Journal of Pharmaceutical Research And Opinion 1:3 (2011) 80 – 84.

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JOURNAL OF PHARMACEUTICAL RESEARCH AND OPINION

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RESEARCH
SELF EMULSIFYING DRUG DELIVERY SYSTEM
Vishesh Kumar Pal*
Sir Madanlal Institute of Pharmacy Etawah, U.P.

ARTICLE INFO ABSTRACT

Received 30 June 2011 Oral route has always been preferred route for formulators and has dominated over
Accepted 17 August 2011 other routes of administrations. The major problem in oral drug formulations is low
and erratic bioavailability, which mainly results from poor aqueous solubility.
Approximately 40% of new chemical entities exhibit poor aqueous solubility and
Corresponding Author: present a major challenge to modern drug delivery system, because of their low
Vishesh Kumar Pal. bioavailability. The aim of this study was to formulate a SEDDS containing a lipophilic
[email protected] drug, loratadine, and to explore the potential of carriers for such system. Formulation
Sir Madanlal Institute of development and screening was done based on results obtained from phase diagrams
Pharmacy Etawah. U.P. and characteristics of resultant microemulsions. The optimized formulation for in
vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10
(31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%).Self micro
emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, co-
surfactant and drug with a unique ability to form fine oil in Water microemulsion
KeyWords: Self emulsifying upon mild agitation following dilution with aqueous phase. Among various approach
drug delivery system, oral selfemulsifying drug delivery system has gained more attention due to enhanced oral
bioavailability, lipid based bio-availability enabling reduction in dose, more consistent temporal profiles of drug
formulations, poorly water absorption, The particle sizes of formulations were influenced by type of oil, in the
soluble drugs. manner that liquid paraffin induced lower particle size in the range of 0.28- 1.8
micron.
©2011, JPRO, All Right Reserved.

INTRODUCTION
One of the most popular and commercially viable oil-in-water (o/w) microemulsions under gentle agitation
formulation approaches for solving these problems is self- following dilution by aqueous phases (i.e., the digestive
emulsifying drug delivery systems (SEDDS). The basic motility of the stomach and intestine provide the agitation
difference between self emulsifying drug delivery systems required for self-emulsifi cation in vivo in the lumen of the
(SEDDS) also called as self emulsifying oil formulation gut) SEDDS are isotropic mixtures of drug, oil/lipid,
(SEOF) and SMEDDS is SEDDS typically produce opaque surfactant, and/ or cosurfactant, which form fine
emulsions with a droplet size between 100 and 300 nm emulsion/lipid droplets, ranging in size from
while SMEDDS form transparent micro emulsions with a approximately 100 nm (SEDDS) to less than 50 nm for self-
droplet size of less than 50 nm also the concentration of oil micro emulsifying drug delivery systems (SMEDDS), on
in SMEDDS is less than 20 % as compared to 40-80% in dilution with physiological fluid.
SEDDS. Efficacy of lipophilic drug is often hindered due to
ADVANTAGES OF SMEDDS
their poor aqueous solubility leading to low absorption
Improvement in oral bioavailability
after in vivo administration. Self-emulsifying drug delivery
Dissolution rate dependant absorption is a major
systems (SEDDS) are mixtures of oils and surfactants,
factor that limits the Bioavailability of numerous poorly
ideally isotropic, and sometimes containing co-solvents,
water soluble drugs. The ability of SMEDDS to present the
which emulsify spontaneously to produce fine oil-in-water
drug to GIT in solubilised and micro emulsified form
emulsions when introduced into aqueous phase under
(globule size between 1- 100 nm) and subsequent increase
gentle agitation6, 7,39,40,41. Recently, SEDDS have been
in specific surface area enable more efficient drug
formulated using medium chain tri-glycoside oils and
transport through the intestinal aqueous boundary layer
nonionic surfactants, the latter being less toxic. The poorly
and through the absorptive brush border membrane
water-soluble drugs such as HIV protease inhibitors,
leading to improved bioavailability. E.g. In case of
glycoprotein inhibitors and anticancer drugs have
halofantrine approximately 6-8 fold increase in
problems to create and maintain a good solubility in
bioavailability of drug was reported in comparison to tablet
gastrointestinal tract. The process of self-emulsification
formulation. [1]
proceeds through formation of liquid crystals (LC) and gel
Dosage form development of SEDDS
phases. SMEDDS formulations are isotropic mixtures of an
Dry emulsions
oil, a surfactant, a co surfactant (or solubilizer), and a drug.
Dry emulsions are powders from which emulsion
The basic principle of this system is its ability to form fine
spontaneously occurs in vivo or when exposed to an

