Self Emulsifying Drug Delivery System: A novel approach

Abstract

Oral route is most common route of drug administration and it is the first way investigated in the development of new dosage forms. In oral drug formulations major problem arises is the low bioavailability due to poor aqueous solubility. Mostly new drug candidates have poor water solubility resulting into low bioavailability, high intra and inter-subject variability and lack of dose proportionality and therapeutic failure. It has been observed that 40% of active substances are poorly water soluble. Various techniques has been developed to enhance the solubity of such type of drugs includes micronization, solid dispersions or cyclodextrines complex formation. Self Emulsifying Drug Delivery System is a unique approach to overcome the problem of low oral bioavailability associated with the lipophillic drugs. Self Emulsifying Drug Delivery System includes the mixtures of oils and surfactants, which are ideally isotropic and sometimes containing co-solvents, which emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase under conditions of gentle agitation. The digestive motility of the stomach and intestine is sufficient to provide the agitation necessary for self-emulsification in vivo. INTRODUCTION: The oral route is the most popular route among all the route of administra-tion. Approximately 40% of new drug candidates have poorwater solubility and the oral delivery of such drugs is frequently associated with low bioavailability, high intra-and inter-subject variability, and a lack of dose proportionality. 1 .

Full text

Journal of Pharmacy Research Vol.5 Issue 1.January 2012
Vijay Sharma et al. / Journal of Pharmacy Research 2012,5(1),500-504
500-504
Review Article
ISSN: 0974-6943 Available online through
www.jpronline.info
*Corresponding author.
Vijay Sharma
Department of Pharmaceutics,
SRMSCET (Pharmacy),
Bareilly, U.P., India.
Tel.: + 91-9458702561
E-mail:vijaysrampur@gmail.com
Self Emulsifying Drug Delivery System: A novel approach
Vijay Sharma*, Pratiush Saxena, Lalit Singh, Pooja Singh
Department of Pharmaceutics, SRMSCET (Pharmacy), Bareilly, U.P., India
Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011
ABSTRACT
Oral route is most common route of drug administration and it is the first way investigated in the development of new dosage forms. In oral drug formulations
major problem arises is the low bioavailability due to poor aqueous solubility. Mostly new drug candidates have poor water solubility resulting into low
bioavailability, high intra and inter-subject variability and lack of dose proportionality and therapeutic failure. It has been observed that 40% of active
substances are poorly water soluble. Various techniques has been developed to enhance the solubity of such type of drugs includes micronization, solid
dispersions or cyclodextrines complex formation. Self Emulsifying Drug Delivery System is a unique approach to overcome the problem of low oral
bioavailability associated with the lipophillic drugs. Self Emulsifying Drug Delivery System includes the mixtures of oils and surfactants, which are ideally
isotropic and sometimes containing co-solvents, which emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase
under conditions of gentle agitation. The digestive motility of the stomach and intestine is sufficient to provide the agitation necessary for self-emulsification
in vivo.
Key words: Self-Emulsifying Drug delivery system, Bioavailability, Lipophillic drugs, surfactant, oil, co-surfactant, pseudoternary phase diagram.
INTRODUCTION:
The oral route is the most popular route among all the route of administra-
tion. Approximately 40% of new drug candidates have poorwater solubility
and the oral delivery of such drugs is frequently associated with low
bioavailability, high intra- and inter-subject variability, and a lack of dose
proportionality.1.
In oral drug formulations major problem arises is the low bioavailability due
to poor aqueous solubility. Mostly new drug candidates have poor water
solubility resulting into low bioavailability, high intra and inter-subject vari-
ability, and lack of dose proportionality and therapeutic failure. ‘Low solu-
bility/high permeability’ (BCS class II drugs), dissolution in the environmen-
tal lumen is the rate controlling step in the absorption process.2 Efforts are on
going to enhance the oral bioavailability of lipophilic drugs in order to in-
crease their clinical efficacy. Various approaches are being used for incorpo-
ration of the active lipophilic component into drug in oils3,solid dispersions
4 emulsions5, liposomes,6 use of cyclodextrins,7 coprecipitates,8
micronization,9,10, nanoparticles.11 SEDDS belong to lipid-based formula-
tions. Lipid formulations can be oils, surfactant dispersions, emulsions,
SEDDS, solid lipid nanoparticles and liposomes. SEDDS are isotropic mix-
tures of drug, oil/lipid, surfactant, and/ or cosurfactant, which form fine
emulsion/lipid droplets, ranging in size from approximately 100 nm (SEDDS)
to less than 50 nm for self-microemulsifying drug delivery systems (SEDDS),
on dilution with physiological fluid. 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 state 12.
