Self-Micro Emulsifying Drug Delivery System: A Novel Approach to Enhanced Drug Delivery

SMEDDS is an acronym for Self-Micro Emulsifying Drug Delivery System. It is a lipid-based formulation intended to increase the solubility, rate of dissolution, and consequently the bioavailability of medications that are poorly soluble in water (lipophilic). Usually, it is composed of an oil (or combination of oils), a surfactant, and a co-solvent or co-surfactant. The formulation naturally creates a fine oil-in-water microemulsion when it comes into touch with gastrointestinal fluids, which increases the drug's surface area and facilitates greater absorption. It usually produces microemulsions with droplets that range in size from 100 to 250 nanometers. Oral administration is considered the most convenient and patient-favored way of medication delivery. The solubility of a medication is a significant determinant of its oral bioavailability since a pharmacological substance must dissolve in the GI tract's aqueous environment in order to be absorbed [1]. Research is being done on microemulsions as a potential new colloidal delivery system for lipophilic medications. Benefits of microemulsions include superior oral bioavailability, increased drug solubilization capacity, remarkable thermodynamic stability, and safety against enzymatic hydrolysis. The biggest issue with microemulsions is their awful palatability, which is caused by their high fat content and compromises patient compliance. Furthermore, microemulsions cannot be encapsulated in hard or soft gelatin pharmaceuticals due to their water-content material; therefore, anhydrous self-emulsifying drug delivery systems may be required [2]. The isotropic combinations of natural or synthetic oils, surfactants, and co-surfactants known as self-micro emulsifying drug delivery systems (SMEDDS) have the singular ability to form magnificent oil- in-water (o/w) micro emulsions upon mild agitation, as demonstrated by dilution in aqueous media, including GI fluids. Lipophilic medications with dissolution rate-limited absorption may also offer repeatable blood-time profiles and an increase in absorption volume and rate [3]. A well-studied technique to improve the oral bioavailability of such drugs is particle size reduction, or micronation. salt production, complexation with cyclodextrins, solubilization via cosolvents, surfactants, or nanosizing, etc. Reducing particle size is not always advantageous, can lead to handling difficulties, and can result in the accumulation of static charges. preferred when very small particles don't have enough wettability [4][5][7]. Formulations based on lipids have garnered a lot of interest in order to increase the oral bioavailability of medications that are not very water soluble. Actually, adding lipophilic medications to inert lipid vehicles including oils, surfactant dispersions, microemulsions, self-emulsifying formulations, self- micro emulsifying formulations, and liposomes is the most popular strategy [5]. This might result in a change in their pharmacokinetic profiles and enhanced solubilization, which would boost therapeutic efficacy. Lipid-based formulations include solutions, suspensions, solid dispersions, and self-micro emulsifying drug delivery systems (SMEDDS). Self-emulsifying formulations are isotropic mixtures of natural or synthetic oils with co-solvents and lipophilic or hydrophilic surfactants that spontaneously emulsify to create an oil-in-water emulsion or micro emulsion [6]. SMEDDS is a particular kind of emulsion that has attracted attention due to its capacity to increase the oral bioavailability of poorly absorbed drugs. These systems are basically co-surfactants that require little energy to form emulsions when combined with water [7].

• ADVANTAGES: -

1. The micro-size droplets support the medication's broad dispersion along the GIT and are swiftly carried via GIT [8].
2. The SMEDDS formulation can alleviate the irritation brought on by extended contact between the drug and the stomach wall. Because the active ingredient can readily move from the oil phase to the aqueous phase, these formulations, when dispersed in water, produce fine droplets with a broad interface, which is not what is expected with oily solutions that include lipophilic active substances [9].
3. Because of their straightforward manufacturing process and low energy use, SMEDDS offer greater stability than emulsions. SMEDDS formulation only requires basic mixing equipment, and preparation time is less than that of emulsions [10].
4. SMEDDS are an efficient way to synthesize low water-soluble medicines with restricted absorption and dissolution rates, resulting in a stable plasma profile. The key phase of drug absorption, or dissolution, is demonstrated by the steady plasma levels of the weakly aqueously soluble medication [11].

