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Department of pharmaceutics-Government college of Pharmacy, Karad..
Vesicular drug delivery systems have recently surfaced as sophisticated carriers that can significantly boost how well a medicine works while cutting down on its harmful side effects. Among these options, emulsomes stand out as a fresh, hybrid approach that blends the best traits of liposomes and emulsions together. They feature a solid lipid core wrapped in several phospholipid layers, a design that makes it easy to pack in both water-friendly and fat-friendly drugs. These nanocarriers provide better stability, high loading capacity, a steady release of the medication, and much-needed help for drugs that usually struggle to dissolve in water. Emulsomes are built from essential ingredients like triglycerides, phospholipids, cholesterol, surfactants, and antioxidants, with each part playing a specific role in keeping the structure strong and functional. Different lab techniques, such as thin-film hydration, reverse-phase evaporation, and ethanol injection, allow scientists to precisely shape how these vesicles behave. Sophisticated testing methods are then used to guarantee the quality, shelf-life, and consistency of every batch. Today, emulsomes are proving their value across a huge range of medical needs, from treating fungus and inflammation to protecting the liver and fighting cancer, as well as managing brain, eye, and skin conditions. In short, emulsomes are a highly versatile and promising tool for sending medicine exactly where it needs to go in modern pharmaceutical research
Over the past few decades, researchers have increasingly focused on developing vesicular drug delivery systems. Today, vesicles serve as preferred carriers in drug delivery, with lipid vesicles proving invaluable in fields like immunology, membrane biology, diagnostic techniques, and especially genetic engineering [1] Vesicular delivery systems are colloidal structures composed of lipid bilayers that effectively encapsulate both hydrophilic and lipophilic therapeutic agents [2]. By facilitating targeted drug release, these systems significantly improve efficacy while minimizing systemic toxicity compared to traditional formulations [3]. While liposomes and niosomes represent the foundational pioneers of vesicular technology [4], they are often hindered by physical instability. Issues such as particle aggregation, premature drug leakage, and membrane fusion can compromise their overall efficiency and shelf-life [5]. To address these structural weaknesses, researchers have recently developed a variety of advanced vesicular systems designed for greater durability and clinical performance [6].
EMULSOME
Emulsomes (EMLs) are nanocarriers consisting of a solid fat core surrounded by phospholipid multilayers. Drugs can be incorporated into either the phospholipid layers or the inner core [7]. Think of emulsomes as a high-performance hybrid that brings together the best parts of liposomes and emulsions. By blending these two designs, they manage to fix many of the classic headaches researchers face with traditional delivery systems—specifically their tendency to break down through oxidation, their sensitivity to moisture (hydrolysis), and the annoying way particles often clump together. This clever structural mix results in a delivery vehicle that is sign [8].
Emulsomes utilize a solid lipid core stabilized by cholesterol and soy lecithin to effectively encapsulate both hydrophobic drugs in the centre and hydrophilic agents within the outer aqueous layers. These biocompatible carriers significantly enhance the solubility and bioavailability of lipophilic medications, achieving a controlled release of 12–15% over 24 hours while ensuring long-term stability. Their nanoscale range (10–250 nm) facilitates passive targeting of liver and spleen macrophages after intravenous administration, providing a safer alternative to conventional formulations that require toxic levels of surfactants. Ultimately, the high entrapment efficiency and sustained release profile of emulsomes make them a superior and highly versatile platform for diverse parenteral therapeutic applications [9].
Figure 1-Emulsome structure
Advantages:
Disadvantages:
COMPOSITION
Lipid Core:
A central feature of emulsomes is their internal hydrophobic core, which consists of lipids that remain in a solid or liquid-crystalline state at a room temperature of 25°C. The pharmaceutical industry offers a vast array of commercially available lipid-based excipients, all of which are broadly categorized as "lipids" when used in these formulations [12]. These formulations can utilize either a single lipid or a complex blend of various fatty acids and their derivatives. In pharmaceutical science, these substances are typically categorized by their melting points, fatty acid profiles, and hydrophilic-lipophilic balance (HLB). Choosing the right lipid is a strategic decision: those with a high melting point and low HLB are ideal for creating a sustained-release effect, while semi-solid options with a higher HLB are better suited for immediate release and boosting a drug's bioavailability [13-19]. Triglycerides that remain solid at 25°C serve as particularly effective core materials, as they help overcome the stability issues that often shorten the shelf life of standard oil-in-water emulsions. Specifically, for emulsome preparation, triglycerides with unbranched fatty acid chains ranging from C10 to C18 are the preferred choice for ensuring a stable and effective delivery system [20].
