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International Journal of Universal Pharmacy and Bio Sciences 3(3): May-June 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13*** Pharmaceutical Sciences REVIEW ARTICLE……!!!

SELF EMULSIFYING DRUG DELIVERY SYSTEM: AN APPROACH TO

IMPROVE THE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS

Dain K Thankachen*, Manju Maria Mathews, Prof. John Joseph

Nirmala College of Pharmacy, Muvattupuzha,Kerala.

KEYWORDS:

Co-surfactant, Oil, Self

emulsifying drug delivery

system (SEDDS),

Surfactant.

For Correspondence:

Dain K Thankachen*

Address:

Department of

Pharmaceutics

Nirmala College of

Pharmacy Ernakulam,

Kerala, India.

E- mail:

[email protected]

ABSTRACT

Oral route is the easiest and most convenient route for drug

administration. The major problem in oral drug formulations is low

and erratic bioavailability, which mainly results from poor aqueous

solubility. This may lead to high inter- and intra subject variability,

lack of dose proportionality and therapeutic failure. As a consequence

of modern drug discovery techniques, there has been a steady increase

in the number of new pharmacologically active lipophilic compounds

that are poorly water soluble. It is a great challenge for pharmaceutical

scientists to convert those molecules into orally administered

formulation with sufficient bioavailability. Self-emulsifying drug

delivery system (SEDDS) has gained more attention for enhancement

of oral bio-availability of poorly water soluble and lipophilic drugs

with reduction in dose. Thus, for lipophilic drug compounds that

exhibit dissolution rate-limited absorption, these systems may offer an

improvement in the rate and extent of absorption and result in more

reproducible blood-time profiles. SEDDS are ideally an isotropic

mixture of oil, surfactants, solvents and sometimes co-

solvents/surfactants. The principal characteristic of these systems is

their ability to form fine emulsions (or micro-emulsions) in gastro-

intestinal tract (GIT) with mild agitation provided by gastric mobility.

Purpose of this review article is to provide brief outline of self

emulsifying drug delivery system as a promising approach to

effectively tackle the problem of poorly soluble molecules along with

the associated problems & its potential to increase the bioavailability

of poorly soluble drugs.

mailto:[email protected]



INTRODUCTION:

One of the most popular and commercially viable delivery approaches used to improve the solubility

and bioavailability of poorly water soluble drugs is self-emulsifying drug delivery system

(SEDDS)1. Self-emulsifying drug delivery systems (SEDDS) are a vital tool in solving low

bioavailability issues of poorly soluble drugs. The use of SEDDS to improve the bioavailability of

poorly water soluble drugs was first reported in 1982 by Pouton. In his work, he identified an

effective self emulsifying system composed of Miglyol 812 (M812, medium chain triglyceride,

MCT) and Tween 85 (T85, polyoxyethelene-20-sorbitan trioleate). SEDDS are formulated with

mixtures of lipid vehicles and non-ionic surfactants in the absence of water, and are assumed to exist

as transparent isotropic solutions. They are able to self emulsify rapidly in the aqueous media, such

as gastrointestinal(GI) fluids, forming fine oil-in-water (o/w) emulsions/lipid droplets or micro

emulsions(SMEDDS) under the gentle agitation provided by gastro-intestinal motion and are

suitable for oral delivery in soft and hard gelatin or hard hydroxypropylmethylcellulose (HPMC)

capsules2. Hydrophobic drugs can be dissolved in these systems, enabling them to be administered as

a unit dosage form for per-oral administration.When such a formulation is released into the lumen of

the gut, it disperses to form a fine emulsion. The drug, therefore, remains in solution in the gut,

avoiding the dissolution step that frequently limits the absorption rate of hydrophobic drugs from the

crystalline state1. SEDDSs typically produce emulsions with a droplet size between 100–300 nm

while self-micro-emulsifying drug delivery systems (SMEDDSs) form transparent micro-emulsions

with a droplet size of less than 50 nm, on dilution with physiological fluid2. Fine oil droplets would

pass rapidly from the stomach and promote wide distribution of the drug throughout the GI tract,

thereby minimizing the irritation frequently encountered during extended contact between bulk drug

substances and the gut wall1.