DISADVANTAGES: -

1. The absence of effective in vitro predictive models for formulation evaluation is one of the obstacles to the development of SMEDDS and other lipid-based formulations.
2. Because these formulations may rely on digestion prior to drug release, conventional dissolving techniques are ineffective.
3. This system's disadvantages include the medication’s chemical instability and the formulations' high surfactant concentrations (about 30–60%), which might aggravate the gastrointestinal tract.
4. Conventional SMEDDS formulations contain volatile co-solvents that are known to move into the shells of hard or soft gelatin capsules and precipitate lipophilic medicines.
5. It might permit less drug loading because of drug leakage [12].

• Composition of SMEDDS :-

The self-Emulsification process is reported to be specific to the nature of the oil surfactant pair. The procedure Is based on: -

1. Oils.

2. Surfactants.

3. Co-Solvents/ Co-Surfactants.

Some of the components used in SMEDDS are:

1. Oils: - To create SMEDDS with varying saturation levels, long-chain triglycerides (like soybean oil) and medium-chain triglycerides (like Capful MCM) were utilized. Oils made a substantial contribution to the SMEDDS performance because of their biocompatibility [13]. New medium-chain semi-synthetic triglycerides that contain substances like Gelucire have recently supplanted medium-chain triglycerides. Animal fats, corn oil, soybean oil, and olive oil are additional acceptable oils and fats for SMEEDS formulation [14].

2. Surfactants: - SMEDDS uses surfactants for self-emulsification, which helps solubilize hydrophobic drugs, increasing dissolution rates and preventing precipitation in vivo [15]. Surfactants can also enhance drug absorption by altering intestinal cell membrane permeability, boosting potency [16]. The HLB value guides surfactant selection, with high HLB surfactants facilitating o/w microemulsion formation [17,18]. For effective SMEDDS formulation, very fine droplets (<100 nm) are needed, requiring high surfactant concentrations, hydrophilic surfactants (HLB > 12), and water-soluble cosolvents with a low octanol: water partition coefficient [19]. Non-ionic surfactants like polysorbates and polyols are preferred due to lower toxicity compared to ionic surfactants [20]. Lipids such as medium and long-chain triglycerides and non-ionic surfactants like HLB-11 foliates are ideal for successful self-emulsification [21].

3. Co-Solvents/Co-Surfactants: - Because they allow water to enter the formulation co- solvents aid in the breakdown of the hydrophobic medication and surfactant in the oil phase [22]. In the micro-emulsion system, these excipients function as co-surfactants. As co- solvents, short-chain alcohols such ethanol, n-butanol, propylene glycol, and polyethylene glycol are employed Co-solvents, including short-chain alcohols, provide flexibility to the interface, allowing the hydrophobic tails of the surfactant to freely move along the interface and giving micro-emulsions their dynamic behaviour When the formulation is put into gelatine capsules, alcoholic co-solvents with a low molecular weight may produce medication precipitation because they will be absorbed into the capsule shells [23].

• Mechanism of self-Emulsification: -

The ability of a mixture of oil, surfactant, and co-surfactant to spontaneously form fine oil-in- water emulsions when diluted with GI fluids is the basis for the self-emulsification mechanism. Co-surfactants improve the fluidity of the interface, whereas surfactants reduce the interfacial tension and create a flexible interfacial layer. Under mild gastric movement, this thermodynamically advantageous procedure enables the oil phase to dispersion into nano/micro droplets, maintaining the drug's solubility and improving absorption.

The following formula can be used to characterize the emulsion’s free energy:

Δ???? = ∑????Π????2????

where Δ???? stands for the number of droplets, ???? for their radius, and ???? for the interfacial energy. A diagrammatic explanation of the method is provided [24,25].