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aqueous solution. Dry emulsions can be useful for further appropriate dilution, a spherical droplet will be formed
preparation of tablets and capsules. Dry emulsion again (figure 1 ).
formulations are typically prepared from oil/ water (O/W) Fig. 1
emulsions containing a solid carrier (lactose, maltodextrin,
and so on) in the aqueous phase by rotary evaporation [2],
freeze-drying [3] or spray drying [4–6]. Myers and Shively
obtained solid state glass emulsions in the form of dry
‘foam’ by rotary evaporation, with heavy mineral oil and
sucrose. Such emulsifiable glasses have the advantage of
not requiring surfactant [2]. In freeze-drying, a slow
cooling rate and the addition of amorphous
cryoprotectants have the best stabilizing effects, while heat
treatment before thawing decreases the stabilizing effects
[3]. The technique of spray drying is more frequently used
in preparation of dry emulsions. The O/W emulsion was
formulated and then spray-dried to remove the aqueous
phase. The most exciting finding in this field ought to be the Representation of the of commonly encountered
newly developed enteric-coated dry emulsion formulation, phases upon addition of water to an oilsurfactant
which is potentially applicable for the oral delivery of Combination (from Jonson et al., Surfactants and Polymers
peptide and protein drugs. This formulation consisted of a in aqueous solution.Wiley, 1998.)
surfactant, a vegetable oil, and a pH-responsive polymer, MATERIALS AND METHODS: Materials
with lyophilization used [7].Recently, Cui et al. prepared Animals
dry emulsions by spreading liquid O/W emulsions on a flat Male Holtzman rats (weighing approximately 250
glass, then dried and triturated to powders ± 30 g) were used for the comparative lipid-lowering
MECHANISM OF SELF-EMULSIFICATION studies. The animals were maintained at a constant light
It is apparent from equation that the spontaneous (14L: 10D), temperature (24°C-25°C), and humidity (60%)
formation of the interface Between the oil and water and were supplied with food and water ad libitum. The
phases is energetically not favored. However, according to animal requirement was approved by the Institute Animal
Reiss 48, self-emulsification occurs when the entropy Ethics Committee IAEC), and all experiments were
change that favors dispersion is greater than the energy conducted as per the norms of the Committee for the
required to increase the surface area of the dispersion. In Purpose of Supervision of Experiments on Animals, India.
addition, the free energy of a conventional emulsion Fenofi brate was obtained as a gift sample from Cipla Ltd
formation is a direct function of the energy required to (Mumbai, India). Loratadine was purchased from Hakim
create a new surface between the two phases and can be Pharmaceutical Co. (Tehran, Iran). Labrafil, Capryol PG,
described by equation48 Where, G is the free energy Transcutol and Labrasol were gift from Gattefosse
associated with the process (ignoring the free energy of (Gattefosse Corp., Saint-Priest, France) and Span 20 from
mixing), N is the number of droplets of radius, r, and s Merck (Germany). Dialysis bag was purchased from Toba
represents the interfacial energy. With time, the two phases Azema Co, Tehran (Iran). Minitab14 software was used for
of the emulsion will tend to separate, in order to reduce the experimental design and the evaluation of the effect of
interfacial area, and subsequently, the free energy of the variables on responses. Cremophor RH 40 (polyoxyl 40
systems. Therefore, the emulsions resulting from aqueous hydrogenated castor oil), Cremophor EL (polyethoxylated
dilution are stabilized by conventional emulsifying agents, castor oil), and Solutol HS 15 (polyoxyethylene esters of 12
which Form a monolayer around the emulsion droplets, hydroxystearic acid) were obtained from BASF (Mumbai).
and hence, reduce the interfacial energy, as well as Gelucire 44/14 (PEG-32 glyceryl laurate) and 50/13 (PEG-
providing a barrier to coalescence. In the case of self- 32 glyceryl palmistearate) were received from Colorcon
emulsifying systems, the free energy required to form the Asia (Mumbai). Span 20 (sorbitan monolaurate), Tween 80
emulsion is either very low and positive, or negative (then, (polyoxyethylene sorbitan monooleate), and PEG 400 were
the emulsification process occurs spontaneously). bought from Merck (Mumbai, India). Deionized water was
Emulsification requiring very little input energy involves prepared by a Milli-Q purifi cation system from Millipore
destabilization through contraction of local interfacial (Molsheim, France). Acetonitrile and methanol used in the
regions. present study were of high performance liquid
chromatography (HPLC) grade. All other chemicals were
reagent grade. Empty hard gelatin capsule shells were
generously donated by ACG Capsules (Mumbai)
In emulsification process the free energy (ΔG)
METHODS
associated is given by the equation In which ‘N’ is Number
Formulation of Self emulsifying drug delivery system
of droplets with radius ‘r’ and ‘σ’ is interfacial energy.
(SEDDS)
Dilution phases Various amount of comprising materials either of
Upon dilution of a SMEDDS formulation, the surfactant, co-surfactant, oil and transcutol P (liquid) as
spontaneous curvature of the Surfactant layer changes via a solubilizer, were formulated by admixing the components
number of possible liquid crystalline phases. The droplet (Table 1). Then loratadine with defined amount added to
structure can pass from a reversed spherical droplet to a the mixture, shake well and then kept at 40 ° C for a time
reversed rod-shaped droplet, hexagonal phase, lamellar period necessary to solve the drug. We used two-phase
phase, cubic phase and various other structures until, after include liquid paraffin oil and Labrafil (liquid). Thus, two