The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant

concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. The ease of

emulsification could be associated with the ease of water penetrating into the various liquids

crystalline or gel phases formed on the surface of the droplet. When compared with emulsions,

which are sensitive and metastable dispersed forms, SEDDS are physically stable formulations that

are easy to manufacture. The spontaneous formation of emulsion presents the drug in a dissolved

form and the resultant small droplet size provide a large interfacial area for diffusion3. The SEDDS

formulation has been well accepted for drugs with poor aqueous solubility and high permeability,

classified as Class II drugs by Biopharmaceutic classification system (BCS) system4. For lipophilic



drugs with dissolution-limited oral absorption, these systems may offer an improvement in the rate

and extent of absorption and more reproducible plasma concentration profiles3. Self emulsifying

formulations are normally prepared as liquid which possesses some disadvantages, for example, high

production costs, low stability and portability, low drug loading and few choices of dosage forms.

Irreversible drugs/excipients precipitation may also be problematic. More importantly, the large

quantity (30-60%) of surfactants in the formulations can induce GI irritation. To address these

problems, transformation of SEDDS in solid dosage forms by addition of large amounts of

solidifying excipients (adsorbents and polymers) have been reported1.

ADVANTAGES

1. Improvement in oral bioavailability enabling reduction in dose: SEDDS is a novel approach

to improve the water solubility and ultimately bioavailability of lipophilic drugs. The ability

of SEDDS to present the drug to GIT in globule size between 1-100 nm and subsequent

increase in specific area enables more efficient drug transport through the intestinal aqueous

boundary layer leading to improvement in bioavailability.

2. Ease of manufacture and scale-up: SEDDS require very simple and economical

manufacturing facilities like simple mixer with agitator and volumetric liquid filling

equipment for large-scale manufacturing.

3. Reduction in inter-subject and intra-subject variability and food effects: SEDDS offer

reproducibility of plasma profile.

4. Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT: One unique

property that makes SEDDS superior as compared to the other drug delivery systems is their

ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors

and their ability to offer protection from enzymatic hydrolysis3.

5. Fine oil droplets empty rapidly from the stomach and promote wide distribution of the drug

throughout the intestinal tract and thereby minimizing irritation frequently associated with

extended contact of drugs and gut wall5-6

.

6. More consistent temporal profiles of drug absorption.

7. Selective targeting of drug(s) toward specific absorption window in GIT.

8. Protection of drug(s) from the hostile environment in gut.

9. High drug payloads7.



DISADVANTAGES

1. Conventional SEDDS, which are mostly prepared in a liquid form and orally administered in

soft or hard gelatin capsules, can make some limitations such as high production costs, low

drug incompatibility and stability, drugs leakage and precipitation, capsule ageing. Then

incorporation of liquid SEDDS into a solid dosage form is compelling and desirable7.

2. The drawbacks of this system include chemical instabilities of drugs and high surfactant

concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%)

irritates GIT.

3. Volatile cosolvents in the conventional self-emulsifying formulations are known to migrate

into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic

drugs8.

4. The traditional dissolution method does not work, because these formulations potentially are

dependent on digestion prior to release of the drug9.

FACTORS AFFECTING OF SEDDS:

1. Nature and dose of the drug: Drugs which are administered at very high dose are not

suitable for unless they have extremely good solubility in at least one of the components of

SEDDS, preferably lipophilic phase. The drugs which have limited or less solubility in water

and lipids are most difficult to deliver by SEDDS. The ability of SEDDS to maintain the drug

in solubilised form is greatly influenced by the solubility of the drug in oil phase.

2. Solubility of drug: The ability of SEDDS to maintain the drug in solubilised form is greatly

influenced by the solubility of the drug in oily phase. If the surfactant and co-surfactant

contribute to a greater extent for solubilisation then there is risk of precipitation.

