An Outlook for a Novel Approach: Self-Micro Emulsifying Drug Delivery System (SMEDDS)

 

Himal Barakoti*, Ananta Choudhury, Biplab Kumar Dey

Faculty of Pharmaceutical Sciences, Assam down Town University, Guwahati–781026, India

 

ABSTRACT:

Self-micro emulsifying drug delivery system (SMEDDS) has been one of the exclusive approaches to improve solubility and increase bioavailability for the poorly aqueous soluble drug. Due to microstructural features of active entity and formulation as a whole, vigorous researches are being carried to explore the significance and possibility of this drug delivery system at present. SMEDDS is an isotropic mixture of oil, surfactant, co-surfactant and water which involves encapsulation of drug into the lipid base and the formulation as a whole have unique ability to form fine o/w emulsion upon gentle agitation. The whole emulsification process requires only little entropy change which is obtained from the peristaltic motion of gut. Due to microstructural features of active entity and formulation as a whole provided by this approach, vigorous researches are being done at present time to interrelate the in vitro results obtained with in vivo responses. Considering the fact that 40% of the newly discovered drugs are lipophilic in nature, it signifies that the study in this approach will continue and more commercial formulation will be made available in near future. This review gives an overview on SMEDDS with sequential demystification thus enabling a greater understanding of their present role in medicine and drug delivery.

 

 

 

INTRODUCTION:

Poor aqueous solubility has been one of the major challenges in modern drug delivery as it hinders the absorption process leading in the decrease of bioavailability¹. The fact that 40% of new chemical entities discovered are lipophilic in nature with poor aqueous solubility which, signifies the need of suitable drug delivery approach for optimal benefit. Various formulation techniques such as solid dispersion/ amorphous formulation, micronization and lipid-based formulations such as of microemulsion are considered to deliver the drug in a more prominent way. Among these, micro-emulsion formulations, with a notable emphasis on self-micro-emulsifying drug delivery system (SMEDDS), have gained much more importance as a promising drug delivery system for both soluble as well as poorly water soluble drugs in recent times².

 

 

Spontaneous breakthrough on micro-emulsion was made after the work of Schulman and Hoar in 1943 although its existence can be dated long back³. Later on 1959 AD, Schulman coined the term micro-emulsion describing a multiphase system containing oil, water, surfactant and co-surfactant. According to Schulman et. al., the use of surfactant and co-surfactant in micro-emulsion forms a mixed membrane, which gives higher stability to micro-emulsion and also promotes interfacial tension. This instantly results in a decrease of micro-emulsion free energy with an increase in the surface area leading to spontaneous micro-emulsion formulation⁴.

 

SMEDDS are defined as isotropic mixtures of synthetic or natural oils, solid or liquid surfactants and co-solvents/co-surfactants which upon mild turbulence followed by dilution in aqueous media, such as GI fluids, can form fine oil-in-water (o/w) emulsions or micro-emulsions⁵. The whole emulsification process requires only little entropy change which is obtained from the peristaltic motion of gut. Due to microstructural features of active entity and formulation as a whole provided by this approach, vigorous researches are being done at present time to interrelate the in vitro results obtained with in vivo responses.

 

Figure 1: Sequential Development of SMEDDS with timeframe^6,7,8

 

SMEDDS because of its ability to be delivered specifically with greater efficacy and relatively high stability is a promising alternative for conventional oral emulsions. Small particle size and polarity of resulting oral droplets determine the drug release profile from SMEDDS. Many animal studies carried out for the assessment of oral bioavailability formulated as o/w emulsion has resulted in a better absorption profile. Deshmukhet al. on 2014 developed solid self-micro emulsifying drug delivery system (SMEDDS) of ritonavir, practically water-insoluble drug and found the relative oral bioavailability to increase by two folds compared to pure ritonavir⁹. Similar study by Zhao K et al. on 2016 using valsartan as a model drug concluded 2.72-fold and 2.97-fold increase in C_max and AUC_0-t after oral administration in rats with notable enhancementin bioavailability in comparison with commercial capsules¹⁰. Further, Tung NT et al. on 2018 developed solidified self-micro emulsifying drug delivery system (SMEDDS) with I-tetrahydropalmatine (I-THP) and found bioavailability of I-THP to increase by 198.63% with a relative increase in mean maximum concentration (Cmax) than that of I-THP suspension¹¹. The first ever marketed product of SMEDDS was cyclosporine which provided 174-239% improvement in bioavailability⁷. Thus from the above citations we can conclude that SMEDDS plays pivotal role of increasing bioavailability for both water soluble and insoluble drug. Although having significant advantages in increasing the bioavalability of both water soluble and insoluble drugs, actual application remains rare due to its poor in vivo-in vitro correlation¹². Also the use of surfactants and co-surfactants at higher concentration for formulation stability purpose sometimes leads to GI irritation and toxicity. At present, extensive study on delivery of anti-neoplastic agents, anti-retroviral agents, drugs for Alzheimer disease and peptides that are prone to enzymatic hydrolysis in GIT are being carried out. Few formulation also has been available but has not shown significant improvement in clinical benefit.

