INTRODUCTION:

As per the BSC classification system, all the drug or chemical substances are divided into four different categories as;

BCS class I: drug substance with High solubility and high permeability, Eg: Diazepam, diltiazem, amiloride, ethambutol,etc.

BCS class II: drug substance with Low solubility and high permeability, Eg: Folic acid, carbamazepine, ibuprofen, itraconazole,etc.

BCS class III: drug substance with High solubility and low permeability, Eg: Abacavir, allopurinol, captopril, cimetidine,etc.

BCS class IV: drug substance with low solubility and low permeability, Eg: Albendazole, acetazolamide, furosemide,etc.(1)

The oral administration of class II and IV drugs are facing the problem of poor bioavailability; the class III drug molecules are hampered by poor bioavailability and high enzymatic degradation while the class I drug is also susceptible for high enzymatic degradation problem. To resolve such limitation of the oral drug delivery various approaches have been adopted like modification in solubility profile of the drug, salt formation, use of surfactant, a permeation enhancer, drug carrier system, etc. Among all these approaches, much attention has been given to the oral emulsions but it is also associated with the stability and manufacturing complexities hence the self-micro emulsifying drug delivery system offers a promising solution for oral drug delivery of various drug substances (2).

Self-micro emulsifying drug delivery system(SMEDDS) are isotropic mixtures of oils, surfactants, along with co-solvents/surfactants that have a unique ability of forming fine oil-in-water (o/w) micro emulsions having droplet size less than 100 nm upon moderate mixing of these ingredients in aqueous media, such as GI (Gastro-Intestinal) fluids (3, 4). The advantages of these systems include not only improved drug solubilization but also enhanced release and absorption properties, due to the already dissolved form of the drug in the formulation and the resulting small droplet size thus providing a large interfacial surface area (5-7).The main purpose to prepare SMEDDS is for “oral bioavailability enhancement of poorly water-soluble drugs.” The first drug marketed as a SMEDDS was “cyclosporine,” and it had significantly improved bioavailability as compared to the conventional solution(3, 6).

In the present study, graduates have gathered the information from the available resources and compiled the article so that it can be available to them in published form. Although the subject is explored one, the intention for the publication of the present work is to seed the interest towards the publication so that they can learn the process thoroughly.

IMPORTANCE OF SMEDDS

To formulate a successful SMEDDS for maximum therapeutic effect, due consideration must be given to various factors such as physicochemical properties of the active moiety as well as excipients, the potential of drug excipient interaction (invitroor in vivo) and physiological factors that promote or inhibit the bioavailability(5). Further, other important factors such as regulatory status, solubilization capacity, miscibility, the physical state of the excipients at room temperature, digestibility and compatibility with capsule shell, chemical stability and cost of the materials should also be considered during the formulation. Such a rationale approach not only helps in reducing the time involved in the formulation development and also reduces the cost of its developments(6, 8).

ADVANTAGES OF SMEDDS

· Improvement in oral bioavailability: SMEDDS present in drug to GIT insolubilized and microemulsified form and increase in specific surface area enable more efficient drug transport through the intestine leading to improved bioavailability. The oil phase can work not only as a carrier but also as a‘shield’ to protect the attack and degradation from enzymes.

· Ease of manufacture and scale up: SMEDDS require very simple and economicalequipment like a simple mixer with an agitator and volumetric liquid filling equipment.

· Reduction in inter-subjects and intra-subjects variability in absorption and food effects. The performance of SMEDDS is independent of food.

· Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT.

· SMEDDS can inhibit the activity of p-glycoprotein which results in an enhancement of oral absorption(9).

DISADVANTAGES OF SMEDDS

· Chemical instabilities of drugs and high % of surfactant may irritate GIT.

· Co-solvents can migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation drugs.

· In vitro models need further development and validation before its strength can be evaluated.

· The precipitation tendency of the drug on dilution may be high due to the dilution effect of the hydrophilic solvent.

· A formulation containing several excipients becomes more challenging to validate(10, 11).

TYPES OF SMEDDS

According to Winsor, there are four types of microemulsion phases exists in an equilibrium, these phases are referred as Winsor phases.They are:

1. Winsor 1: with two phases, the lower (o/w): microemulsion phases in equilibrium with the upper excess oil.

2. Winsor 2: with two phases, the upper (w/o): microemulsion phases in equilibrium with lower excess water.

3. Winsor 3: with three phases, middle: microemulsion phases (o/w plus w/o, called bicontinuous) in equilibrium with upper excess oiland lowerexcess water.