In various approaches SEDDS have been formulated using medium chain tri-
glyceride oils and nonionic surfactants, the latter being less toxic. Upon
administration,of this systems formulation of fine emulsions (or micro-
emulsions) in gastro-intestinal tract (GIT) with mild agitation provided by
gastric mobility take place.13,14 Potential advantages of these systems include
enhanced oral bioavailability enabling reduction in dose, more consistent
temporal profiles of drug absorption, selective targeting of drug(s) toward
specific absorption window in GIT, and protection of drug(s) from the hos-
tile environment in gut.15,16
Advantage of SEDDS over simple oily solutions is larger interfacial area for
partitioning of the drug between oil and water. Thus, for lipophilic drugs with
dissolution-limited oral absorption, these systems offer an improved rate
and extent of absorption and more reproducible plasma concentration pro-
files.17
Need of SEDDS
Oral delivery of poorly water-soluble compounds is to pre-dissolve the
compound in a suitable solvent and fill the formulation into capsules. The
main benefit of this approach is that pre-dissolving the compound over-
comes the initial rate limiting step of particulate dissolution in the aqueous
environment within the GI tract. However, a potential problem is that the
drug may precipitate out of solution when the formulation disperses in the
GI tract, particularly if a hydrophilic solvent is used (e.g. polyethylene
glycol). If the drug can be dissolved in a lipid vehicle there is less potential for
precipitation on dilution in the GI tract, as partitioning kinetics will favor the
drug remaining in the lipid droplets.2
In various strategies for poorly soluble drugs one is to formulate in a solid
solution using a water-soluble polymer to aid solubility of the drug com-
pound. For example, solid dispersion technique involving polyvinylpyrroli-
done (PVP) and polyethylene glycol (PEG 6000) for preparing solid solu-
tions with poorly soluble drugs. Major problem with this type of formula-
tion is that the drug may favor a more thermodynamically stable state, which
result in the crystallization of compound in the polymer matrix. Therefore
the physical stability of such formulations needs to be assessed using differ-
ential scanning calorimetry (DSC) or X-ray crystallography techniques. For
this type of case SEDD system becomes a good option.
Potential advantages of these systems include;
1. Reduction in dose due to enhanced oral bioavailability,

Journal of Pharmacy Research Vol.5 Issue 1.January 2012
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500-504
2. More consistent temporal profiles of drug absorption,
3. Selective targeting of drug(s) toward specific absorption window in GIT,
4. Protection of drug(s) from the hostile environment in gut.
5. Control of delivery profiles.
6. Reduced variability including food effects.
7. Protective of sensitive drug substances.
8. Increased drug loading capacity.
9. Liquid or solid dosage forms.
DISADVANTAGES OF SEDDS
1. Lack of good predicative in vitro models for assessment of the
formulations.
2. Traditional dissolution methods do not work, because formula-
tions dependent on digestion prior to release of the drug.
3. in vitro model needs further development and validation.
4. Different prototype lipid based formulations needs to be devel-
oped and tested in vivo.
5. Chemical instabilities of drugs and high surfactant concentrations
in formulations (approximately 30-60%) may irritate GIT.
6. volatile co solvents may migrate into the shells of soft or hard
gelatin capsules, resulting in the precipitation of the lipophilic
drugs.