 

Table 1: Few drugs under research and development process^13-31

S. N.	Drug use as/in	Examples
1.	Anti-neoplastic	Anethonetrithione, Exemestane, Paclitaxel, Nobilitin
2.	Cardio-vascular disorder drugs	Vinpocetine, Alprostadil, Crvedilol
3.	Hyperlipidemic	Simvastatin, Atorvastatin
4.	Liver cirrhosis	Silymarin
5.	Antiviral	Acyclovir
6.	Antimicrobial	Enilconazole, Xibornol
7.	Anticoagulant	Heparin
8.	Antihypertensive	Nimedipine
9.	Alzeimer disease	Idebenone
10.	Anti-malarial	Halofantine
11.	NSAIDS	Celecoxib, Peroxicam

 

SMEDDS being a novel and versatile approach to improve water solubility and ultimate bioavailability of lipophilic drugs has numerous advantages: safe and easy composition, more consistent temporal profiles of drug absorption, ease of manufacture and scale up, prolonged release of medicaments when a polymer is incorporated, selective drug targeting toward a specific absorption window in the GI tract and also drug protection from the hostile environment in the gut³². Greater bioavailability leads to less drug need to be used which not only lower total medication cost but at same time lowers the toxicity of drugs taken via oral route³³. Thus the overall benefits suggest that the study on SMEDDS will continue and more drugs compounds formulated as SMEDDS will reach pharmaceutical market in near future.

 

MECHANISM OF SELF-EMULSIFICATION:

The self-emulsification process occurs due to the entropy change in the SMEDDS system which is provided by the peristaltic movement in the gut wall. At this point, the energy produced by the randomness of a molecule (entropy) is greater than the energy required to increase the dispersion surface area. Soon after gentle shaking of a self-emulsifying system within the GI medium, the water instantly penetrates to the aqueous core leading to interface disruption and micro-droplet formation. In conventional emulsion formulation, free energy is directly proportional to the energy required to create new surface within two phases of the system. The equation can be given as:

 

ΔG = ƩNπr2σ

 

Where ΔG is the associated free energy in the process, N is numbers of the droplet with radius "r" and "σ‟ is interfacial energy with time³².

In order to decrease the interfacial area and simultaneously, the free energy of the system, phases of emulsion will have a high affinity to separate. Here, in a self-emulsifying system, the free energy required to form the emulsion is very low, positive or negative thus the emulsion process occurs spontaneously. Very small amount of energy required for the emulsification involves the destabilization through concentration of local interfacial region³⁴.

 

SELECTION OF DRUG FOR SMEDDS:

A drug with low aqueous solubility possess disadvantages of low dissolution profile thus minimizing the absorption leading to decreased bioavailability. Drugs of Biopharmaceutical classification system II and IV are usually selected for solubility enhancement approach thus leading to an increase in bioavailability via SMEDDS approach^34,35.

 

As solubility and permeability being the two interchanging factors for drug absorption, BCS classifies drug into four classes:

 

Class I drugs exhibit high dissolution and high permeability profile. Gastric emptying time becomes the rate-limiting step for this class. IVIVC correlation cannot be expected and bioequivalence and bioavailability study is unnecessary for these product³⁵. These drugs are highly suitable for the preparation of sustained-release and controlled-release formulation.