4. Winsor 4:In single phases, with oil, water,and surfactant homogenously mixed.

FORMULATION AND COMPOSITION OF SMEDDS

The basic concept of SMEDD formulation is the spontaneous emulsification by the gentle agitation (Gastro intestinal motility) in the physiological fluid (aqueous phase)(12). The selection of a suitable self-emulsifying formulation depends upon the assessment of

1. Physicochemical properties of the drug, such as pKa, polarity,and solubility in various components

2. Physicochemical nature of oily phase, surfactant,and co-surfactant

3. The area of the self-emulsifying region as obtained in the phase diagram,

4. The ratio of the components, especially oil to surfactant ratio

5. The droplet size distribution of the resultant emulsion following self-emulsification(11)

SMEDDS mainly composed the suitable ratio of the drug, oil phase, surfactant, co-surfactant,and co-solvent (fig. 1). The major components of SMEDD are discussed below

1. Drug ( API )

2. Oil

3. Surfactant

4. Co-Surfactant(13)

Figure 1:Composition of SMEDDS formulation.

1. Drug:The drug with poor aqueous solubility and permeability are classified as class II drug by Biopharmaceutical classification system (BCS). These drugs are used to formulate SMEDDS.

2. Oil:

· Oils are the most important excipient.

· Help in solubilizing the lipophilic drug in high amount.

· Facilitate self-emulsification and increase the fraction of lipophilic drug transported.

· Increase absorption from the GI tract.

· Both long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used for the formulation of SMEDDS.

· Lipid Ingredients(Corn oil, Olive oil, Sesame oil, Soyabean oil, Peanut oil, Hydrogenated soyabean oil, Hydrogenated vegetable oils)(14)

3. Surfactant:

· Non-ionic surfactants with high hydrophilic-lipophilic balance (HLB) values are used in the formulation of SMEDDS.

· Surfactant strength ranges between 30-60% w/w of the formulation to form a stable SMEDDS.

· A large quantity of surfactant may irritate the GIT.

· Non-ionic surfactants are less toxic as compared to ionic surfactants.

· List of Surfactants

a. Polysorbate 20 (Tween 20 )

b. Polysorbate 80 (Tween 80 )

c. Sorbitan monooleate (Span 80)

d. Polyoxy-40-hydrogenated castor oil

4. Co-Surfactant:

· Co-surfactant helps to dissolve a largenumber of hydrophilic surfactants or the hydrophobic drug in the lipid base.

· The solvents sometimes play the role of co-surfactant in the microemulsion system.(15)

Formulation Strategy

A general formulation strategy of SMEDDS involves the mixing of the appropriate amount of drug with the melted lipid phase this makes a lipidic solution which is further mixed with the suitable quantity of surfactant and co-surfactant. This physical mixture is finely homogenized to prepare a SMEDD formulation which when exposed to the biological fluid with gentle agitation gets emulsified inside the body (fig 2) (4, 15).

Figure 2: Formulation strategy of SMEDDS

FACTORS AFFECTING SMEDDS

1) Dose and nature of the drug:High dose of drugs are not suitable for SMEDDS if at least one of the component of SMMEDS not shows extremely good solubility, preferably lipophilic phase. In water and the lipids with log p-value of approximately two are most difficult to deliver by SMEDDS, which exhibit the limited solubility. The drug in solubilized form is affected by the solubility of the drug in oil.

2) The concentration of surfactants or co-surfactants: Risk of precipitation occurs if surfactant and co-surfactant conducive to the greater extent of drug solubilization. Lowering of the solvent capacity of the surfactant and co-surfactant is occurs as dilution of SMEDDS(16).

3) The polarity of lipophilic phase: Drugs release from the microemulsion is governed by one of the factors that arethe polarity of the lipid phase. HLB, the molecular weight of the micronized drug, the chain length and degree of unsaturation of fatty acid govern the polarity of the droplet.

4) Temperature:Increasing the temperature decreases the nucleation rate. At higher temperatures, the binding between drug and polymer is decreased, due to increased solubility of drug and weakening of intramolecular interactions.