Excipients used
Pharmaceutical acceptability of excipients and the toxicity issues of the
components is critical for the selection of excipients. Self emulsification
process is depends opn the nature of the oil/surfactant pair; the surfactant
concentration and oil/surfactant ratio; the concentration and nature of co-
surfactant and surfactant/co-surfactant ratio and the temperature at which
non-ionic surfactants due to relatively high hydrophilic-lipophilic balance
(HLB) is the first choice in the formulation. The commonly used emulsifiers
are various solid or liquid ethoxylated polyglycolyzed glycerides and
polyoxyethylene 20 oleate. Emulsifiers of natural origin are preferred since
they are considered to be safer than the synthetic surfactants. 27 Ethoxylated
polyglycolysed glycerides, Tween 80, and other long chain alkyl sulfonate
sulfatesurfactants (sodium dodecyl benzene sulfonate, sodium lauryl sul-
fate, dialkyl sulfo succinate) and quaternary ammonium salts, fatty alcohols
(lauryl, cetyl and stearyl, glyceryl esters, fatty acid esters and
polyoxyethylene) derivatives are also employed.However, these surfactants
have a limited self-emulsification capacity. Non-ionic surfactants are less
toxic than ionic surfactants but they may lead to reversible changes in the
permeability of the intestinal lumen. 28 The lipid mixtures with higher surfac-
tant and co-surfactant/oil ratios lead to the formation of SEDDS. 29 Non-
ionic surfactants are known to be less toxic compared to ionic surface-active
agents, but they may cause moderate reversible changes in intestinal wall
permeability.30The concentration of the surfactant may affect the droplet
size. In some cases it is observed that increasing the surfactant concentration
may lead to droplets with smaller mean droplet size, this can be explained by
the stabilization of the oil droplets as a result of the localization of the
surfactant molecules at the oil-water interface. 31 while on the other hand, in
some cases the mean droplet size may increase with increasing surfactant
concentrations. 32 This phenomenon could be attributed to the interfacial
disruption elicited by enhanced water penetration into the oil droplets medi-
ated by the increased surfactant concentration and leading to ejection of oil
droplets into the aqueous phase.The usual surfactant concentration in SEDDS
required forming and maintaining a emulsion state in the GI tract ranged from
30 to 60 % w/w of the formulation.33 it is essential to investigate the effect
of formulation and surfactant concentration on gastrointestinal mucosa.
Cosolvents
For effective self-emulsifying system a relatively high surfactant concentra-
tions (usually more than 30% w/w) of cosolvents are needed. Organic sol-
vents such as ethanol, propylene glycol (PG), polyethylene glycol (PEG),
etc. are used to dissolve larger amounts of either the hydrophilic surfactant or
the drug in the lipid base. These solvents play major role of the co-surfactant
in the self emulsion systems. Organic solvents are suitable for oral adminis-
tration are ethanol, propylene glycol, and polyethylene glycol, which may
help to dissolve large amounts of hydrophilic surfactant or drug in liquid
base. 34 Addition of an aqueous solvent such as Triacetin, (an acetylated
derivative of glycerol) for example glyceryl triacetate or other suitable sol-
vents act as co-solvents. Triacetin is suitable since it is miscible in the oil
lipid phases and it can be used to solubilize a hydrophobic drug. 35
Mechanism of self emulsification
Different approaches have been reported in the literature. No single theory
explains all aspects of microemulsion formation. Schulman et al. 36 Forma-
tion of emulsion droplets was due to the formation of a complex film at the
oil-water interface by the surfactant and co-surfactant. According to theory
of thermodynamic, emulsification takes place due to the entropy change that
favours dispersion is greater than the free energy required to increase the
oil
The oil is one of the most important excipients because it can solubilize the
required dose of the lipophilic drug or facilitate self emulsification as well as
increases the fraction of lipophilic drug transported via the intestinal lym-
phatic system, thereby increasingabsorption from the GI tract depending on
the molecular nature of the triglyceride.20Unmodified edible oils are not
preffered over Modified or hydrolyzed vegetable oils because of their poor
ability to dissolve large amounts of hydrophobic drugs and their relative
difficulty in efficient self-micro emulsification. Modified or hydrolyzed veg-
etable oils are widel yused to formulate SEDDS owing to their
biocompatibility.21 Long and medium chain triglyceride oils are commonly
used for the design of self-emulsifying formulations due to different degrees
of saturation since these excipients form good emulsification systems with a
large number of surfactants to exhibit better drug solubility properties. 22
Recently novel semi synthetic medium chaintriglycerides containing com-
pound such as GELUCIRE has replaced the medium chain triglycerides.
Because of higher fluidity these excipients, better solubilising potential and
self-microemulsification ability form a good emulsification systems,. Other
suitable oil phases are digestible or non- digestible oils and fats such as olive
oil, corn oil, soya bean oil, palm oil and animal fats. 23 It has reported that
more lipophilic surfactant may play the role of the hydrophilic oil in the
formulation24,25. Solvent capacity for less hydrophobic drugs can be im-
proved by blending triglycerides with mono- and di-glycerides.26
Surfactants
Several surfactants are employed for the design of self-emulsifying systems,
but the choice is limited as very few surfactants are orally acceptable. The
self-micro emulsification occurs.18,19 In self emulsified drug delivery system
the specific combinations of pharmaceutical excipients play a major role.
The formulated Self-Micro Emulsifying Drug Delivery Systems is specific
to that particular drug only.
δG =ΣN4πr2ρ
δG the change in free energy (ignoring the free energy of the mixing), N is the
number of droplets of radius r whereas s is the interfacial energy.