3. Polarity of the lipophilic phase: The polarity of lipid phase is one of the factors that govern

the release of the drug from the micro-emulsion. HLB, chain length, degree of unsaturation

of the fatty acid, molecular weight of the hydrophilic portion and concentration of the

emulsifier govern polarity of the droplets. The polarity reflects the affinity of the drug for oil

and/or water, and the type of forces formed. The high polarity will promote a rapid rate of

release of the drug into the aqueous phase. The highest release was obtained with the

formulation that had oil phase with highest polarity9-10

.

CRITERIA OF DRUG PROPERTIES:9

BCS (Bio-pharmaceutical classification system) classifies the drug based on solubility and

permeability of a drug. Mainly Class 2 (Low Solubility, High Permeability) is used for SEDDS. Ex.



Glibenclamide, Azithromycin,Danazol, Phenytoin, Dapsone, Carbamazepine, Nifedipine,

Carvedilol, Chlorpromazine, Cisapride, Ciprofloxacin.

COMPOSITION OF SEDDS

The self-emulsifying process depend on11

;

● The nature of the oil–surfactant pair

● The surfactant concentration and surfactant/ cosurfactant ratio.

● The temperature at which self emulsification occurs.

Oils:

Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient

because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported

via the intestinal lymphatic system, thereby increasing absorption from the GI tract12

. Long-chain

triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used

in the design of SEDDS. Unmodified edible oils provide the most `natural' basis for lipid vehicles,

but their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in

efficient self-emulsification markedly reduce their use in SEDDS. In contrast, modified or

hydrolyzed vegetable oils have contributed widely to the success of the above systems. Novel semi

synthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the

regular medium- chain triglyceride12

. Nature of oil is very important in the formation of SEDDS.

Chemical structure of the oil components and interactions of these components with the various

enzymes, surfactants and proteins associated with digestion and absorption process, for example,

fatty acid chain length is important factor for chylomicron formation. Short and medium chain acids

are predominantly absorbed by portal blood system while longer chain fatty acid may be re-esterified

in the cell lining the small intestine and absorbed via the lymphatics. The absorption enhancement is

greater when using unsaturated fatty acids. M. Cheema et al reported that a greater degree of

unsaturation led to a more rapid onset of lipoprotein synthesis as a result of faster absorption or

greater affinity of fatty acid binding to protein because unsaturated fatty acids have lower melting

points as compared to saturated with increasing fluidity. Liquid crystal formation from oil depends

on oil polarity, which would influence the emulsification process. Very polar or non-polar oils tend

to form poor emulsions. Miglyol 812 and 840 both have intermediate polarity which shows

favourable emulsification properties with Tween85. Solubility of the drug in the oil-surfactant

mixture is very important whereas solubility of drug in vegetable oil is not a problem. The simplest



and most desirable formulation may well be a simple oil solution which is self emulsified in the gut

during digestion13

.

Examples include mineral oil, vegetable oil, silicon oil, lanolin, refined animal oil, fatty acids and

mono-/di-/tri-glycerides.

• Fractionated coconut oil and palm seed oil (medium-chain triglycerides)

• Corn oil, Olive oil, Sesame oil, Soybean oil, Peanut oil (long –chain triglycerides)2

Surfactant:

The choice of surfactants is limited because very few surfactants are orally acceptable. The most

widely used surfactants are nonionic surfactants with high hydrophilic–lipophilic balance (HLB)

value. The surfactants used in SEDDS include Tween, Span, Labrasol, Labrafac CM 10,

Cremophore. The usual surfactant strength ranges between 30–60% w/w of the formulation in order

to form a stable SEDDS. Surfactants having a high HLB and hydrophilicity, which assists the

immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media.

Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively large amounts of

hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and

for prolonged existence of drug molecules11

. The lipid mixtures with higher surfactant and co-

surfactant/oil ratios lead to the formation of self-micro emulsifying formulations(SMEDDS). The

surfactants used in these formulations will improve the bioavailability by various mechanisms

including: improved drug dissolution, increased intestinal epithelial permeability, increased tight

junction permeability and decreased/inhibited p-glycoprotein drug efflux4. A large quantity of

surfactant may irritate the GI tract. Thus, the safety aspect of the surfactant vehicle should be

carefully considered in each case.