Fig. 1: Mechanism of SMEDDS

The medicine is added to the oil, surfactant, and cosurfactant combination during preparation, and then the mixture is vortexed. In certain situations, the drug dissolves in one of the excipients, and the drug solution is then supplemented with the remaining excipients . After that, the solution needs to be well mixed and checked for any indications of cloudiness. If required, the solution should be boiled to a clear solution after equilibrating for 48 hours at room temperature. Volume, the mixture must to be kept in suitably sized capsules [26].entails overtaxing after the drug has been introduced to the mixture of oil, surfactant, and co- surfactant. In some cases, the medication dissolves in one of the excipients before the excipients are added to the drug solution . After that, the solution needs to be fully included before being examined for cloudiness. After equilibrating for 48 hours at room temperature, the solution should, if required, be heated until it becomes clear. The combination must be stored in appropriately sized capsules [27].

• • Methods of preparation:-

Phase Titration Methods:- Microemulsions are formed through spontaneous emulsification (phase titration method) and can be studied using phase diagrams [28] . These diagrams help visualize the interactions between components, revealing various structures like emulsions, micelles, lamellar, hexagonal, and cubic phases [29] . The phase type—water-in-oil (w/o) or oil-in-water (o/w)—depends on the composition. Understanding phase equilibrium and boundaries is essential, and careful observation is needed to avoid metastable systems [30].

Fig.2: Phase Titration Method

Fig.3: Phase Inversion Method

• Characterization of SMEDDS: -

1) Visual Evaluation: - SMEDDS stability can be assessed visually: a milky-white, opaque solution shows microemulsion formation, while a clear, isotropic solution indicates stability. Drug precipitation suggests instability, but increasing surfactant concentration can prevent this, especially when water-soluble co-solvents are used [35]. Visual evaluation of SMEDDS shows microemulsion formation: a milky-white appearance indicates microemulsion, while a clear, isotropic solution suggests stability. If no drug precipitation is visible, the formulation is stable. Increasing surfactant concentration can prevent precipitation, especially with water- soluble co-solvents [36].

2) Droplet Size Analysis: - Surfactant type and concentration mainly determine droplet size in SMEDDS. For effective drug release and stability, dilution should produce uniformly small droplets. Droplet size is analyzed using techniques like photon correlation spectroscopy, microscopy, and dynamic light scattering with a zeta meter [37]. Before size analysis, samples must be well diluted. Polydispersity index (PDI) provides useful information about size distribution [38].

3) Zeta Potential Measurement: - Zeta potential, measured using a zeta meter or analyzer, indicates emulsion stability after dilution. Higher zeta potential means better stability. It’s usually negative due to free fatty acids but turns positive with cationic lipids like oleylamine. Positively charged droplets interact well with the GIT mucosa, enhancing adhesion and absorption through electrostatic interactions [39].

4) Emulsification Time:- Self-emulsification time is measured using a USP Type II dissolution device by adding the formulation drop-wise into water stirred at 50 rpm. Formation of a clear solution indicates self-emulsification efficiency [40]. Emulsification rate depends on the oil type and oil/surfactant ratio. Higher surfactant levels speed up emulsification by aiding water penetration. Emulsification time can also be visually assessed after shaking the formulation in 0.1 N HCl at body temperature to mimic GI conditions [41].

5) Cloud Point Determination:- The cloud point is the temperature where a clear solution becomes cloudy, measured by heating the formulation in a water bath. It should be above 37 °C to maintain self-emulsifying properties. Above the cloud point, surfactant dehydration can cause phase separation and reduced drug solubility. Cloud point is influenced by drug lipophilicity and formulation components [42].

6)Viscosity Measurements:- Viscosity of diluted SMEDDS microemulsions is measured using rheometers like the Brookfield viscometer. During titration, viscosity first rises then falls, indicating a transition from W/O to O/W microemulsion. Rheology, based on shear stress and shear rate, shows the presence of small, spherical droplets [43].

7) Dilution Studies:- The effect of dilution on microemulsion clarity is evaluated by diluting the preconcentrate in water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). Stable clarity without drug precipitation indicates formulation stability. Diluting SMEDDS 100 times with these diluents mimics in-vivo conditions 44].