The two phases of emulsion tend to be separate with respect of time in order
to reduce the interfacial area, and due to this the emulsion is stabilized by
emulsifying agents and form a monolayer of emulsion droplets and ulti-
mately reduces the interfacial energy which act as a barrier around the oil
droplets to prevent coalescence.38
surface area between the oil and aqueous phases of the dispersion. Process of
emulsification involves the change in free energy (δG) can be expressed by37

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BIOPHARMACEUTICAL ASPECTS
It is well known that bioavailability of poorly water soluble drugs can be
enhanced by using lipids or food. A number of potential mechanisms are
available by which lipids may enhance bioavailability are
a) Slower delivery to the absorption site and increasing the time available for
dissolution by reducing gastric transit. 39
b) By Increasing effective luminal drug solubility. Lipids in the GI tract
stimulates the secretion of bile salts and endogenous biliary lipids including
phospholipids and cholesterol causing increase in the solubilization capacity
of the GI tract. However, intercalation of administered (exogenous) lipids
into these bile salts structures either directly (if sufficiently polar), or sec-
ondary to digestion, leads to swelling of the micellar structures and a further
increase in solubilization capacity.39
c) Stimulation of intestinal lymphatic transport. The lymphatic transport
and increase bioavailability of highly lipophilic drugs may be enhanced by
the lipids, which may be directly or indirectly via a reduction in first-pass
metabolism. Whereas, a hydrophilic drug absorbs less through the lymphatic
(chylomicron) and instead may diffuse directly in to the portal supply.
Hence in this case, emulsions provide increased dissolution from the large
surface area which may be important contributing factor in enhancing ab-
sorption of drugs. 40
d) Changes in the biochemical barrier function of the GI tract. Some lipids
and surfactants may effect the activity of intestinal efflux transporters, as
indicated by the glycoprotein efflux pump, and thus reduce the extent of
enterocyte based metabolism. 40
Formulation
The formulation of a self-emulsifying drug delivery system with a view for
increasing the bioavailability of a drug and/or pharmaceutical ingredient by
emulsifying the drug with the self-emulsifying excipient includes various
steps as described below 41
1. Preparation of phase diagram 42
2. Poorly water-soluble drug and/or pharmaceutical ingredient is
solubilised in a mixture of surfactant, co-surfactant and solvent.
The oil phase prepared is mixed with the solubilized drug formu-
lation and if necessary, by heating or other preparatory means
3. The emulsion thus obtained can then be added to a suitable dosage
form such as soft or hard-filled gelatin capsules and allowed to
cool.
Formulation techniques
Capsule Filling with liquid and semisolid self-emulsifying Formulations
Capsule filling is the most common and simplest and technology used for
encapsulating liquid or semisolid self-emulsifying formulations for the oral
route. Semisolid self-emulsifying formulations encapsulation includes four
steps:
(i) heating of the semisolid excipient to at least 208oC above its
melting point;
(ii) with continuous stirring active substance is incorporated into
melt.
(iii) molten mixture is then filled into capsules.
(iv) Lastly, cooling to room temperature.
Whereas for liquid formulations, it involves a two-step process:
1. filling of the formulation into the capsules, and
2. sealing of the body and cap of the capsule, either by banding
or by microspray sealing 43
In addition an advanced technology called liquid-Oros technology (Alza
Corporation) has been designed. It is based on the principle of osmosis and
therefore is a liquid self emulsifying formulation system. In this system
osmotic layer expands after coming into contact with water and drug is
pumped through an orifice in the hard or soft capsule.44,45
Spray drying
In this technique, formulation is prepard by mixing lipids, drug, surfactants,
solid carriers, and solubilization of the mixture before spray drying. The
liquid formulation is then atomized into a spray of droplets. These droplets
are introduced into a drying chamber, the volatile phase (e.g. the water con-
tained in an emulsion) evaporates, resulting in the formation of dry particles
under controlled temperature and airflow conditions. The particles thus ob-
tained can be prepared into tablets or capsules. The selection of atomizer,
temperature, airflow and drying chamber design is based on the characteriza-
tion of the product and powder specification
Adsorption to solid carriers
Solid carriers are used to adsorb liquid self-emulsifying formulations to get
free flowing powders. In this process liquid formulation is added on the
carrier in a blender and mixed. The powder obtained may then be filled
directly into capsules or, alternatively, may be mixed with suitable excipients
to form tablets by compression. The most important significance of this
method is that it gives good content uniformity. SEDDS can be adsorbed at
high levels (up to 70% (w/w)) onto suitable carriers 46
Solid carriers can be microporous inorganic substances, cross-linked poly-
mers, high surface-area colloidal inorganic adsorbent substances or nanoparticle
adsorbents, for example, silica, silicates, magnesium trisilicate, crospovidone,
cross-linked sodium carboxymethyl cellulose, magnesium hydroxide, talcum
and crosslinked polymethyl methacrylate.47 Cross-linked polymers are used
to create a favorable environment to sustain drug dissolution. 48 Porous
silicon dioxide (Sylysia 550), carbonnanotubes, carbon nanohorns, fullerene,
charcoal and bamboocharcoal are the adsorbents involved in Nanoparticle.49
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 tem-
peratures. As a ‘one-step’ operation, melt granulation having several advan-
tages as compared to conventional wet granulation, since the liquid addition
and the subsequent drying phase are omitted. The granulation process can be
control by several parameters such as impeller speed, mixing time, binder
particle size, and the viscosity of the binder.