Co-solvents:

Co-solvents dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid

base and can act as co-surfactant in the self emulsifying drug delivery systems. The co-solvents

includes Transcutol (Diethylene glycol monoethyl ether), Polyethylene glycol 400, Glycerol,

Propylene glycol, Ethanol, Polyoxyethylene, Propylene carbonate, Tetrahydrofurfuryl alcohol

polyethylene glycol ether (Glycofurol)7. The production of an optimum SEDDS requires relatively

high surfactant concentration (usually more than30%w/w), however the use of co-surfactant in self

emulsifying systems is not mandatory for many non-ionic surfactants.

Other excipients:



Oil soluble antioxidants include α-tocopherol, β-carotene, butylated hydroxyl toluene (BHT),

butylated hydroxyl anisole (BHA), propylgallate and ascorbylpalmitate2.

MECHANISM OF SELF EMULSIFICATION

Self emulsification occurs when the entropy change that favors dispersion is greater than the energy

required to increase the surface area of the dispersion14

. The free energy of the conventional

emulsion is a direct function of the energy required to create a new surface between the oil and water

phases and can be described by the equation;

ΔG = Σ N π r2

σ

Where, ΔG is the free energy associated with the process (ignoring the free energy of mixing), N is

the number of droplets, r is the radius of droplets and σ represents the interfacial energy.

The two phases of emulsion tend to separate with time to reduce the interfacial area and

subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion

droplets and hence reduce the interfacial energy as well as providing a barrier to prevent

coalescence. In the case of self-emulsifying systems, the free energy required to form the emulsion is

either very low and positive, or negative (then, the emulsification process occurs spontaneously)15

.

In self emulsifying system the interfacial tension is made sufficiently low that interfacial energy

become comparable and lowers their entropy of dispersion and free energy of formation become

zero or negative. Thus the main driving force of SSEF is ultra low interfacial tension, which is

achieved by using two or more emulsifier in combination, but sometime single nonionic surfactant

may work.

The ease of emulsification is suggested to be related to the ease of water penetration into various

liquid crystal (LC) or gel phase formed on the surface of the droplet16-18

. The addition of binary

mixture (nonionic surfactant/ oil) water interface is formed between oil and continuous aqueous

phase. This is followed by solubilization of water within oil phase as a result of aqueous penetration

through interface. This will occur until the solubilization limit is reached close interphase which lead

to dispersed LC phase so in the end all globule in close proximity will be LC which mainly depend

on surfactant concentration in binary mixture19

.

The presence of the drug may alter the emulsion characteristics, possibly by interacting with the

liquid crystalline phase20

.

METHOD OF PREPARATION:

A) Solidification techniques for transforming liquid/semisolid: Various solidification techniques

are listed below;



1) Capsule filling with liquid and semisolid self-emulsifying formulations: Capsule filling is the

simplest and the most common technology for the encapsulation of liquid or semisolid SE

formulations for the oral route. For semisolid formulations, it is a four-step process: A) Heating of

the semisolid excipient to at least 20˚C above its melting point. B) Incorporation of the active

substances (with stirring). C) Capsule filling with the molten mixture and D) Cooling to room

temperature. For liquid formulations, it involves a two-step process. Filling of the formulation into

the capsules followed by sealing of the body and cap of the capsule, either by banding or by micro

spray sealing 21

.

B) Spray drying: Essentially, this technique involves the preparation of a formulation by mixing

lipids, surfactants, drug, solid carriers, and solubilization of the mixture before spray drying. The

solubilized liquid formulation is then atomized into a spray of droplets. The droplets are introduced

into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates

forming dry particles under controlled temperature and airflow conditions. Such particles can be

further prepared into tablets or capsules. The atomizer, the temperature, the most suitable airflow

pattern and the drying chamber design are selected according to the drying characteristics of the

product and powder specification.