Antioxidant:
To protect the lipid core from breaking down, these formulations can include one or more antioxidants. Alpha-tocopherol and its various derivatives—both part of the Vitamin E family—are the most common choices, though others like butylated hydroxytoluene (BHT) are also used. These additives are crucial because they block the formation of peroxides and other oxidative byproducts that typically degrade unsaturated lipids. Interestingly, if the core is designed using entirely saturated fatty acids, the need for these chemical antioxidants can often be reduced or eliminated altogether [20].
Negatively charged particles;
Adding negatively charged lipids—such as oleic acid or specific phospholipids like phosphatidic acid, phosphatidylinositol, and phosphatidylserine—can significantly enhance the stability of emulsomes by increasing their zeta potential. This process creates phospholipid bilayers with opposing charges, leading to electrostatic repulsion between the layers [20].
This repulsion expands the aqueous compartments surrounding the lipid core, allowing the system to hold a larger volume of water-soluble components. From a stability standpoint, these negative charges prevent the particles from clumping together, effectively minimizing issues like coalescence, flocculation, or fusion [21].
Surfactant:
Selection of surfactant should be done on the basis of Hydrophilic Lipophilic Balance (HLB) value. As HLB is a good indicator of the vesicle forming ability of any surfactant, HLB number in between 4 and 8 was found to be compatible with vesicle formation [22] Transition temperature of surfactants also affects the entrapment of drug in vesicles. Spans with highest phase transition temperature provide the highest entrapment for the drug and vice versa [23-24]. The drug leaching from the vesicles is reduced due to high phase transition temperature and low permeability [25]. High HLB value of Span 40 and 60 results in reduction in surface free energy, which allows forming vesicles of larger size and hence large area exposed to the dissolution medium [26-28].
Phospotidylcholine:
Phosphatidylcholine is the standout ingredient in lecithin and acts as an amphipathic surfactant. While it doesn't dissolve well in water on its own, it is incredibly versatile; depending on the temperature and hydration levels, its phospholipids naturally organize into micelles, bilayer sheets, or lamellar structures. These are the same building blocks found in biological membranes and are typically sourced from everyday items like soybeans or egg yolks. When used in these formulations, adding lecithin can push drug entrapment levels as high as 96.1%. It also plays a key role in refining the physical structure of the delivery system—by increasing hydrophobicity, it actually helps shrink the vesicles down to a smaller, more efficient size [29]. Antioxidants Protect the lipids from oxidation or rancidity Charged particles Zeta potential of the composition, stabilizing the particles and reduce the particles aggregation [30].
Cholesterol:
Cholesterol and its esters play distinct roles in the structural layout of an emulsome. Because cholesterol contains a polar alcohol group, it naturally gravitates toward the outer phospholipid layers rather than staying in the center. For this reason, it is best viewed as a stabilizing part of the protective envelope rather than a core ingredient. On the other hand, cholesteryl esters—particularly those derived from long-chain fatty acids like palmitoyl or oleoyl—are better suited for the interior. These esters can make up a significant portion of the formulation, sometimes reaching as much as 50 mol % of the solid lipid core. By strategically placing these components, researchers can fine-tune the stability and storage capacity of the entire delivery system [31].