 

Class II drugs exhibit low dissolution and high permeability profile. In vivo drug dissolution becomes the rate-limiting step for this class. IVIVC correlation is usually unexpected. This drug class is highly referred for SMEDDS formulation.

 

Class III drugs exhibit high dissolution and low permeability profile. Drugs are dissolved immediately but the drug penetration via biological membrane is not possible thus permeability plays the rate-limiting step³⁶.

 

Class IV drugs show both low dissolution and low permeability profile thus oral dosage for this drug has higher challenges during formulation. They are unabsorbed from intestinal mucosa and higher variability is seen. This drug class is also referred for bioavailability enhancement by SMEDDS formulation.

 

Table 2: Biopharmaceutical classification system (BCS)

Solubility Permeability	High	Low
High	Class I Eg. Naproxen, Diltiazem, Verapamil, Propanolol etc.	Class II Eg. Ketoconazole, phenytoin, ritonavir etc.
Low	Class III Eg. Cimetidine, Ranitidine, Captopril, Atenolol etc.	Class IV Eg. Taxol, Furesimide, Hydrochlorothiazide etc.

 

FACTORS AFFECTING SMEDDS FORMULATION

1.     It is preferable that drug solubilizes in all components used in the formulation. Solubility must be higher at least in oil so higher drug proportion can be administered with predicted bioavailability³⁷.

2.     All the excipients used should be compatible with drug and each other, thus no interaction with drug and within the components will be seen.

3.     The use of higher concentration of surfactants and co-surfactants may cause precipitation during formulation and also may cause GI irritation after in vivo micro-emulsion formation³⁸.

4.     Higher the polarity of lipid base, higher drug release profile is seen.

5.     Smaller droplet size increases the surface area leading to higher absorption.

6.     Use of cationic surfactant may give a positive charge to the droplets which can lead to higher membrane penetration with increased bioavailability³⁹.

 

COMPONENTS OF SMEDDS:

SMEDDS formulation contains the following components:

1.     Oil

Oil is the most important component as it solubilizes the lipophilic drug and also results in increased absorption via intestinal mucosa in the area of emulsification⁴⁰. Edible natural and synthetic oils are usually considered in the formulation of SMEDDS but as many natural oils are easily degraded by the microorganism and also by acidic environment in the stomach, hydrolyzed vegetable oils are used, which gives good emulsification system and are also compatible with larger number of surfactants approved for oral absorption⁴¹. Both long chain triglyceride and medium chain triglyceride are used having a varying degree of saturation.

 

Example: cottonseed oil, soybean oil, palm oil, castor oil, hydrogenated specialty oil (hydrolyzed corn oil) etc.

 

2.     Surfactant:

Surfactant, also called surface active agent rest on the water-air interface and thus decrease the surface tension of water (force per unit area needed to make available surface). A surfactant has two parts with different affinities for solvents. Hydrophilic part decreases the surface tension for polar solvent (water) and lipophilic part for non-polar solvent respectively⁴². For the preparation of SMEDDS, a compound exhibiting surfactant properties is limited as only a few surfactants are orally accepted. There are four types of surfactants based on their charges:

 

a.     Anionic surfactants:

Surfactants, where the hydrophilic group carries a negative charge such as sulfate (ROSO3-), carboxyl (RCOO-) or sulphonate (RSO3-) are anionic surfactants⁴³.

 

Examples: Potassium laurate, sodium lauryl sulphate.

 

b.    Cationic surfactants:

Surfactants, where the hydrophilic group carries a positive charge.

 

Example: quaternary ammonium halide.

 

c.     Zwitterionic surfactants:

Surfactants contain both positive and negative charge.

Example: sulfobetaines.

 

d.    Non-ionic surfactants:

Surfactants where hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O)

Example: Sorbitan esters (Spans), polysorbates (Tweens).

 

To form a stable SMEDDS, surfactant concentration ranges between 30-60% w/w of the formulation⁴³. As the higher concentration of surfactant and co-surfactant may cause GI irritation upon administration, concentration is to be determined carefully. Nonionic surfactants with high hydrophilic-lipophilic balance (HLB) values are usually preferred in the formulation of SMEDDS. Surfactants tend to increase the bioavailability of formulation either by increasing drug dissolution, intestinal epithelial permeability, tight junction permeability or by decreasing p-glycoprotein drug efflux⁴⁴.