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series of formula was obtained, which in both surfactant formation of self-micro emulsifying formulations
Span 20 and co-surfactant Capriol (liquid) were used. (SMEDDS)40,64,65,66. Formulations consisting only of the
surfactant mixture may form emulsions or microemulsions
EXCIPIENTS USED IN SEDDS
(when surfactants exhibit different low and high HLB) 43,
Oils:
micelle solution or, in some particular cases, niosomes,
Both long- and medium-chain triglyceride (MCT)
which are non-ionic, surfactant-based bilayer vehicles67.
oils with different degrees of saturation have been used for
the design of self-dispersing formulations. Unmodified Co-solvents
edibleoils provide the most `natural' basis for lipid vehicles, Relatively high surfactant concentrations (usually
but their poor ability to dissolve large amounts of more than 30% w/w) are needed in order to produce an
hydrophobic drugs and their relative difficulty in efficient effective self-emulsifying system. Organic solvents, suitable
self-emulsification markedly reduce their use in SEDDS.In for oral administration (ethanol, propylene glycol (PG),
contrast, modified or hydrolyzed vegetable oils have polyethylene glycol (PEG), etc.) may help to dissolve large
contributed widely to the success of the above systems40, amounts of either the hydrophilic surfactant or the drug in
57, 58. Since they exhibit formulative and physiological the lipid base. These solvents
advantages. These excipients form good emulsification Characterization of particle size
systems, with a large number of non-ionic surfactants Thus, 1 mL of formulated solution was added to
approved for oral administration, while their degradation 100 mL of 0.1N hydrochloric acid, and then the particle size
products resemble the end products of intestinal digestion. was measured using particle size analyzer. The mean
MCTs were preferred in the earlier self-emulsifying particle diameter and polydispersity index (PDI) of
formulations39,59. Because of higher Fluidity, better dispersions were calculated by laser light diffractometry,
solubility properties and self-emulsification ability, but using Malvern Master Sizer SM 2000K (High Performance
evidently, they are considered less attractive compared to Particle Sizer; Malvern Instruments Ltd., Malvern, United
the novel semi-synthetic medium chain derivatives40 Kingdom).
which can be defined rather as amphiphilic compounds
Exhibiting surfactant properties. In such cases, the more EVALUATION
lipophilic surfactant may play the role of the hydrophilic oil Thermodynamic stability studies: The physical stability
in the formulation40,43. Solvent capacity for less of a lipid –based formulation is also crucial to its
Hydrophobic drugs can be improved by blending performance, which can be adversely affected by
triglycerides with mono- and di glycerides.45 precipitation of the drug in the excipient matrix. In
Surfactants addition, poor formulation physical stability can lead to
Non-ionic surfactants with a relatively high phase separation of the excipient, affecting not only
hydrophilic± lipophilic balance (HLB) were advocated for formulation performance, but visual appearance as well. In
the design of self-dispersing systems, where the various addition, incompatibilities between the formulation and
liquid or solid ethoxylated polyglycolyzed glycerides and the gelatin capsules shell can lead to brittleness or