Table no 1-Material and uses [31]
|
MATERIAL |
USES |
|
Antioxidant |
Protect the lipids from oxidation or rancidity |
|
Charged particle |
Zeta potential of the composition, stabilizing the particles and reduce the particles aggregation |
|
Cholesterol |
Incorporation of cholesterol influence vesicles stability, excessive cholesterol leads to instability of the formulation |
|
Soya Lecithin |
Bilayer sheets, micelles, or lamellar structures and also increases the entrapment efficiency |
|
Stearyl amine |
Impart positive charge for target delivery and raised the zeta potential of the formulation |
|
Surfactant |
Provide the highest entrapment for the drug |
|
Triglycerides |
Used as hydrophobic lipid core, Lipids with low HLB value provides sustained released formulation |
METHOD OF FORMULATION:
Thin Film Hydration:
The Bangham method remains the definitive technique for lipid-based carrier synthesis. The procedure begins by dissolving phospholipids and cholesterol in a 2:1 organic solvent mixture of chloroform and
methanol. This solution is then subjected to rotary evaporation under vacuum, leaving behind a uniform thin lipid film on the vessel walls. Upon adding an aqueous buffer and maintaining the temperature above the lipid’s phase transition point, the film hydrates to form large, multilamellar vesicles (MLVs) with diameters typically between 400 and 3500 nm [30]. A critical factor in this process is encapsulation efficiency: while hydrophilic molecules often show low entrapment (5–15%), the hydrophobic nature of the bilayer allows lipophilic drugs to achieve significantly higher loading, often reaching up to 80% [31].
Figure 2-Thin Film Hydration Method
Reverse Phase Evaporation Method:
The Reverse-Phase Evaporation (REV) method begins by dissolving lipids in an organic solvent to form inverted micelles, which then transform into a water-in-oil microemulsion upon adding an aqueous buffer. As the solvent is removed via rotary evaporation, the mixture becomes a viscous gel that eventually collapses at a critical point. This collapse forces the lipids to reorganize into bilayers around the remaining droplets, resulting in the formation of large vesicles. This technique is particularly valued for its high encapsulation efficiency, reaching up to 86%, making it ideal for the successful formulation of stable emulsomes. Studies confirm that this structured process ensures a highly controlled and efficient drug release profile for therapeutic applications [33].
Figure 3-Reverse Phase Evaporation Method
Ethanol Injection Method:
The ethanol injection technique is a streamlined approach where a lipid-ethanol solution is rapidly introduced into an aqueous buffer, causing lipids to spontaneously assemble as the solvent diffuses. This method is highly efficient for producing small unilamellar vesicles and is valued for its speed and consistent reproducibility. Because it is easily adapted to continuous systems like microfluidic mixers, it is much more scalable for industrial production than traditional hydration methods. However, it often results in lower encapsulation for water-soluble drugs and requires an additional step to strip away residual ethanol. Ultimately, the process offers precise control over particle size, making it a modern favourite for high-volume manufacturing [32].
Figure 4-Ethanol Injection Method
Detergent Removal Method:
The detergent removal method is a gentle technique where lipids are first solubilized using a detergent solution to create mixed micelles. In these aggregates, the detergent molecules act as a shield, protecting the hydrophobic lipid tails from the surrounding water. As the detergent is gradually removed—most simply through buffer dilution—the micelles become increasingly lipid-rich and begin to expand. This process triggers a structural transition from spherical micelles to elongated cylinders, eventually closing into stable unilamellar vesicles. This transformation is driven by changes in spontaneous curvature as the water-soluble detergent leaves the lipid matrix. Because it avoids harsh mechanical energy or heat, this method is ideal for producing uniform populations of vesicles, particularly when incorporating sensitive proteins or enzymes.
The detergent removal method concludes when the detergent concentration drops below its critical micelle concentration, triggering the formation of stable liposomes. While techniques like dialysis offer excellent reproducibility and size homogeneity, they often leave behind trace amounts of detergent and result in lower drug entrapment. To address these limitations, alternative purification steps such as gel chromatography, centrifugation, or resin adsorption are frequently employed. Ultimately, this self-assembly process is driven by the molecular geometry of the lipids, which naturally transition from micellar structures to bilayers as the detergent is stripped away [34].
Figure 5-Detergent Removal Method
Cast Film Method:
To create emulsomes, phospholipids and triglycerides are typically blended in a 0.5:1.0 weight ratio. It is essential that the triglycerides have a phase transition temperature above 25°C to ensure the core remains solid at room temperature. The process begins by dissolving these lipids in volatile organic solvents like dichloromethane or diethyl ether, which are then stripped away using rotary evaporation or an inert gas stream to leave behind a uniform lipid film.