5) Packing ratio:Type of microemulsion is determined by the HLB of surfactant by influencing the packing and film curvature for surfactant association’s leading to the formation of the microemulsion.(13)

CHARACTERIZATION OF SMEDDS

1. Differential scanning calorimetry

Differential scanning calorimetry for SMEDDS can be determined using DCS 60. Liquid and the solid sample should be placedin the aluminum pan and result can be recorded any chemical interaction shouldbe determined using DSC.

2. Fourier transport infrared spectroscopy

Fourier transport infrared for SMEDDS can be determined using FT-IR. The liquid sample should be placed in the liquid sample holder,andthe result can be recorded. Any chemical interaction should be determined.

3. Macroscopic evaluation

The macroscopic analysis was carried out to observe the homogeneity of microemulsion formulation. Any change in color and transparency or phase separation occurred during normal storage condition was observed inoptimizedmicroemulsion formulation(17).

4. Visual assessment

To assess the self-emulsificationproperties, the formulation was introduced into 100ml of water in a glass Erlenmeyer flask at 25°C,and the content was gently stirred manually.The tendency to spontaneously form a transparent emulsion was judged as good,and it was judgedbad when there was poor or no emulsion formation.

5. Determination of self-emulsificationtime

The emulsification time of SMEDDSwas determined according to USP 22, dissolution 2.300 mg of each formulation added dropwise to 500ml purification water at 37° C. Gentle agitation was provided by a standard stainless steel dissolution paddle rotating 50 rpm.Emulsification time was assessed visually.

6. Solubility studies

An unknown amount of selectedvehicle was added to each cup vial containing an excess of the drug.After sealing the mixture was heated at 40°C in a water bath to facilitate the solubilization.

7. Transmittance test

Stability of optimized microemulsion formulation concerning dilution was checked by measuring transmittance through U.V. spectrophotometer(18).

8. Zeta potential measurements

Zeta potential of microemulsion was determined using Zetaasizer HSA3000.The samplewas placedinclear disposable zeta cell,andthe resultwas recorded. Before putting the fresh sample, cuvettewas washed with the methanol using the sample to be measured for each experiment(17).

EVALUATION OF SMEDDS

1) Droplet size

a) It determines the rate and extract of drug release as well as the stability of the emulsion.

b) The size of the droplet is below 200 nm, lead to the formation of SMEDDS which are stable isotropic and clear O/W dispersion.

c) Microscopic techniques or a colter Nano sizes are used for determination of emulsion droplet size(19).

2) Zeta potential measurement

It is used to identify the change of the droplets in conventional SEDDS the change on an oil droplet in negative due to the presence of free acids(20).

3) Refraction index and percent transmission

a) Refractive index and percent transmission prove the transparency of formation.

b) The refractive index of the system is measured by refractometer by putting a drop of solution and compare with water.

c) The percent transmittance of the system is measured at particular wavelength using UV spectrophotometer

d) Refractive index of system should be similar to that of water, its show than 99% transparent(21).

· Thermodynamic stability

· Heating cooling cycle

Six cycles between temperature 4^oC and 45^oC with storage at each temperature of not less than 48 Hour is studied. Those formulations which are stable at these temperatures are subjected to centrifugation test.

· Centrifugation

Passed formulations are centrifuged at room temperature at 3500 rpm for 30 min. Those formulations that do not show any phase separation are taken for the freeze-thaw stress test.

· Freeze-thaw cycle

Freeze was employed to evaluate the stability of the formulation. Thermodynamic stability was evaluated ata different temperature to check the effect of temperature the formation was subjected to freeze-thaw cycle for 2-3 days(22).

5) Dispensability test

The efficiency of self-emulsification of oral Nano or microemulsion. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vivo performance of the formulations is visually assessed using the following grading system.

Grade A: Rapidly forming Nanoemulsion having a clear appearance.

Grade B:Rapidly forming a slightly less clear emulsion having a white appearance.

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

GradeD: Dull gray wish white emulsion hasa slightly oily appearance that is slow to emulsify(23).

6) Turbid metric evaluation

Nephesoturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quality of the self-emulsifying system is added to fixed quality of suitable medium under continuous stirring on the magnetic hot plate at the appropriate temperature,and the increase in turbidity is measured by using the turbid meter.