 

3.     Co-surfactant:

Generally, more than 30% w/w of surfactant is considered in the preparation of an optimum SMEDDS, thus various co-surfactant are incorporated to reduce the concentration of surfactant used⁴⁵.Co-surfactant in formulation along with surfactant tends to lower the interfacial tension to very small transient value. At this point, interface expands due to the formation of a finely dispersed droplet and subsequently adsorb more surfactant and surfactant/co-surfactant until their bulk condition is depleted enough to make interfacial tension positive again⁴⁶. Short-chained alcohol like methanol and ethanol, propylene glycol (PG), polyethylene glycol (PEG), etc. are usually preferred which helps to dissolve large amounts of hydrophilic surfactant/drug in lipid base⁹.

 

4.     Other excipients:

Various pH adjusters, flavoring agents and antioxidants agents to increase the stability and compliance of SMEDDS formulation. Few free radicals (ROO-, RO-, -OH) generated during formulation approach may damage drug and induce toxicity. Lipids undergo auto-oxidation forming peroxides ions and pH of the solution also may accelerate hydrolysis of lipid⁴⁴. Thus to maintain the stability, lipophilic antioxidants like α-tocopherol, propyl gallate or BHT are used.

 

FORMULATION APPROACH:

SMEDDS can be prepared by the following procedure:

a.     Solubility study of the drug

Solubility study of the drug is carried in various edible oils. An excess amount of drug (300-500mg) is mixed with 2 gm of selected oil and sealed in a vial. The mixture is then shaken for 48 hours in a temperature regulated environment at about 30 ± 0.5 ◦C. The mixture is then transferred to centrifuge and mixed at 3000 rpm for 5 min which is followed by filtration using 0.45mm membrane filter⁴⁷. The filtrate is diluted using chloroform and spectrophotometrically quantified using chloroform as a blank. Each experiment is being carried out in triplicate.

 

b.    Screening of Surfactants:

Out of the group of surfactants eligible for oral use, screening is carried out checking its emulsification ability. An equal proportion of oil and surfactant is made. For homogeneity, the mixture is heated at 40°C and mixed with a stirrer for some time period. Addition of distilled water to the mixture to form a homogenous and transparent mixture is performed using different kinds of surfactants. The prepared transparent emulsion is stored for 2 hours and percentage transmittance is calculated at suitable wavelength using UV-spectrophotometer using distilled water as a reference⁴⁸. Any change in physical appearance, stability or phase separation is carried out by visual observation.

 

c.     Screening of Co-surfactants:

Orally used several co-surfactants are considered and checked for their emulsification ability and compatibility with the surfactant. The Mixtures of co-surfactant selected surfactant and selected oil phase were prepared in the ratio 1:2:3 and emulsion formation capability is evaluated in a similar manner as of surfactant.

 

d.    Drug-excipient compatibility:

The FTIR spectra of pure drug, a physical mixture containing drug and oily excipients; and all with all components of SMEDDS are recorded using Fourier transform IR spectrophotometer with diffuse reflectance principle over a frequency range 4000 – 400 cm^-1. Any spectral change in the latter is observed and compared with that of pure drug and compatibility of excipient is studied.

 

e.     Construction of pseudo-ternary Phase Diagram:

Phase diagrams play an important role to determine the number and types of phases in a microemulsion system, the weight percentage along with the composition of each phase in a given temperature can be located using phase diagram. Mixture of surfactant and oil is prepared in different ratio (e.g. 0:10, 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, 10:1) in different vials³⁸. Water titration method is followed to form a clear emulsion. Microemulsion formed following each water addition, the resultant mixture is evaluated by Visual observation and the area of emulsification formed is marked in the phase diagram. The region of clear and isotropic solution determines the micro-emulsion area with suitable excipient ratio.

 

f.      Formulation and optimization:

Accurately weighed drug will be placed in a glass vial, oil, surfactant and co-surfactant are added in the ratio obtained from the phase diagram micro-emulsion area. To dissolve the drug completely, the components are mixed by gentle stirring which is followed by vortex mixing and are heated at 40˚C on a magnetic stirrer to give a clear and isotropic solution³⁸.

