Krupanidhi College Of Pharmacy Bengaluru.
Generally, the desired route for administration of drug is the oral route as per formulators when compared to other methods. But oral administration presents a significant challenge due to poor aqueous solubility, which often results in low and unpredictable bioavailability. Around 40% of new active substances face this issue, as their bioavailability is low and for modern drug delivery systems these drugs are becoming major challenge. However, recently herbs or herbal formulations are gaining lots of importance majorly due to their safety profile, as they produce few toxic metabolites. In spite of benefits provided by herbal medicines, they also have certain limitations like, inadequate solubility and ultimately it will have an impact on bioavailability. A potential solution to this challenge involves utilizing various advanced drug delivery technologies, among them a promising approach known as the self-emulsifying drug delivery system has emerged as a key development. This technique is employed mainly for drugs with poor solubility and bioavailability issues. It’s composed of isotropic blend of oil, surfactant, co-surfactant and drug. This mixture forms an oil-in-water nano or microemulsion in gastric medium with gentle mixing. This review article mainly emphasizes on formulation, characterization and enhancement of bioavailability of various herbal drugs used in treating different diseases through SEDDS.
One of the oldest forms of therapy that is known to human is herbal therapy which utilizes entire plants or parts of plants to help with treating various diseases and promote good health. Numerous herbal formulations have been identified for their efficacy in reducing symptoms of numerous diseases, including depression, cold, and flu.[1] This growing interest in natural active and inactive ingredients is mainly because of lack of side effect in them as compared to synthetic compound. Since, pharmaceutical ingredients which is extracted from plants produce negligible toxic metabolites. For centuries herbs have been utilized for treatment and prevention of various diseases and serious conditions like diabetes, cancer, stroke, Alzheimer’s, and atherosclerosis.[2] Even though herbal medicines offer numerous benefits, it will also exhibit some drawbacks such as low absorption, reduced bioavailability, and poor penetration across biological membranes, which show negative impact on their efficacy.[3] To overcome these barriers, novel approaches like self-emulsifying drug delivery systems have been developed. These systems are stable and isotropic which comprises oil, co-solvents, surfactants along with drug components, when water is added to this mixture it forms a microemulsion. The principle of SEDDS is that they spontaneously form an emulsion in the gastrointestinal tract with minute agitation, that will enhance drug`s dissolution rate. This method delivers the drug in solubilized form, along with smallest droplets size, which will increase the interfacial surface area available for absorption. SEDDS has significant impact on drug absorption by enhancing its solubility, permeability, and lymphatic uptake. Better drug distribution along the gastrointestinal tract can be achieved due to rapid movement of oil droplets through stomach. Additionally, its oral bioavailability will be improved by bypassing first-pass metabolism since absorption occurs via lymphatic system.[4]
Figure 1: Mechanism of SEDDS oral absorption
Self-nano emulsifying drug delivery systems (SNEDDS) mainly consist of two liquids which are immiscible in nature making it a heterogeneous system and are having droplet size ranging from lesser than 100 nanometres. Self-micro emulsifying drug delivery systems (SMEDDS) which is characterized by droplet size of 100-250 nanometre on a micrometre. A major difference between conventional emulsion and micro emulsion is their droplet size. SMEDDS are thermodynamically stable and produce optically clear emulsions. Since the system has smallest droplet size it enhances absorption and dispersion which allows for rapid penetration into gastrointestinal system for potential absorption. [4]
Figure 2: SEDDS, SMEDDS and SNEDDS are shown in diagram.
SEDDS provide key benefits over conventional emulsion:
Generally, SEDDS contains oil, surfactant, co-surfactant and drug.
Oils: It helps to dissolve hydrophobic drugs, promote self-emulsification, along with this it improves the amount drug that is absorbed and transported by the intestinal lymphatic system. The chosen oil phase should possess highest drug solubility in order to maximize drug loading.[6]
Table 1: Types of oils employed in SEDDS
|
Classification |
Common Examples |
Brand name |
|
Fixed oils Medium chain triglycerides |
Castor oil, Soyabean oil Triglycerides of caprylic acids |
Labrafac CC, Miglyol 812 |
|
Medium chain mono and diglycerides |
Medium chain monoglycerides and diglycerides of caprylic acids |
Capmul MCM, Imwitor 742 |
|
Long chain monoglycerides |
Glyceryl momooleate |
Capmul GMO, Peceol |
|
Fatty acids |
Oleic and Caprylic acid |
Crossential O94 |
|
Vitamins |
Vitamin E |
- |
Co-surfactant: Co-surfactant work to reduce the interfacial tension, which helps the system emulsify more effectively. By providing flexibility to the interfacial film, they allow for the formation of microemulsions with varying curvatures and concentrations. By adding co-surfactant, the higher amounts of surfactant (approximately 30%) can be simulated.[5]
Examples: Propylene glycol, LauroglycolTM, Polyethylene glycol (PEG), Transcutol®, Polyoxyethylene, etc.