7) Viscosity determination

The SMEDDS system is administered in self-gelatin or hard gelatin capsule. So it should be easy to pour. The rheological properties of the micro emulsionare evaluated,and viscosities are also determined(24).

8) Electroconductivity study

SMEDDS system contains an ionic or Nonionic surfactant, oil,and water. This test is performed for measurement of electroconductive nature of system it is measured by conduct meter,and the charge of oil droplet is negative due to fatty acids(19).

9) In vitro diffusion studies

They carried out to study the drug release behavior of formulation from liquid crystal-like phase around the droplet using dialysis technique.

10) Drug content

Drug from pre-weighed SMEDDS is extracted by dissolving in a suitable solvent. The drug content in the solvent extract was analyzed by suitable analytical method against the standard solvent solution of the drug(25).

APPLICATIONS OF SMEDDS

1. Super Saturable SMEDDS (SS-SMEDDS)

The high surfactant level typically present in SMEDDS formulation can lead to GI side effects and a new class of supersaturable formulation including supersaturable SMEDDS. (S-SMEDDS) formulations have been designed and developed to reduce the surfactant side effects and achieve rapid absorption of poorly soluble drugs.

2. Solid SMEDDS

SMEDDS are normally prepared as liquid dosage form that can be administered in soft gelatine capsules, which has more disadvantages,especially in the manufacturing process. An alternative method is the incorporation of a liquid self-emulsifying ingredient into a powder to create solid dosage form (Tablet, capsules). A pellet formulation of progesterone in SMEDDS has been prepared by extrusion/super-ionization to provide a good in-vitro drug release (100% within 15 min. T50% in 13 min.) (26)

3. Solubilization in SMEDDS

Owing to their frequently high content oil, as well as of surfactant, SMEDDS are usually efficient solubilizers of substances of a wide range of lipophilicity. Thus, the solubilizing capacity of a w/o Microemulsion for water-soluble drugs is typically higher than that of o/w Microemulsion, while the reverse is true for oil-solubledrugs. Furthermore, the solubilization depends on the SMEDDS composition.

4. Sustain Release from SMEDDS

Due to a wide range of structures occurring in them, SMEDDS display a rich behavior regarding the release of solubilized material. Thus in case of O/W Micro emulsions, hydrophobic drugs solubilized mainly in the oil droplets, experience hindered diffusion and are therefore released further slowly (depending on the O/W partitioning of the substance). Water-soluble drugs, on the other hand, diffuse essentially without obstruction (depending on the volume fraction of dispersed phase) and are release fast. For Micro balanced emulsions, relatively fast diffusion and release occur for both water soluble and oil soluble drugs due to the bicontinuous nature of Micro emulsion “structure.” Apart from the Micro emulsions structure, the Microemulsion composition is important for the drug release rate(23).

RECENT ADVANCEMENTS IN SMEDDS

· Dry emulsion

Dry emulsions are powders from which emulsion spontaneously occurs in vivo are when exposed to an aqueous solution. The dry emulsion can be useful for further preparation of tablets and capsules. Dry emulsion formulations are typically prepared from oil/water emulsion containing a solid carrier in the aqueous phase by rotatory evaporation. This formulation consists of surfactant variables oil, a PH responsive polymer lyophilization used.Recently prepared dry emulsion by spreading liquid oil/water emulsion on a flat glass then died & triturated to powder(27).

· Self-Emulsified capsules

After administration of capsules containing conventional liquid SE formulation, microemulsion droplets from a subsequently dispersed in the GI tract to reach the site of absorption. However, if reversible phase separation on the micro-emulsion occurs an impartment of drug absorption cannot be an aspect. Such adsorption was also applied to prepare SE tablet of gentamicin that, in clinical use was limited use administration as injectable are topical dosage form.(28)

· Self-Emulsified solid dispersion

Although solid dispersion cloud increases the dissolution rate and bioavailability of poorly water-soluble drug some manufacturing difficulties and stability problems existed out that these difficulties surmounted by the use of SE excipient this excipient have the potential to increase further the absorption of poorly water-soluble drug relative to previously used PEG solid dispersion an may also be filled directly into hard gelatin capsule in the molten state(1).

· Self-Emulsified suppository

SMEDDS could increase not only GI adsorption but also rectal/vaginal adsorption. Glycyrrhizin which, by the oral route, barely achieves therapeutics plasma concentration can obtain satisfactory therapeutics level or chronic hepatic disease by other vaginal are rectal SE suppository(2).