 

SOLIDIFICATION TECHNIQUES FOR TRANSFORMING LIQUID SMEDDS TO SOLID SMEDDS:

SMEDDS are kinetically stable, spontaneous and require low energy input in emulsion formation process in comparison with traditional emulsion formulation thermodynamically unstable⁴⁹.However, liquid SMEDDS formulations can also be solidified to improve stability, reproducibility, and patient compliance⁵⁰.Different techniques are used for conversion of liquid SMEDDS into solid SMEDDS such as encapsulation of liquid and semisolid SMEDDS, spray drying, adsorption to a solid carrier, melt extrusion etc⁵¹.

 

1.     Encapsulation of liquid and semisolid Self-emulsifying formulation:

Capsule filling of a liquid and semisolid formulation is one of the most common and simplest technique with suitability for both low dose potent drug and high dose drug loading (up to 50%) for conversion to solid SMEDDS⁵².For liquid formulation, direct filling and sealing of capsule are possible whereas for a semisolid formulation, they are heated to a minimum of 20°C above the melting temperature which will be followed by active component incorporation with continuous agitation into the capsule and sealing it.

 

2.    Spray drying:

Liquid or semisolid formulation of SMEDDS is prepared by mixing the essential components viz. oil phase, aqueous phase, surfactants, co-surfactants and drug and is prepared for spray drying. This formulation is then introduced into a spray of droplets in a drying chamber under controlled temperature and airflow condition, where the volatile phase (e.g. water present in the system) gets vaporized forming dry particles which can be either prepared into tablet or capsule formulation⁵³. Total design of temperature and airflow parameters are selected as per the drying characteristics of the drug product and powder specification.

 

3.     Adsorption to a solid carrier:

Various adsorbent like magnesium trisilicates, silica, magnesium hydroxide, talcum, aerosil 200 is used to absorb liquid or semisolid SMEDDS forming free-flowing powders or granules depending upon the drug characteristics. The process is simple and involves the addition of liquid SMEDDS into carriers by mixing in blenders. Thus obtained powder can be directly filled into a capsule or can be proceeded to tablet formulation by mixing of suitable excipients. Good content uniformity is obtained with high-level absorption (up to 70% w/w) by use of suitable adsorbent⁵⁴. At recent times, various nanoparticle absorbents like carbon nanotubes, charcoal, bamboo charcoal, silicon dioxide are also used.

 

4.     Melt granulation:

Melt granulation encompasses the technique of addition of binders to the formulation which relatively melts at a low temperature resulting in the formation of granules. This process is more relevant to that of spray drying as it omits drying phase and one step granulation is achieved^53,54. The mixture is subjected to impeller with specified impeller speed, binder particle size and viscosity and total mixing time. Gelucire 1 is commonly used as a binder which is derived from mixtures of mono-/di-/tri-glycerides and polyethylene glycols (PEG) esters of fatty acids.

 

CHARACTERIZATION:

a.     Visual assessment:

The prepared SMEDDS is evaluated for its appearance after dilution with distilled water and the preparation which shows clear, isotropic and transparent solution indicates microemulsion^55,56.

b.       Macroscopic evaluation/Droplet size:

Formulated SMEDDS (50 mL) is introduced into 50 mL of distilled water at 37 °C and the contents are mixed gently with a magnetic stir bar at 100 rpm. Thus formed microemulsion is then subjected to macroscopic evaluation. Macroscopic size of the globule is measured at the 90° angle at the temperature of 25 °C using Zetasizer⁵⁷. The average of three readings is noted and a mean is calculated.

 

c.        Dispersibility test:

The self-emulsification efficiency of prepared SMEDDS is carried out using standard USP dissolution apparatus type II. 1 ml of each formulation is added to 500 mL of water at 37 ± 0.5⁰C. A gentle agitation of 50 rpm to the formulation using is provided. Visual observation is carried out to access the in vitro performance of the formulations using following grading system⁵⁸:

·       Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance.

·       Grade B: Rapidly forming, slightly less clear emulsion, having a bluish-white appearance.

·       Grade C: Fine milky emulsion that formed within 2 min.

·       Grade D: Dull, grayish white emulsion having a slightly oily appearance that is slow to emulsify (longer than 2 min).

·       Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface.