C) Adsorption to solid carriers: Free flowing powders may be obtained from liquid SE

formulations by adsorption to solid carriers. The adsorption process is simple and just involves

addition of the liquid on to carriers by mixing in a blender. The resulting powder may then be filled

directly into capsules or, alternatively, mixed with suitable excipients before compression into

tablets. A significant benefit of the adsorption technique is good content uniformity. SEDDS can be

adsorbed at high levels up to 70% w/w onto suitable carriers22

. Solid carriers can be microporous

inorganic substances, high surface-area colloidal inorganic adsorbent substances, cross-linked

polymers or nanoparticle adsorbents. For example, silica, silicates, magnesium trisilicate,

magnesium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose and

crosslinked polymethyl methacrylate are typical solid carriers23

. Crosslinked polymers create a

favourable environment to sustain drug dissolution and also assist in slowing down drug

reprecipitation24

. Nanoparticle adsorbents include porous silicon dioxide (Sylysia 550), carbon

nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal25

.

At present, colloidal silicon dioxide is widely used as an adsorbing agent for various drugs like

ketoprofen, ezetimibe, and Siramesine hydrochloride. It has been reported that porous polystyrene



beads can be used as carriers for a self-emulsifying system containing loratadine. Silicone dioxide

has been used as an adsorption carrier for ketoprofen.

D) Melt granulation: Melt granulation is a process in which powder agglomeration is obtained

through the addition of a binder that melts or softens at relatively low temperatures.

E) Melt extrusion/extrusion spheronization: Melt extrusion is a solvent-free process that allows

high drug loading (60%)21

, as well as content uniformity. Extrusion is a procedure in which a raw

material with plastic properties is converted into a product of uniform shape and density, by forcing

it through a die under controlled temperature, product flow, and pressure conditions26

. The size of

the extruder aperture determines the approximate size of the resulting spheroids. The extrusion-

spheronization process is commonly used in the pharmaceutical industry to make uniformly sized

spheroids (pellets).

EVALUATION:- 27-29

A) Thermodynamic stability studies:

The physical stability of a lipid –based formulation is also crucial to its performance, which can be

adversely affected by precipitation of the drug in the excipient matrix. In addition, poor formulation

physical stability can lead to phase separation of the excipient, affecting not only formulation

performance, but visual appearance as well. In addition, incompatibilities between the formulation

and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or

incomplete release of drug.

a) Heating cooling cycle: Six cycles between refrigerator temperature (4OC) and 45

OC with storage

at each temperature of not less than 48 hr is studied. Those formulations, which are stable at these

temperatures, are subjected to centrifugation test.

b) Centrifugation: Passed formulations are centrifuged thaw cycles between 21OC and +25

OC with

storage at temperature for not less than 48 hr is done at 3500 rpm for 30 min. Those formulations

that does not show any phase separation are taken for the freeze thaw stress test.

c) Freeze thaw cycle: Three freeze for the formulations. Those formulations passed this test showed

good stability with no phase separation, creaming, or cracking.

B) Dispersibility test

The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard

USP XXII dissolution apparatus II. One milliliter of each formulation was added to 500 ml of water

at 37 ± 0.50C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle



agitation. The in vitro performance of the formulations is visually assessed using the following

Grading system:

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 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.

Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While

formulation falling in Grade C could be recommend for SEDDS formulation.

C) Turbidimetric Evaluation

Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of

Selfemulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under

continuous stirring (50 rpm) on magnetic hot plate at appropriate temperature, and the increase in

turbidity is measured, by using a turbidimeter. However, since the time required for complete

emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of

emulsification)

D) Viscosity Determination

The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it can be

easily pourable into capsules and such systems should not be too thick. The rheological properties of

the micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform

whether the system is w/o or o/w. If the system has low viscosity then it is o/w type of the system

and if a high viscosity then it is w/o type of the system.

E) Droplet Size Analysis and Particle Size Measurements

The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses

the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to

measure sizes between 10 and 5000 nm. Light scattering is monitored at 25°C at a 90° angle, after

external standardization with spherical polystyrene beads. The nanometric size range of the particle

is retained even after 100 times dilution with water which proves the system’s compatibility with

excess water.