· Self-Emulsifying Nanoparticles

Nanoparticles techniques have been useful in the production of SE Nanoparticles. Solvent injections are one of these techniques. In this method, the lipid, surfactant, and drugs were melted together and injected drop wish into a stirrednonsolvent. These resulting SE Nanoparticles were after that filtrated out and dried.(20)

SOME DRUG DELIVERY SYSTEM USING SMEDDS

(A) Oral delivery

· Self-emulsifying capsule: After administration of capsules containing conventional liquids SE formulations, microemulsion droplets form and subsequently disperse in the GIT to reach the site of absorption. If irreversible phase separation of microemulsion occurs an improvement of drugs absorption can’t be expected. For handling this problem, sodium dodecyl sulfate was added into the SE formulation(28).

· Self-emulsifying sustained/controlled release: Combination of lipids and surfactant has presented great potential preparing SE tablets. SE tablets are of great utility in obviating adverse effect. The inclusion of indomethacin (or other hydrophobic NSAID) for example, into SE tablets, may increase its penetration efficacy through GI mucosal membrane potentially reducing GI bleeding.

· Self-emulsifying sustained/control release pellets: Pellets, as a multiple unit dosage forms, possess many advantages over conventional solid dosage form, such as flexibility of manufacture, reducing intrasubject and inter-subject variability of plasma profile and minimizing GI irritation without lowering drug bioavailability.

· Self-emulsifying solid dispersions: Solid dispersions could increase the dissolution rate and bioavailability of poorly water-soluble drugs, but still some manufacturing difficulties and stability problems existed.(3, 29)

(B) Topical Delivery: Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first-pass metabolism of the drugs and related toxicity effects.

(C) Oculars and Pulmonary delivery: For the treatment of eye disease, drugs are essentially delivered topically o/w microemulsion have been investigated for ocular administration, to dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile.

(D) Parenteral delivery: Parenteral administration of drugs with limited solubility is a major problem in the industry because of the extremely low amount of drug deliveredto the target site.

(E) Ophthalmic delivery: In conventional ophthalmic dosage forms, water-soluble drugs are delivered in aqueous solution while water-insoluble drugs are formulated as suspensions or ointments. Low corneal bioavailability and lack of efficiency in the posterior segment of ocular tissue are some of the serious drawbacks of these systems. Recent research efforts have therefore focused on the development of new and more effective delivery systems. Microemulsion has emerged as a promising dosage form for ocular use.

(F) Nasal delivery: Microemulsion is now being studied as a delivery system to enhance uptake across the nasal mucosa. Addition of a mucoadhesive polymer helps in prolonging the residence time on the mucosa. The nasal route for administration of diazepam might be a useful approach for the rapid onset of action during the emergency treatment of status epileptics.

(G) Drug Targeting: Drug targeting to diseased cells can be achieved by exploiting the presence of various receptors, antigens/proteins on the cell membrane which may be uniquely expressed or overexpressed in these cells as compared to the normal cells. Specific antibodies to the surface proteins and ligands for the receptors can be used to target specific cells. The submicron size range of these systems confers excellent opportunities to overcome the physiological barriers and enables efficient cellular uptake followed by intracellular internalization.(21, 30)

CONCLUSION:

Self-microemulsifying drug delivery systems are the recent and effective approach for the augmentation of oral bioavailability of many poor water-soluble drugs provided that the drug should be potent with high lipid solubility. SMEDDS promotes lymphatic delivery of extremely hydrophobic drugs with good solubility in triglycerides. Faster and enhanced drug release can be attained with smaller droplets which in turn promotes bioavailability. The present review is involved in obtaining a robust and stable dosage form. Further research in developing SMEDDS with surfactants of low toxicity and to developin vitro methods to better understand the in vivo fate of these formulations can maximize the availability of SMEEDS in the market.In all, it was good to see that the students were propelled towards the said target and they have now known the basics of the publication process. Henceforth, this article will definitely prove to be a milestone in their future research carrier.

AKNOWLEDGMENT:

The author wants to show a sincere gratitude to the Rungta College of Pharmaceutical Sciences and Research for providing necessary facilities for the completion of work.

CONFLICT OF INTEREST:

None.

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