A wide range of solid and semisolid lipids can be applied as meltable binders.,
Gelucire1 derived from the mixtures of mono-/di-/tri-glycerides and polyeth-
ylene glycols (PEG) esters of fatty acids, is having ablity to further increase
the dissolution rate as compared to PEG usually used. 50 Other lipid-based
excipients evaluated for melt granulation to create solid SEDDS include leci-
thin, partial glycerides, or polysorbates. The melt granulation process was
usually used for adsorbing SES (lipids, surfactants, and drugs) onto solid
neutral carriers (mainly silica and magnesium aluminometa silicate) 51,52
Melt extrusion/extrusion spheronization
Melt extrusion is a solvent-free process used for high drug loading (60%) 54
as well as content uniformity. Extrusion is a procedure of converting a raw
material with plastic properties into a product of uniform shape and density,
by forcing it through a die under controlled temperature, product flow, and
pressure conditions.55 The size of the extruder aperture will determine the
approximate size of the resulting spheroids. In recent most of the pharma-
ceutical industry involves extrusion–spheronization process to make uni-

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formly sized spheroids (pellets).The extrusion–spheronization process in-
volves various steps such as dry mixing of the active ingredients and excipi-
ents to achieve a momogenious powder, wet massing with binder; extrusion
into a spaghetti-like extrudate, spheronization from the extrudate to sphe-
roids of uniform size; drying, sifting to achieve the desired size distribution
and coating. Generally, it is seen that the higher the water level, the longer the
disintegration time.56 The rheological properties of wet masses may be
measured by an extrusion capillary. It has been shown that SEDDS contain-
ing wet mass with a wide range of rheological characteristics can be pro-
cessed, but a single rheological parameter cannot be used to provide complete
characterization of how well it can be processed by extrusion–
spheronization57.
EVALUATION OF SEDDS
1. Visual assessment may provide important information about the
self-emulsifying property of the SEDDS as well as about the re-
sulting dispersion.13,58,59 Efficiency of the self-emulsification can
be estimation by evaluating the rate of emulsification and particle
size distribution.60 Turbidity measurement is also used to identify
efficient self-emulsifying can be done to establish whether the
dispersion has reached equilibrium rapidly and in reproducible
time.13
2. Droplet polarity and droplet size are also an important emulsion
characteristics. Polarity of oil droplets is governed by the HLB
value of oil, chain length and degree of unsaturation of the fatty
acids, the molecular weight of the hydrophilic portion and concen-
tration of the emulsifier. Small droplets with appropriate polarity
(lower partition coefficient o/w of the drug) permit acceptable rate
of release of the drug. Estimation of polarity of the oil droplets is
done by the oil/water partition coefficient of the lipophillic drug. 61
3. Size of the emulsion droplet is also a factor to characterize the
self-emulsification / dispersion performance, since it determine the
rate and extent of drug release and absorption.26,51 The Coulter
nano-sizer can be used to provide comparative measure of mean
particle size for such system. This instrument detects dynamic
changes in laser light scattering intensity due to particle oscillates
due to Brownian movement. This technique is used when particle
size range is less than 3µm, size range for SEDDS is 10 to 200
nm.13
4. For sustained release characteristic, dissolution study will be done
for SEDDS. Drugs known to be insoluble at acidic pH can be made
fully available when it is incorporated in SEDDS. 62
CONCLUSION
Self Emulsifying Drug Delivery Systems is an unique approach used to
overcome the problem of the lipophillic drugs having poor oral bioavailability.
SEDDS can be a mile stone in the world of pharmacy for this type of drug.
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Source of support: Nil, Conflict of interest: None Declared