 

d.    Cloud point determination:

The prepared formulation (0.5ml) is added to the distilled water (50ml) and placed on a water bath. The temperature is raised at the rate of 0.5 °C /min then the emulsion is cooled until they become cloudy and they are checked spectrophotometrically⁵⁹.

 

e.     Refractive Index:

This evaluation is carried out to characterize the isotropic property of the formulation. The constant refractive index shows the thermodynamic stability of the formulation. Refractometers are used for the measurement and result are compared with water. It directly depends on the nature and amount of co-surfactant used and the globule size of the formulation. Lower the refractive index, higher the co-surfactant concentration, and lower the rigidity of microemulsion.

 

f.      Percentage transmittance:

The formulation is added in water and checked spectrophotometrically. If it is near to 100% then the emulsion is clear and transparent.

 

g.     Zeta potential measurement:

Zeta potential measures the charge on the surface of the droplet of a microemulsion. The formulation (0.1 ml) was diluted 100 times using double distilled water and analyzed using Zetasizer¹².

 

h.    Conductivity measurement:

Conductivity measurement is performed to determine the specific point where the system changes from W/O to O/W upon addition of water phase. By this aid, it also helps to monitor phase inversion phenomena. Electroconductivity of an emulsion can be checked by electro conductometer^12,54. Electroconductivity is used to confirm the formulation is O/W or W/O based on the values. Water being in continuous phase has a higher value than oil.

High value - O/W

Low value - W/O

 

i.      Turbidity:

Turbidimetric evaluation is done to monitor the growth of emulsification. A fixed quantity of SMEDDS is added to a fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) using magnetic stirrer at room temperature, and the increase in turbidity is noted using a turbidimeter⁶⁰.

 

j.      Viscosity determination:

Brookfield viscometer is used to calculate the viscosity and rheological properties. This viscosities determination also confirm whether the system is w/o or o/w. Low viscosity denotes o/w type of the system and high viscosity denotes the system is w/o type.

 

k.    Robustness to dilution:

Robustness to dilution is studied by diluting the SMEDDS formulation hundred and thousand times with various dissolution media viz. 0.1N HCl and buffer pH 6.8. Any sign of drug precipitation or phase separation is observed after storing the diluted micro-emulsion for 12 hours⁶¹.

 

l.      Thermodynamic stability:

 i.     Heating cooling cycle (Temperature)

SMEDDS formulations are stored for 48 hours in between the refrigerator temperature 4˚C and 45˚C. Those formulations, which are stable at these ambient temperatures, are subjected to centrifugation test.

 

ii.       Centrifugation:

Passed formulations are centrifuged at 3500 rpm for 30min. Those formulations which do not show any remarkable change and any phase separation are further taken for the freeze-thaw cycle test.

 

iii.       Freeze-thaw cycle:

SMEDDS formulations are further stored for 48 hours in between three freeze-thaw cycles between ‐ 21 ˚ C and +25 ˚C. Those formulations, which passed these thermodynamic stress tests, are taken to assess the efficiency of self‐emulsification using dispersibility test⁶².

 

m.     Percentage Drug Content:

The samples of SMEDDS in 100ml volumetric flask are added with an extracting solvent. Then it is shaking for 1 hour (Mechanical Shaker) and kept aside for 24 hours. The sample is then filtered, and absorbances are taken in UV. Drug content is calculated by Beer-Lambert law with the use of a calibration curve of pure drug.

 

n.       In vitro dissolution study:

Based on the drug content determinations self-micro emulsifying formulations containing 10 mg drug were filled in hard gelatin capsule shells. The dissolution is carried out using dissolution test apparatus USP Type II, at 37±50C, 50 rpm paddle speed. Dissolution is performed in two different mediums viz. 0.1N HCl and 6.8 pH Phosphate buffer 900 ml⁶³. The samples are withdrawn at predetermined time intervals and are filtered using membrane filter and were analyzed for drug concentration at suitable wavelength using a UV-Visible spectrophotometer.