This film is hydrated with an aqueous solution—containing the drug if it wasn't already added to the organic phase—and dispersed through vigorous shaking. To achieve the desired dimensions, the suspension is processed through a high-shear homogenizer at pressures reaching 800 bar. This results in a stable nanoemulsion with particle diameters usually spanning 10 to 250 nm. For pharmaceutical precision, these size distributions are characterized by weight percentage rather than simple particle count, ensuring a consistent and effective drug delivery system [35].
Figure 6-Cast Film Method
SIZE REDUCTION AND HOMONIZATION:
Once the initial lipid vesicles are formed, they often require further processing to reach the precise dimensions and uniformity needed for effective drug delivery. This is achieved through size reduction and homogenization techniques, primarily sonication and extrusion.
SONICATION:
Sonication utilizes high-frequency ultrasonic energy to break down large, multi-layered vesicles into smaller, more manageable units. This can be performed using two different setups:
EXTRUSION:
Mechanical extrusion is considered one of the most reliable methods for creating a "homogeneous" or uniform population of vesicles. The process involves forcing the lipid suspension through polycarbonate membranes with specifically defined pore sizes.
ANALYTICAL CHARACTERIZATION:
Because liposomes have such intricate physical and chemical structures, we need reliable analytical tools to truly understand how they will behave in the body. Key traits like particle size, surface charge, and how well they hold or release a drug are more than just numbers—they determine whether the treatment actually reaches its target effectively.
By prioritizing thorough characterization, researchers can achieve:
To get the full picture, a mix of advanced techniques is used. This includes Dynamic Light Scattering (DLS) to measure size, HPLC to track drug content, and Zeta Potential to predict shelf-stability. For a direct look at the structure itself, Cryo-TEM provides high-resolution images of the vesicles in their natural state [37].
Table no 2-Analytical parameter [37]
|
Analytical parameter |
Importance |
Common techniques |
|
Particle Size & Distribution |
Influences biodistribution, drug release |
DLS, NTA, AF4, TEM |
|
Surface Charge (Zeta Potential) |
Predicts colloidal stability |
Electrophoretic Light Scattering (ELS) |
|
Encapsulation Efficiency (EE%) |
Determine drug loading capacity |
HPLC, UV-Vis Spectroscopy |
|
Morphology & Lamellarity |
Confirms vascular uniformity |
Cryo-TEM, SEM |
|
In vitro drug release |
Evaluates release kinetics |
Dialysis, HPLC, UV Spectroscopy |
|
Stability study |
Ensures shelf life and batch uniformity |
Differential Scanning Calorimetry (DSC), DLS |
APPLICATION:
Emulsome In Antifungal Therapy:
Amphotericin B (AmB) is a potent antifungal medication, but its effectiveness is often limited by its poor absorption when taken orally. Furthermore, traditional treatments using this drug are notorious for harsh side effects, including fever, nausea, and significant kidney strain that can lead to anemia or electrolyte imbalances like low potassium and magnesium. To combat these issues, researchers have developed lipid-based versions of AmB. These specialized formulations are much easier on the body, specifically helping to protect the kidneys from damage while maintaining the drug's ability to fight serious infections [38].
Emulsome In Inflammation Therapy:
Lornoxicam is a modern NSAID from the oxicam family, known for its powerful pain-relief properties. Because it has a relatively short window of effectiveness—with a plasma half-life of only about three hours—keeping consistent relief in the system can be a challenge. To solve this, researchers have developed soy lecithin-based emulsomes designed for skin-deep delivery. This specialized approach is particularly effective for managing the steady, nagging pain and swelling found in musculoskeletal and joint conditions like rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. By delivering the medication directly through the skin, these nanoparticles provide a more targeted and long-lasting way to handle moderate pain [39].