F) Refractive Index and Percent Transmittance

Refractive index and percent transmittance proved the transparency of formulation. The refractive

index of the system is measured by refractometer by putting a drop of solution on slide and

comparing it with water (1.333). The percent transmittance of the system is measured at particular

wavelength using UV-spectrophotometer by using distilled water as blank. If refractive index of

system is similar to the refractive index of water (1.333) and formulation have percent transmittance

> 99 percent, then formulation have transparent nature.

G) Electro Conductivity Study

The SEDD system contains ionic or non-ionic surfactant, oil, and water. This test is performed for

measurement of the electro conductive nature of system. The electro conductivity of resultant system

is measured by electro conductometer. In conventional SEDDSs, the charge on an oil droplet is

negative due to presence of free fatty acids.

H) In vitro Diffusion Study

In vitro diffusion studies are carried out to study the drug release behavior of formulation from liquid

crystalline phase around the droplet using dialysis technique.

I) Drug Content

Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the

solvent extract was analyzed by suitable analytical method against the standard solvent solution of

drug.

BIOPHARMACEUTICAL ASPECTS30

The ability of lipids and/or food to enhance the bioavailability of poorly water soluble drugs is well

known. Although incompletely understood, the currently accepted view is that lipids may enhance

bioavailability via a number of potential mechanisms, including:

1. Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption site and

increasing the time available for dissolution.

2. Increases in effective luminal drug solubility. The presence of lipids in the GI tract stimulates

an increase in the secretion of bile salts (BS) and endogenous biliary lipids including

phospholipids (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal

mixed micelles and an increase in the solubilisation capacity of the GI tract. However,

intercalation of administered (exogenous) lipids into these BS structures either directly (if

sufficiently polar), or secondary to digestion, leads to swelling of the micelle structures and a

further increase in solubilisation capacity.



3. Stimulation of intestinal lymphatic transport. For highly lipophilic drugs, lipids may enhance

the extent of lymphatic transport and increase bioavailability directly or indirectly via a

reduction in first-pass metabolism.

4. Changes in the biochemical barrier function of the GI tract. It is clear that certain lipids and

surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the p-

glycoprotein efflux pump, and may also reduce the extent of enterocyte based metabolism.

5. Changes in the physical barrier function of the GI tract. Various combinations of lipids, lipid

digestion products and surfactants have been shown to have permeability enhancing

properties. For the most part, however, passive intestinal permeability is not thought to be a

major barrier to the bioavailability of the majority of poorly water-soluble, and in particular,

lipophilic drugs.

RECENT ADVANCEMENTS IN SEDDS

Self-emulsifying sustained/controlled-release tablets

Combinations of lipids and surfactants have presented great potential of preparing self-emulsifying

tablets that have been widely researched. After evaluation the effect of some processing parameters

(colloidal silicates X1, magnesium stearate mixing time X2, and compression force X3) on hardness

and coenzyme Q10 (CoQ10) dissolution from tablets of eutectic-based SMEDDS. The optimized

conditions (X1 = 1.06%, X2 = 2 min, X3 = 1670 kg) were achieved by a face-centered cubic design31

.

In order to reduce significantly the amount of solidifying excipients required for transformation of

SEDDS into solid dosage forms, a gelled SEDDS has been developed by Patil et al. In their study,

colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the oil-based systems,

which served the dual purpose of reducing the amount of required solidifying excipeints and aiding

in slowing down of the drug release32

.

Self-emulsifying capsules:

After administration of capsules containing conventional liquid SE formulations, micro emulsion

droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if

irreversible phase separation of the micro emulsion occurs, an improvement of drug absorption

cannot be expected. For handling this problem, sodium dodecyl sulfate was added into the SE

formulation33

. With the similar purpose, the super saturatable SEDDS was designed, using a small

quantity of hydroxyl propyl methyl cellulose (HPMC) (or other polymers) in the formulation to

prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. This

system contains a reduced amount of a surfactant, thereby minimizing GI side effects34-35

. The



SEDDS formulations, empty soft gelatin capsules were filled with the formulation using a syringe

and sealed with hot gelatin. Besides liquid filling, liquid self emulsifying ingredients also can be

filled into capsules in a solid or semisolid state obtained by adding solid carriers.

