsomes consists of solid lipids that encapsulate lipophilic drugs, enabling their sustained release. Additionally, emulsomes offer the advantage of higher drug content, leading to increased entrapment efficiency and reduced dosing frequency.

CONCLUSION

In conclusion, emulsomes represent a significant advancement in nanotechnology for targeted drug delivery and therapeutics. Their unique structure, combining the benefits of both liposomes and solid lipid nanoparticles, allows for the efficient encapsulation and controlled release of lipophilic drugs, improving bioavailability and therapeutic efficacy. The ability to tailor the lipid composition and surface properties of emulsomes enables the targeting of specific tissues, enhancing their potential in treating a variety of diseases, including cancer, infections, and autoimmune disorders. Additionally, their biocompatibility, stability, and versatility in formulation make emulsomes a promising candidate for overcoming the challenges faced by conventional drug delivery systems. With ongoing research and development, emulsomes hold the potential to revolutionize the delivery of poorly water-soluble drugs, providing more effective and safer therapeutic options for patients.

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