 

o.       In vitro drug diffusion:

A 4-5 cm long portion of the dialysis tubing is made into dialysis sac by folding and tying up one end of the tubing with thread. Examination for the presence of any leaks in the system is done by filling up with phosphate buffer saline pH 7.4 into the sac. The sac is then emptied and SMEDDS formulation equivalent to 5 mg of drug is placed into the sac. Available formulations are transferred into the separate sac. The sacs are now suspended in the glass beaker containing 50 ml of phosphate buffer saline, which act as the receptor compartment. At predetermined time intervals, 5 mL samples are withdrawn from the receptor compartment, filtered and analyzed using a suitable wavelength by UV spectrophotometer^37,63. A fresh buffer is used to replace the receptor compartment at each time the sample is withdrawn. The diffusion studies are done in a triplicate manner and the study is continued for 8 hours.

 

SOLID STATE CHARACTERIZATION:

 i.        Morphological analysis:

The surface morphology of the solid SMEDDS is studied by scanning electron microscopy (SEM). The samples for SEM were prepared by lightly sprinkling the powder on a double adhesive tape stuck to an aluminum stub which is then placed in the scanning electron microscope chamber. The samples are then randomly scanned and photomicrographs are taken and the SEM results were obtained.

 

ii.     Flow properties⁶⁰

·         Angle of repose

The angle of repose of S-SMEDDS is determined by the funnel method. Certain amount of sample is weighed and passed via funnel. A funnel is placed vertically in a way that the tip just touches the heap of powder. After passing the S-SMEDDS, the height of pile and diameter of powder come is measured. Following formula is used to calculate the angle of repose:

 

tan𝜃 = height of pile/radius of pile base

 

·         Bulk density

Both loose bulk density (LBD) and tapped bulk density (TBD) are determined. A quantity of 2 g of S-SMEDDS was introduced into a 10 ml measuring cylinder. Initial volume is observed, the cylinder is allowed to fall under its own weight onto a hard surface from a height of 2.5 cm at 2-sec intervals. The tapping is continued until no further change in volume is noted. Following formulae were used to calculate LBD and TBD:

 

LBD=𝑊𝑒𝑖𝑔h𝑡𝑜𝑓𝑝𝑜𝑤𝑑𝑒r/ intial𝑣𝑜𝑙𝑢𝑚𝑒 (before tapping)

TBD = 𝑊𝑒𝑖𝑔h𝑡𝑜𝑓𝑝𝑜𝑤𝑑𝑒r/ 𝑣𝑜𝑙𝑢𝑚𝑒after tapping

 

·         Compressibility Index

The compressibility of the granules is determined by Carr’s Compressibility Index.

Carr's compressibility index (%) = (𝑇𝐵𝐷 – 𝐿𝐵𝐷)/ 𝑇𝐵𝐷 × 100

 

·         Hausner ratio

Hausner ratio can be calculated by the formula:

Hausner ratio = 𝑇𝐵𝐷/𝐿𝐵𝐷

 

iii.       Differential Scanning Calorimetry (DSC)⁶¹

The DSC thermograms are recorded for drug and SSMEDDS using differential scanning calorimeter. Approximately 2-5 mg of each sample is heated in an aluminum pan (Al- Crucibles, 40 Al) from 30˚C to 300˚C at a heating rate of 10˚C/min under a stream of nitrogen at a flow rate of 50ml/min.

 

iv.       X-ray powder diffraction (XRD)⁶³

X-ray diffraction patterns of the powdered samples of the drug and formulation are scanned by X-ray diffractometer from diffraction angle (2θ) 5 to 500. Diffraction pattern for drug and S-SMEDDS were obtained.

 

v.        Fourier transform infrared spectroscopy

A liquid sample should be placed in the liquid sample holder of FTIR and the result can be recorded. This technique enables the researchers to find out the presence of newly formed bonds between functional groups present in the drug as well as selected excipients.