Self-emulsifying nanoparticle:

Nanoparticle technology can be applied to the formulation of self emulsifying nanoparticles. Solvent

injection is one of these techniques. In this method, the lipid, surfactant and drugs were melted

together . This lipid molten mass was injected drop wise into a non solvent system. This is filtered

and dried to get nanoparticles. By this method 100 nm size particle with 70-75% drug loading

efficiency was obtained36

.

Second technique is sonication emulsion diffusion evaporation; by this method co-load 5-flurouracil

and antisense EGFR (epidermal growth factor receptor) plasmids into biodegradable PLGA/O-CMC

nanoparticles. The mixture of PLGA (poly-lactide-coglycolide) and O-CMC (O-carboxmethyl-

chitosan) had a SE effect, with no additional surfactant required37

.

Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and

glyceryl monooleate (GMO) for the delivery of paclitaxel (PTX). These chitosan/ GMO

nanoparticles, with bioadhesive properties increased cellular association and was prepared by

multiple emulsion (o/w/o) solvent evaporation methods38

.

Self-emulsifying sustained/controlled-release pellets

To formulate and prepare SEDDS, there were some basic guidelines needed to conform: safety,

compatibility, drug solubility, efficient self-emulsification efficiency and droplet size, etc.39

. Pellets,

as a multiple unit dosage form, possess many advantages over conventional solid dosage forms, such

as flexibility of manufacture, reduction of intrasubject and intersubject variability of plasma profiles

and minimizing GI irritation without lowering drug bioavailability. Thus, it seems very appealing to

combine the advantages of pellets with those of SEDDS by SE pellets. Spherical pellets with low

friability and self-emulsifying properties can be produced by the standard extrusion/spheronization

technique. The pellets are capable of transferring lipophilic compounds into the aqueous phase and

have a high potential to increase the bioavailability of lipophilic drugs40

.

M. Serratoni et al. presented controlled drug release from self-emulsifying pellets. The prepared self

emulsifying system were formed by mixing oilsurfactant within solublised drug in appropriate

concentrations, because higher quantity of drug incorporated into SES, could be precipitated when

diluted with water. This SES was added into damp mass of microcrystalline cellulose and lactose

monohydrate, water was then added to the prepared wet mass for extrusion-spheronization to form



pellets. These pellets were coated by hydrophilic polymers namely ethyl cellulose then coated by

aqueous solution of hydroxypropylmethyl cellulose in a fluid bed coater.

The ability of this formulation to enhance dissolution of the model drug, where dissolution results

for the uncoated pellets containing methyl or propyl parabens with and without the addition of self

emulsifying system were compared41

.

Self-emulsifying microsphere:

You et al. formulated solid SE sustained-release microspheres using the quasi-emulsion solvent

diffusion method for the spherical crystallization technique. Zedoary turmeric oil release behavior

could be controlled by the ratio of hydroxypropyl methylcellulose acetate succinate to Aerosil 200 in

the formulation. The plasma concentration time profiles were achieved after oral administration of

such microspheres into rabbits, with a bioavailability of 135.6% with respect to the conventional

liquid SEDDS42

.

Self-emulsifying beads:

Self emulsifying system can be formulated as a solid dosage form by using less excipients. Patil and

Paradkar discovered that deposition of SES into the microchannels of porous polystyrene

beads(PPB) was done by solvent evaporation. Porous polystyrene beads with complex internal void

structures were typically produced by copolymerising styrene and divinyl benzene. It is inert and

stable over a wide range of pH, temperature and humidity. Geometrical features, such as bead size

and pore architecture of PPB, were found to govern the loading efficiency and in vitro drug release

from SES-loaded PPB43

.