Surfactant: When formulating self-emulsifying systems, non-ionic surfactants which are having high hydrophilic-lipophilic balance (HLB) are typically preferred. There surfactants are favoured over cationic and anionic ones due to their non-toxic nature. For a stable SEDDS formulation, the surfactant concentration should be within a range of 30% to 60% by weight. Even though they are non-toxic their high concentration can cause gastrointestinal discomfort, which is a major limitation SEDDS. In SEDDS formulation the surfactants will use various mechanisms to improve bioavailability. The mechanisms are reducing or inhibiting the efflux of drugs by P-glycoprotein, improving the solubility of active pharmaceutical ingredients and increasing intestinal epithelial permeability.[4]
Examples: Sorbitan monooleate, Sorbitan monolaurate, Poloxamer 188, Labrafil, Labrasol, Tween 20, Tween 80 etc.
Table 2: Different classes and examples of surfactants used in SEDDS
|
Classification |
Common examples |
Trade name |
|
Sorbitan esters |
Sorbitan monolaurate Sorbitan monooleate |
Span 20 Span 80 |
|
Polysorbates |
Polyoxyethylene-20-sorbitan monolaurate Polyoxyethylene-20-sorbitan monooleate |
Tween 20
Tween 80 |
|
Polyoxyethylene castor oil |
Polyoxyethylene 35 and castor oil |
Cremophor EL |
|
PEO-PPO-block copolymers |
Poloxamer 188 Poloxamer 407 |
Pluronic F68 Pluronic F127 |
|
Polyoxyethylene hydrogenated castor oil |
Polyoxyethylene 40 hydrogenated castor oil Polyoxyethylene 60 hydrogenated castor oil |
Cremophor RH40, HCO-40
Cremophor RH60, HCO-60 |
|
Polyglycolyzed glycerides |
Oleoyl macrogol glycerides Caprylocaproyl macrogol glycerides Lauroyl macrogol glycerides |
Labrafil 1944 CS Labrasol
Gelucire 44/14 |
Mechanism of SEDDS:
When the increase in the system’s entropy, which favours the dispersal of matter, surpasses the energy prerequisite for extending dispersion’s surface area then only self-emulsification occurs. The total energy of the system in a conventional emulsion is closely linked to the energy required to create new interfaces between the oil and water. This is expressed as;
|
DG = S N1 p r1
|
Where, ΔG = the energy related with process
N = total droplets count
r = radius
S = Interfacial energy
Over time, the two phases of an emulsion naturally tend to coalesce and separate in order to reduce the interphase area. Emulsifying agents forms a protective layer on the surface of the droplets, thus are used to stabilize the emulsion. This layer reduces the interphase energy and acts as a barrier, which prevents coalescence. The free energy which is essential to form an emulsion in self-emulsifying systems, it might be very less and negative or positive then only emulsion forms spontaneously. When the interfacial structure has no resistance to surface shearing then emulsification occurs.[7]
Pseudo ternary phase diagram: These are often represented as equilateral triangle. In these diagrams, each corner of the triangle represents a biphasic blend of two components, for instance an oil/drug, surfactant/co-surfactant blend or a water/drug mixture. Single component is represented on single side of the triangle (oil, water or surfactant) and is divided into 100 equivalent portions. Thus, each components mass fraction must be calculated as percentage by weight in order to precisely plot a ternary diagram. Creating a phase diagram is a tedious process; however, during formulation of microemulsions it is a crucial step. With the help of these diagram one can identify microemulsion region and it also helps to analyse the impact of different surfactant/cosurfactant ration on stability of microemulsion region. A simple and most preferred method used for preparing ternary diagram includes plotting the experimental data depending on oil, water and surfactant percentage. Once the diagram is created, the optimal formulation is determined by locating the centroid of the largest microemulsion region. [8]
Figure 03: Ternary phase diagram
Preparation Methods of Self-Emulsifying Drug Delivery System:
Generally, several methods are employed in formulating self-emulsifying system depending upon the materials selected. Some of the methods are: Sonication method, high pressure homogenization, micro-fluidization, high energy approach etc. [5] [10]
High pressure homogenization: Generally, a high pressure is needed for preparing a nano-formulation and based on high shear stress applied fine emulsion will be formed. Through this method a nano-emulsion with a size of lesser than 100 nm can be obtained. While preparing nano-emulsion by this method various factors need to be considered like, type of homogenizer, composition of the sample and operating conditions of homogenizer including time, intensity and temperature.[5] In the formulation of red ginger extract self-emulsifying system to show its anti-diabetic properties this method was employed. [9]
Micro-fluidization: In this method micro-fluidizer device is used. With the help of positive displacement pump product is pushed towards interaction chamber and this system has microchannel which is a narrow channel that funnels small droplets. The resulting product is then transferred into impingement area, here the fine droplets are further processed to form an a nanoemulsion. [5]
High energy technique: Optimum mechanical energy is used in this method to produce nanoemulsion. Due to this mechanical energy a strongest disruptive force will be produced which helps in breaking the large size droplets to droplet of nano-size and helps in producing emulsion with highest kinetic energy.[10]
Sonication method: by utilizing this method SNEDDS can be produced. The energy which is required for emulsification is obtained by using device called sonicator probes and these probes often contain quartz crystals that expand in response to alternation in electric energy. Alternatively, they may use piezoelectric crystals. When the sonicator’s tip make contact with aqueous phase, it creates mechanical vibration and cavitations. Cavitation helps in forming and subsequent breaking of tiny bubbles that directly leads to formation of emulsion. In consideration with operation and cleaning ultrasonication is favourable method when compared to other high energy methods.[11] In formulation of self-emulsifying systems of Commiphora wightii, to enhance its hypolipidemic activity this method was employed. [12]
Solvent displacement method: Spontaneous nanoemulsion can be formulated by utilizing this method. This method involves dissolving the oily phase in water-miscible organic solvents like, ethanol, ethyl methyl ketone or acetone. Aqueous phase contains surfactant, to which organic phase is introduced that results in the rapid formation of nanoemulsion since organic solvent diffuses rapidly. Vacuum evaporation method can be utilized for removing organic solvent from nanoemulsion.[11]
Spontaneous emulsification: Nanoemulsion is formed spontaneously by utilising this method. Here uniform and consistent organic solution is prepared which consist of hydrophilic surfactant phase, a water-miscible surfactant, oil and a lipophilic surfactant. the lipid phase is slowly added into the aqueous phase while using continuous magnetic stirring. This forms a stable o/w emulsion and by using evaporation method aqueous phase is removed. [11]
Phase inversion temperature (PIT) method: This method is used for preparing both nanoemulsions and microemulsions. It mainly depends on temperature responsiveness, that leads to changes in physical aspects, including changes in particle size, physicochemical alterations, and in vitro and in vivo drug release rates. Generally non-ionic surfactants are sensitive to temperature changes and they transform from O/W nanoemulsions at lower temperatures to W/O nanoemulsions at higher temperatures. [11]
In order to ensure the quality of self-emulsifying systems several tests are conducted such as: visual evaluation, zeta potential analysis, droplet size, dynamic light scattering, permeability assay, emulsification time, viscosity measurements, turbidimetric test, test of thermodynamic stability, NMR studies etc.