Table 3: List of few patents on SMEDDS^64-76

S N	Title	Patent Number	Date	Inventors	Refe-rence
1.	SMEDDS containing Taxoid	EP1498143A1 (European Patent)	19th Jan, 2005	Cote S, Gaudel G, Peracchia MT	[64]
2.	Self-microemulsifying drug delivery systems of a HIV protease inhibitor	US 2007/0104740 A1 (United States Patent Application)	10th May, 2007	Jody Firmin Marceline Voorspoels	[65]
3.	Process and Preparation of Self micro/nano emulsifying system and compositions thereof	208589 (Indian Patent)	2 Aug, 2007	Vandana Bharat Patravale, Imran Ahmed Khan	[66]
4.	SMEDDS pharmaceutical composition suitable for oral administration forming an in-situ oil-in-water emulsion upon contact with gastrointestinal fluids comprising one or more NO-releasing NSAID, one or more surfactants, of which at least one is phospholipid	US 7815933 B2 (United States Patent)	19th Oct, 2010	Christina Holmberg	[67]
5.	Preparation of Sorafenib self-microemulsifying drug delivery system for oral administration or intravaneous injection and use thereof.	CN 10158466 1B (China Grant)	8 June, 2011	L. Asem, S. Jiani, Z. Qiang, W. Xueqing, F. Ming	[68]
6.	A self micro-emulsifying oral pharmaceutical composition of a hydrophilic drug or its pharmaceutical acceptable salt and the preparation method thereof	EP 2425818 A1 (European Patent Application)	7th March, 2012	Chang-Shan Hsu	[69]
7.	Self microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10 using combination of a hydrophilic surfactant and a lipophilic co-surfactant forming a surfactant pair.	US 8252326 B2 (United States Patent)	28 Aug, 2012	Jing Lin	[70]
8.	Self-microemulsifying drug delivery systems and micro emulsions used to enhance the solubility of pharmaceutical ingredients comprising a polyoxyethyleneSorbitan fatty acid ester emulsifier; a fatty acid ester co-emulsifier and an oil.	US 8592490 B2 (United States Patent)	26 Nov, 2013	Igor Legan, JanezKare, PolonaJurkovic	[71]
9.	self-microemulsifying drug delivery system comprising a compound abiraterone or abiraterone acetate, a selective inhibitor of an enzyme essential for the biosynthesis of androgens and oestrogens	WO 2014009434 A1	26 Jan, 2014	Igor Legan, Luka Peternal, Mateja Novak Stagoj, Miha Homer, TanjaRozmanPaterka, UrosKlancar	[72]
10.	Self-micro/ nanoemulsifying drug carrying system for oral use of Rosuvastatin	WO 2015/142307 Al (World Intellectual Property Organization)	24 Sept, 2015	H. YesimKarasulu, SebnemApaydin, EvrenGundogdu, IlginYildirimSimsir UgurOnsel Turk, ErcumentKarasulu, CandegerYilmaz, TugceTurgay.	[73]
11.	Self-emulsifying compositions and formulations of Diindolylmethane (DIM) and certain derivatives of DIM related indoles	US 9918965 B2 (United States Patent)	20th March, 2018	Michael A. Zeligs, Irwin C. Jacobs	[74]

 

Table 4: List of few commercially available SMEDDS formulation

S. N.	Generic Name	Brand Name	Company	Class	Formulation
1	Fenofibrate	Lipirex®	Genus	Antihyperlipidimic	Hard Gelatin Capsules
2	Valproic acid	Convulex®	Pharmacia	Antiepileptic	Soft Gelatin Capsules
3	Cyclosporine A/I	Neoral®	Novartis	Immune Suppressant	Soft Gelatin Capsules
4	Cyclosporine A/II	Sandimmune®	Novartis	Immune Suppressant	Soft Gelatin Capsules
5	Bexarotene	Targretin®	Ligand	Antineoplastic	Soft Gelatin Capsules
6	Calcitriol	Rocaltrol®	Roche	Calcium regulator	Soft Gelatin Capsules
7	Ritonavir	Norvir®	Abbott Laboratories	HIV Antiviral	Soft Gelatin Capsules
8	Sequinavir	Fortovase®	Hoffmann-La Roche inc.	HIV Antiviral	Soft Gelatin Capsules
9	Amprenavir	Agenerase®	GlaxoSmithkline	HIV Antiviral	Soft Gelatin Capsules

 

CONCLUSION:

The presence of only a few drugs products formulated as SMEDDS made available into the commercial market signifies the difficulties in formulating poorly water-soluble drug compounds into such formulation. But the fact of SMEDDS being one of the novel and versatile approaches to improve the bioavailability of approximately 40% of poorly water-soluble drugs implies that the study on SMEDDS must continue so that more drugs compounds formulated as SMEDDS will reach the pharmaceutical market in near future.

 

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 16.12.2018         Modified on 21.01.2019

Accepted on 14.02.2019         © RJPT All right reserved