Emulsomes With Hepatoprotective Activity:
Silybin (SIL), a natural extract from the milk thistle plant, has long been a go-to remedy for treating liver conditions like hepatitis and cirrhosis, as well as protecting the liver from toxins and oxidative stress. However, its potential as a medicine is often held back because it doesn't dissolve well in water and is poorly absorbed by the body when taken orally. To bridge this gap, Silybin can be tucked inside the solid lipid core of an emulsome. This setup significantly boosts its bioavailability and creates a "slow-release" effect, ensuring the medication stays active in the system longer than a standard solution would. Because these emulsomes carry a high electrical charge (zeta potential), the particles naturally repel each other, keeping the formula stable and preventing clumping. This makes emulsomes a highly promising way to deliver Silybin for more effective liver therapy [40].
Emulsome In Anti-Neoplastic Therapy:
Emulsomes are advanced lipid-based nanocarriers that optimize the delivery of potent agents like Methotrexate in cancer therapy. By utilizing a solid lipid core surrounded by phospholipid bilayers, these vesicles achieve high drug loading and a controlled-release profile, ensuring steady therapeutic levels at the tumor site. In skin cancer applications, this architecture enhances deep dermal penetration to reach malignant cells more effectively than standard topicals. Ultimately, by localizing drug action, emulsomes maximize antitumor efficacy while significantly reducing systemic toxicity and side effects. [41].
By loading curcumin and piperine into emulsomes, researchers have created a powerful combination therapy that significantly enhances the treatment of colorectal cancer. While curcumin is effective at fighting cancer, it is usually held back by poor solubility and rapid breakdown in the body; piperine solves this by acting as a bio-enhancer that keeps curcumin active for longer. The emulsome's solid lipid core allows both compounds to be delivered directly to HCT116 cancer cells, where they work together to trigger cell cycle arrest and programmed cell death (apoptosis). This dual-loading approach not only increases the concentration of the drugs at the tumor site but also provides a steady, controlled release that improves overall anticancer activity. By using these lipid-based nanocarriers, the treatment becomes more effective at a lower dosage, offering a more efficient and targeted way to manage intestinal malignancies [42].
Sulforaphane, a natural compound found in broccoli, is a powerful anticancer agent that unfortunately degrades quickly when exposed to heat or oxygen. By loading it into emulsomes, researchers can protect this sensitive molecule within a stable lipid core, ensuring it remains active and reaches its target. When tested on MCF7 breast cancer cells, these emulsomes significantly cut down cell growth over 72 hours by maintaining a steady, controlled release of the drug. Most importantly, tests on MCF10A healthy cells showed that the treatment is highly selective, leaving normal cells unharmed while attacking the malignancy. This targeted delivery effectively bypasses the stability issues of raw sulforaphane, making it a much more reliable and safer option for long-term breast cancer therapy [43].
By encapsulating Febuxostat into emulsomes, researchers have significantly boosted its potential as a treatment for colon cancer. Although traditionally used for gout, Febuxostat can actually inhibit tumor growth; however, its poor water solubility often limits its effectiveness. The emulsomal formulation solves this by using a solid lipid core to house the drug, which improves its stability and allows for a 4-fold increase in its ability to kill HCT116 cancer cells compared to the free drug. These lipid nanocarriers work by delivering the medication directly into the cells, where they trigger programmed cell death (apoptosis) and prevent cancer cells from dividing. This targeted delivery not only makes the drug more potent but also helps maintain steady therapeutic levels, offering a promising "repurposed" strategy for more effective and safer colorectal cancer therapy [44].
Piceatannol is a powerful natural antioxidant, but its effectiveness against cancer is often hampered by its poor solubility and low bioavailability. By loading Piceatannol into emulsomes, researchers have created a delivery system that significantly boosts its ability to stop the growth of colon cancer cells. These lipid-based carriers protect the compound and ensure it is released steadily, which leads to much higher rates of programmed cell death (apoptosis) compared to the drug in its standard form. The emulsomal structure allows for better absorption into the HCT116 cell lines, making the treatment far more potent even at lower doses. This targeted approach not only enhances the overall anticancer activity but also offers a safer way to utilize natural polyphenols in the long-term management of colorectal malignancies [45].