Self-emulsification time: Generally, SEDDS should produce a stable microemulsion instantly when it makes contact with GI fluid. Generally, the ratio of surfactant/co-surfactant and oil phase helps to determine the time required to undergo emulsification. Basket dissolution apparatus was used to determine emulsification time and this equipment helps to observes the development of clear solution upon agitation generally at 100 rpm, followed by drop wise addition of formulation to a water-filled basket. [5] [12]
Zeta potential measurements: This helps in determining flocculation effect and stability of emulsion. However, stability of emulsion is directly related to zeta potential, higher the zeta potential the emulsion is considered as highly stable. When particles having surface charge and zwitterionic charge are compared, it has been shown than zwitterionic charge particles are more biocompatible and has a long residence time in blood. Zeta potential is determined using zetasizer. [5] [12]
Cloud point determination: It is a temperature at which the formulation lost its transparent nature, this is because when the temperature exceeds the cloud point, micelle forming property of surfactant is lost. It is determined by gradually raising the temperature and determining turbidity and to have a good self-emulsification the formulation should have a cloud point greater than 37°C. [5]
Turbidimetric evaluation: In order to observe the growth of emulsion nepheloturbidimetric method is used. In this method a suitable solvent or medium is selected to which fixed quantity of self-emulsifying systems are added with a continuous stirring at 50 rpm, at optimum temperature and an increase in turbidity is measured. [12]
Dispersibility test: To determine potency of self-emulsification of oral nano or micro emulsion USP II dissolution apparatus is used. Standard dissolution paddle made up of stainless steel is used with 50 rpm along with maintaining system with a temperature of 37 ± 0.5 °C. Using a grading system in-vitro performance of formulations were assessed: [13]
|
Grade A |
Nanoemulsion formed rapidly, with a clear or bluish appearance |
|
Grade B |
Emulsion formed rapidly which is less clear, with bluish white appearance |
|
Grade C |
Emulsion formed within 2 minutes with fine milky appearance |
|
Grade D |
Slowly formed emulsion wit dull greyish white appearance |
|
Grade E |
It exhibits minimal or poor emulsion with large oil droplets |
Viscosity determination: Generally, SEDDS are administered in the form of capsule or tablet through oral route, hence its viscosity must be optimum so that can it should be easily pourable. Brookfield viscometers are used to determine viscosity, this instrument helps to analyse the system as o/w or w/o. The system is considered as o/w if the viscosity is less and vice versa. [13]
Droplet size and particle size determination: Photon correlation spectroscopy was commonly used to determine droplet size, which helps to detect sizes ranging from 10 to 5000 nm. After performing external standardization with the help of spherical polystyrene beads light scattering is monitored at 25°C at a 90° angle. [13]
Refractive index and percentage transmittance: Both these tests are necessary to prove transparency of the formulation. Refractometer is used to determine refractive index, in which a drop of solution is placed on slide and comparing it with water. Percentage transmittance is determined at a particular wavelength by using UV-spectrophotometer. If the formulation has similar refractive index as that of water and percentage transmittance is more than 99% then formulation is said to be transparent. [13]
Generally, self-emulsifying systems are considered as the most preferred form of formulations which helps ion enhancing bioavailability issues of the drug which shows poor solubility. Nowadays it is also employed in herbal formulations, since most of the herbal drugs are lipophilic in nature its solubility will become a major problem. So SEDDS is a novel approach in improving solubility of herbal medicines. Apart from this, recently various researches are going on modification of these systems. Like solid self-emulsifying systems, supersaturable SEDDS, targeted as well as controlled SEDDS, osmotic self-emulsifying systems, floating and gastroretentive SEDDS, mucoadhesive and combination SEDDS and self-emulsifying systems including ionic drug-polymer binding.
Solid SEDDS: Generally, these systems are used to enhance the bioavailability of drugs with solubility issues. Basically, self-emulsifying systems are developed as liquid dosage form, but it possesses drawbacks like low stability, inadequate drug encapsulation and irreversible precipitation of drug or excipients. To surpass these problems solid-self emulsifying drug delivery systems (S-SEDDS) can be utilized as an effective strategy. S-SEDDS exhibits some advantages like enhanced portability, stability, and improved patient compliance also improving bioavailability. S-SEDDS are isotropic blend of surfactant, co-surfactant, oil and solvents, which is formulated by solidifying liquid or semi-solid self-emulsifying components into powder form. On comparison with conventional SEDDS, solid-SEDDS possess certain advantages like, it reduces gastric irritation, helps in achieving controlled or sustained release of drug, reduces production cost, improves patient compliance, increases stability and prolonged shelf-life.[14]
