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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:
dainkaduppil@gmail.com
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.
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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
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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.
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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.
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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
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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:
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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;
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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
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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
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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.
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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.
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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
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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
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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
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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-
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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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