Emulsome In Treatment of Skin Disorders:
By formulating Lopinavir into emulsomes, researchers have created a specialized delivery system that significantly improves how the drug treats complex skin conditions. These lipid nanocarriers act as a protective housing that helps the medication bypass the skin's tough outer barrier, reaching deeper layers more effectively than standard ointments. Once applied, the emulsomes provide a slow and steady release of the drug, which maintains a constant healing effect while reducing the need for frequent reapplication. This targeted approach not only boosts the drug’s potency but also minimizes skin irritation and the risk of side effects. Ultimately, this method offers a much more efficient and comfortable way to manage localized dermatological disorders [46].
Emulsome In CNS Disorders:
By tailoring the surface of emulsomes for intranasal delivery, researchers have found a way to send Vinpocetine directly to the brain, effectively bypassing the blood-brain barrier. These specialized lipid carriers are designed to adhere to the nasal passage, allowing the medication to travel quickly along nerve pathways for a faster onset of action. This method significantly increases the amount of drug that reaches the central nervous system compared to traditional oral tablets, which are often broken down by the liver. Because the delivery is so targeted, patients can achieve better cognitive support with smaller doses, which helps to avoid unnecessary systemic side effects. Ultimately, this approach offers a much more direct and efficient way to manage neurological health [47].
Emulsomes In Ophthalmic Treatment:
The development of nano-emulsomes for delivering Ganciclovir offers a significant breakthrough in treating infections at the back of the eye, such as CMV retinitis. Traditionally, getting medication to this area is difficult because the eye's natural barriers effectively block most standard drops, often requiring invasive injections. These nano-emulsomes act as microscopic "delivery vehicles" that protect the drug and help it penetrate deep into the ocular tissues more effectively. By providing a slow, sustained release of the medication, the emulsomes keep the drug active at the target site for much longer periods. This not only improves the overall success of the treatment but also reduces the need for frequent, painful procedures, making the process much easier and safer for patients [48].
Emulsome In Psychiatric Disorder:
Mucoadhesive emulsomes offer a faster, more effective way to treat migraines by delivering medication directly to the brain through the nasal passages. By sticking to the nasal lining, these lipid vesicles allow the drug to bypass the digestive system and travel along nerve pathways for rapid relief. This targeted approach ensures a steady release of the medication, maintaining its therapeutic effect for much longer than traditional tablets. Ultimately, it provides superior symptom management with lower doses and fewer side effects, greatly improving patient comfort [49].
CONCLUSION
The rise of emulsomes (EMLs) marks a significant leap in how we deliver medicine. By blending the best traits of liposomes and solid lipid nanoparticles, these "hybrid" carriers solve age-old issues like drug leakage and instability. At their heart is a solid fat core wrapped in protective phospholipid layers—a design that allows them to shield both water-soluble and oil-soluble drugs simultaneously while extending their shelf life.
This versatility is opening new doors across medicine. In oncology, they act as precision transport vehicles for drugs like Methotrexate and Curcumin, zeroing in on tumors while sparing healthy tissue. They are also proving revolutionary for reaching "difficult" areas; through nasal sprays or eye drops, emulsomes can slip past the blood-brain barrier or deep ocular defences, treating brain and eye conditions without invasive surgery. Moreover, their ability to release medication slowly over 24 hours makes them a perfect fit for managing chronic pain in arthritis or providing steady liver protection.
While we are still working on maximizing drug capacity and refining injectable forms, advanced manufacturing like high-shear homogenization is bringing large-scale production within reach. As researchers continue to "fine-tune" these particles to stick more effectively to target tissues, emulsomes are becoming a cornerstone of nanomedicine—offering a more targeted, effective, and patient-friendly approach to healing.
REFERENCES
Sayali Khabale, Avinash Hosmani, Rutuja Patil, Chetan Shahare, Pratiksha Kambale, Emulsomes as Advanced Lipid Nanocarriers: A Comprehensive Review of Design, Method of preparation, Analytical Characterization and Targeted Delivery Applications, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 3356-3370, https://doi.org/10.5281/zenodo.19675518
10.5281/zenodo.19675518