8) Refractive Index:- The refractive index, measured by refractometers, identifies dilute SMEDDS as isotropic. Stable refractive index values at 4°C and 25°C indicate a stable, thermodynamically stable microemulsion. The refractive index is influenced by co-surfactant amount and bead size, decreasing as co-surfactant concentration increases due to reduced microemulsion stiffness [45].

9) Percentage Transmittance:- This test measures the transparency of diluted SMEDDS using spectrophotometry, with water as a blank. A 100% transmission value indicates a clear, transparent microemulsion [46].

10) Transmission Electron Microscopy (TEM) Study:- Transmission electron microscopy (TEM) is used to study the morphology and structure of microemulsions from diluted SMEDDS. Samples are stained, placed on copper grids, and dried before imaging. TEM reveals droplet size, shape, and homogeneity using stains like uranyl acetate, phosphotungstic acid, or methylamine vanadate [47].

11) Differential Scanning Colorimetry:- Differential scanning calorimetry (DSC) is used to characterize micro-emulsions formed by diluting SMEDDS with water, revealing whether water is bound or free through corresponding peaks. A sharp peak around -17°C indicates the freezing point of pure water. Podlogar and associates demonstrated that in micro-emulsions, water is often bound to surfactants, with peaks around -45°C at a 15% W/W ratio. They found that when water concentration exceeds 35% (p/w), the micro-emulsion transitions to an oil- in-water (O/W) system [48].

12) NMR Techniques:- Pulsed gradient spin echo (PGSE) and 129Xe NMR are used to study the diffusion behavior and droplet size in micro-emulsions after diluting SMEDDS. PGSE-NMR helps determine droplet size by tracking signal shifts, while self-diffusion NMR identifies micro-emulsion type (e.g., W/O to bi-continuous to O/W) during dilution. In these studies, components diffuse slower than pure substances, and the presence of droplets (O/W or W/O) is indicated. A bi-continuous micro-emulsion occurs when oil and aqueous phases have similar sizes and high diffusion coefficients [49].

13) Small-Angle X-Ray and Neutron Scattering:- Small-angle X-ray scattering (SAXS) is used to characterize structures formed by diluting SMEDDS, which affect formulation stability and drug release. Goddeeris et al. found that at 10% w/w water, a random lamellar structure formed, while at 20% w/w, lamellar structures appeared, and at 40% w/w, lamellar or hexagonal formations were seen. Temperature changes (25°C to 37°C) did not significantly affect liquid-crystalline structures. Small-angle neutron scattering (SANS) helps determine droplet size, shape, and structural transitions during dilution [50].

14) Studies on Thermodynamic Stability:- These studies assess the impact of temperature changes on formulation stability. After dilution with an aqueous phase, samples are centrifuged under various conditions and then subjected to freeze-thaw cycles between -20°C and 40°C. Thermodynamically stable formulations show no phase separation or visual changes [51].

15) In-vitro Dissolution Profile:- Drug release from SMEDDS-filled capsules can be evaluated using USP Apparatus I (100 rpm), II (50 rpm), or the dialysis method at 37 ± 0.5 °C. Sampling over time allows for active ingredient analysis. Drug release is faster with higher oil droplet polarity, influenced by surfactant HLB, hydrophilic segment properties, and lipid unsaturation. Jantratid et al. found USP Apparatus III (reciprocating cylinder) provided more consistent results than the paddle method, due to better oil layer dispersion from cylinder movement and net inserts [52].

16) Stability Assessment:- As per ICH guidelines, stability testing of SMEDDS in gelatin capsules involves regularly monitoring appearance, color, active content, pH, and dissolution profile. The formulation is considered stable if these properties remain unchanged during storage [53]. The various marketed formulations of SMEDDS are shown in Table 1.

1. Improving Solubility and Bioavailability:- By increasing medication solubility and rate of dissolution, BCS class II medicines can have their bioavailability increased many times.