Self-emulsifying suppositories:

Some investigators proved that Solid-SEDDS could increase not only GI adsorption but also

rectal/vaginal adsorption44

. Glycyrrhizin, which, by the oral route, barely achieves therapeutic

plasma concentrations, can obtain satisfactory therapeutic levels for chronic hepatic diseases by

either vaginal or rectal SE suppositories. The formulation included glycyrrhizin and a mixture of a

C6–C18 fatty acid glycerol ester and a C6–C18 fatty acid macrogol ester45

.

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. Serajuddin pointed out

that these difficulties could be surmounted by the use of SE excipients46-47

. SE excipients like

Gelucire 144/14 , Gelucire 150/02, Labrasol I1, Transcuto I1 and TPGS (tocopheryl polyethylene

glycol 1000 succinate) have been widely used in this field46-49

. Gupta et al. prepared SE solid



dispersion granules using the hot-melt granulation method for seven drugs, including four carboxylic

acid containing drugs, a hydroxyl-containing drug, an amide containing drug (phenacetin) and a drug

with no proton donating groups (progesterone) in which Gelucire 50/13was used as the dispersion

carrier, while Neusilin US2 was used as the surface adsorbent50

.

APPLICATIONS:

Improvement in Solubility and bioavailability:

If drug is incorporated in SEDDS, it increases the solubility because it circumvents the dissolution

step in case of Class-II drug (Low solubility/high permeability). Ketoprofen, a moderately

hydrophobic non steroidal anti-inflammatory drug (NSAID), is a drug of choice for sustained release

formulation but it has has high potential for gastric irritation during chronic therapy. Also because of

its low solubility, ketoprofen shows incomplete release from sustained release formulations. It is

reported that the complete drug release from sustained release formulations containing ketoprofen in

nano crystalline form51

.

This formulation enhanced bioavailability due to increase the solubility of drug and minimizes the

gastric irritation. Also incorporation of gelling agent in SEDDS sustained the release of Ketoprofen.

In SEDDS, the lipid matrix interacts readily with water, forming a fine particulate Oil in-water (o/w)

emulsion. The emulsion droplets will deliver the drug to the gastrointestinal mucosa in the dissolved

state readily accessible for absorption. Therefore, increase in AUC i.e. bioavailability and Cmax is

observed with many drugs when presented in SEDDS.

Protection against Biodegradation:

The ability of self emulsifying drug delivery system to reduce degradation as well as improve

absorption may be especially useful for drugs, for which both low solubility and degradation in the

GI tract contribute to a low oral bioavailability. Many drugs are degraded in physiological system,

may be because of acidic PH in stomach, enzymatic degradation or, hydrolytic degradation etc. Such

drugs when presented in the form of SEDDS can be well protected against these degradation

processes as liquid crystalline phase in SEDDS might be act as barrier between degradating

environment and the drug.

Controlling the release of drug:

Different formulation approaches that have been sought to achieve sustained release, increase the

bioavailability, and decrease the gastric irritation of ketoprofen include preparation of matrix pellets

of nano-crystalline ketoprofen, sustained release ketoprofen microparticles and floating oral

ketoprofen systems and transdermal systems of ketoprofen. Preparation and stabilization of nano-



crystalline or improved solubility forms of drug may pose processing, stability, and economic

problems. This problem can be successfully overcome when Ketoprofen is presented in SEDDS

formulation. This formulation enhanced bioavilability due to increase the solubility of drug and

minimizes the gastric irritation. Also incorporation of gelling agent in SEDDS sustained the release

of Ketoprofen9.

CONCLUSION

Self-emulsifying drug delivery system is a promising approach to improve solubility, absorption and

bioavailability of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic

drugs can be made possible by SEDDS, which have been shown to substantially improve oral

bioavailability. SEDDS has the flexibility to develop into different solid dosage form. With future

development of this technology, SEDDS will continue to enable novel applications in drug delivery

and solve deficiency associated with the delivery of poorly soluble drugs. Thus this field required

further exploration and research so as to bring out commercially available self emulsifying

formulation.

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