Mucoadhesive SEDDS: These are the systems in which includes combination of mucoadhesion with SEDDS, which helps in enhancing solubility of drug in saliva and permeation through mucosal membrane. In this a fiber system is formulated which comprises fusion of thiolated polyacrylic acid fibers and by utilizing parallel electrospinning method self-emulsifying formulations are loaded into these fibers. The mucoadhesive electrospun SEDDS patches which is formed was evaluated for various parameters such as, characteristics of fiber, time for self-emulsification, mucoadhesive property and drug permeation in buccal tissues and compatibility. These systems exhibited a high drug loading capacity, with no leakage or defects in the fibers and by utilizing this system drug residence time in buccal cavity can be increased by 200 folds due to usage of thiolated polyacrylic acid fiber and it also enhanced drug penetration into buccal tissue. Thus, mucoadhesive electrospun SEDDS patches has approach to overcome current challenges in the oromucosal delivery of lipophilic drugs to enhance their therapeutic potential.[15]
Osmotic SEDDS: Osmotic pumps combined with a self-emulsifying system can achieve zero-order rate kinetics, which allows for a controlled release of the drug over time. The system contains osmotic agents like, sodium chloride or mannitol, which mainly helps in drawing water into the formulation through semipermeable membrane. This process results in generating osmotic pressure, which expels drug from a precisely perforated orifice. Recently Isradipine osmotic SEDDS was developed, it is an antihypertensive drug with less solubility along with short half-life and low bioavailability of 24%, SEDDS formulation has helped in achieving controlled release for up to 12 hours along with improving its bioavailability. The formulation comprised of osmotic agents like, mannitol, fructose and citric acid and to maintain zero-order kinetics optimization of the following factors were performed such as, orifice size and coating material.16]
Supersaturable SEDDS: These are advanced form of SEDDS in order to overcome certain problems of self-emulsifying systems. Supersaturable SEDDS are the systems which contains precipitation inhibitors, that helps in maintaining drug supersaturation followed by dispersion and digestion in gastrointestinal tract and ultimately enhancing drug bioavailability. In addition to this, this approach is also used to overcome challenges of liquid or solid dosage forms. For several drugs supersaturable-SEDDS has been employed in order to enhance bioavailability such as, celecoxib, curcumin, cyclosporin-A, fenofibrate etc. researchers found that supersaturable-SEDDS has greater performance compared to conventional SEDDS. Along with this various mechanism of action of precipitation inhibitors has shown a significant role in drug absorption.[17]
Ionic-drug polymer binding in SEDDS: A hydrophobic ionic drug-polymer complexes was developed so as to obtain sustained release of drug from self-emulsifying systems. This system includes complexation of anionic drug captopril with cationic polymers like Eudragit RL, E and RS in different charge ration and it was blended into SEDDS formulations. Generally, hydrophilic drugs rapidly release because of their high aqueous solubility. However, when an ionic complex of drug with lipophilic excipients are formed, it enhances retention period of drugs within oil droplets of SEDDS. Since the drug is released for a prolonged period, its therapeutic effect is also enhanced especially for those drugs that rapidly eliminated from body.[18]
Self-double emulsifying system: These techniques are employed for improving the intestinal permeability of the drugs which are categorized under Biopharmaceutics Classification System (BCS) class. For instance, zanamivir a drug belonging to antiviral class, it shows oral absorption at suboptimal range along with 1–5%. Bioavailability. To overcome this issue a novel oral formulation of zanamivir has been developed: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS). This system consisting a microemulsion when it interacts with water it forms a double nanoemulsion (W1/O/W2). Two different formulations were created: SDNE-WDS1, it is a W/O microemulsion system and SDNE-WDS2, it is bi-continuous microemulsion. After self-emulsification, droplet size of zanamivir-loaded nanoemulsion for zSDNE-WDS1 was determined at 542.1 ± 36.1 nm and for zSDNE-WDS2 measured at 174.4 ± 3.4 nm, respectively. Research has showed that both type of emulsion has the capacity to improve zanamivir transport across artificial membrane. A research work has been conducted in order to determine permeability of drug loaded SDNE-WDSs a in situ rat intestinal perfusion studies were performed and it has shown an enhancement in zanamivir permeability through small intestine wall. [19]
This review article emphasises on development of self-emulsifying drug delivery systems also describes the formulation process and challenges involved in these systems. This article highlights the importance of pseudo ternary phase diagram in creating self-emulsifying systems and from this article one can understand the importance of these systems in addressing the issues of herbal extracts. Even though herbs exhibit lots of health benefit, it also possesses some limitations like solubility and permeability issues, all these problems can be overcome by utilizing these systems. Various formulations of SEDDS exists, such as solid SEDDS, liquid SEDDS, supersaturable SEDDS etc, selection of these formulations mainly depends on specific properties of herbs or herbal extract. Apart from these there are several advancements can be seen in self-emulsifying systems such as ionic-drug polymeric binding, self-double emulsifying systems etc, all these novel formulations can be utilized to overcome the problems associated with herbal drugs. Many of the herbal drugs have been successfully formulated as self-emulsifying systems, which indicates SEDDS can remarkably enhances solubility, permeability, absorption and bioavailability of herbal drugs.
REFERENCES
Sindhu Subramanya Bhat*, Dr. Nimisha Jain, A Novel Approach to Herbal Medicine: Enhancing Drug Delivery with Self-Emulsifying Formulations, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 1603-1613 https://doi.org/10.5281/zenodo.17118919
10.5281/zenodo.17118919