2. Protection of the medication from Biodegradation: - Because of the pH shift surrounding the medication, many drug formulations break down in physiological fluids or systems. The LC phase creates a barrier between the medicine and the deteriorating environment because the stomach's acidic pH causes enzymatic or hydrolytic breakdown.

3. No Impact of Lipid Digestion Process: - This drug delivery method is immune to lipolysis because it is not broken down by bile salts and pancreatic lipases, which just aid in the formulation's self-emulsification.

4. Enhancement of Drug Loading Capacity:- The formulation's high drug loading capacity is a result of the formulation excipients' high drug solubility.

5. SMEDDS for Herbal and Traditional Medicines:- Since most herbal and traditional medicines contain solid and volatile oils, a lot of them are used to create SMEDDS.

6. Peptide Delivery:- Because this drug delivery system may carry peptides, hormones, substrates, and enzyme inhibitors, it provides protection from enzymatic degradation in the GIT.

7. Controlled Release Formulation:- The medicine is released gradually and under control thanks to the polymer that is added to the SMEDDS formulation [54,55].

• Recent trends in SMEDDS:-

1) Self-micro Emulsifying Mouth Dissolving Film (SMMDF):- SMMDF (Self-Micro emulsifying Drug Formulation) was developed for water-soluble medications like indomethacin. It combines self-emulsifying segments with a solid support (hypromellose, low-substituted HPMC, MCC), enabling the active ingredient to fully release in 5 minutes. The formulation meets the 2010 Chinese Pharmacopoeia standards. Compared to liquid SMMDF and SMEDDS, SMMDF shows higher pharmacokinetic parameters (Cmax, AUC), indicating better absorption than traditional mouth-dissolving films or tablets with low water solubility.

2) Sponges Carrying SMEDDS: - Sponges, though limited in use due to their liquid state, can enhance the solubility of lipophilic drugs by incorporating SMEDDS. The sponges, made with a hydrophilic polymer, expand through nanosponge structures, with 9 nm SMEDDS detected after drying. Upon rehydration, the release of Nile Red from the nanosponge varies depending on the drying method. The drying process significantly affects the water absorption of the nanosponge, suggesting that SMEDDS could be a promising approach for hydrophobic drug delivery.

3) Herbal SMEDDS:- SMEDDs were used to create stable, safe dosage forms for herbal extracts by filling hard gelatin capsules. The formulation, based on solubility and phase diagram results, included Cremophor RH 40%, Plurol Oleique 30%, and herbal extract 30%. In vitro testing showed full release within 10 minutes. After three months of storage, SMEDDS passed solubility tests according to ICH guidelines, demonstrating improved dissolution and bioavailability for herbal remedies.

4) Self-micro Emulsifying Floating Dosage form :- Poor oral bioavailability of medications can be improved using a floating mechanism that prolongs release by increasing residence time in the stomach. A controlled-release floating matrix was developed using excipients like HPMC E50 LV, HPMC K4M, and NaHCO3. In another study, floating alginate beads with Tetra- hydrocurcumin (SEDDS) were created to enhance solubility and extend drug residence time. The floating ability and drug release rates of the beads depended on the amounts of calcium chloride, sodium alginate, and water-soluble pore formers [56,57].

• Future perspective: -

When it comes to drugs that are somewhat poorly soluble in GIT fluids, SMEDDS may be a useful solution. The combination of dispersion and in-vitro digestion may help to clarify the role of gut lipids in solubilizing lipid-based formulations. The creation of SMEDDS in the future removes all issues related to the administration of medications with low solubility. Bioavailability research, the creation of in-vitro and in-vivo correlation (IVIVC), and various dosage forms are just a few of the many topics that need to be covered before new SMEDDS products are released onto the market since more SMEDDS must be used [58]. Patents Self- micro emulsifying medication delivery systems have been studied for a number of possible uses in drug delivery and diagnostic technologies throughout the last few decades. Numerous patents for self-micro emulsifying drug delivery systems have been awarded by the pharmaceutical industry. A couple of these issued patents are shown in Table 2 .