polyoxyethylene 20 oleate (Tween 80) are the most deformation, delayed disintegration, or incomplete release
frequently used excipients. Emulsifiers derived from of drug. 1. Heating cooling cycle: Six cycles between
natural sources are expected to be safer than synthetic refrigerator temperature (40C) and 450C with storage at
ones and are recommended for SDLF (self dispersed lipid each temperature of not less than 48 h is studied. Those
formulation) use40,58,60,61, despite their limited ability to formulations, which are stable at these temperatures, are
self-emulsify. Non-ionic surfactants are known to be less subjected to centrifugation test.
toxic compared to ionic surface-active agents, but they may Centrifugation: Passed formulations are centrifuged thaw
cause moderate reversible changes in intestinal wall cycles between 21 0C and +25 0C with storage at each
permeability6, 62. Amemiya et al. proposed a new vehicle temperature for not less than 48 h is done at 3500 rpm for
based on a fine emulsion using minimal surfactant content 30 min. Those formulations that does not show any phase
(3%) to avoid the potential toxicological problems separation are taken for the freeze thaw stress test.
associated with high surfactant concentration 63. The usual Freeze thaw cycle: Three freeze for the formulations.
surfactant concentration in self-emulsifying formulations Those formulations passed this test showed good stability
required to form and maintain an emulsion state in the GI with no phase separation, creaming, or cracking. 68
tract ranged from 30 to 60% w/w of the formulation. A
large quantity of surfactant may irritate the GI tract. Thus, Dispersibility test
the safety aspect of the surfactant vehicle should be The efficiency of self-emulsification of oral nano or micro
carefully considered in each case. The high HLB and emulsion is assessed using a standard USP XXII dissolution
subsequent hydrophilicity of surfactants is necessary for apparatus 2. One milliliter of each formulation was added
the immediate formation of o/w droplets and/or rapid to 500 mL of water at 37 ± 0.5 0C. A standard stainless steel
spreading of the formulation in the aqueous environment, dissolution paddle rotating at 50 rpm provided gentle
providing a good dispersing/selfemulsifying performance. agitation. The in vitro performance of the formulations is
The surfaceactive agents are amphiphilic by nature, and visually assessed using the following grading system:
they are therefore usually able to dissolve and even Grade A: Rapidly forming (within 1 min) nanoemulsion,
solubilize relatively high quantities of the hydrophobic having a clear or bluish appearance.
drug. The latter is of prime importance for preventing Grade B: Rapidly forming, slightly less clear
precipitation within the GI lumen and for the prolonged emulsion,having a bluish white appearance.
existence of the drug molecules in soluble form, which is Grade C: Fine milky emulsion that formed within 2 min.
vital for effective absorption 59. The lipid mixtures with Grade D: Dull, grayish white emulsion having slightly oily
higher surfactant and co-surfactant/oil ratios lead to the appearance that is slow to emulsify (longer than 2 min).

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Grade E: Formulation, exhibiting either poor or minimal sought to achieve sustained release, increase the
emulsification with large oil globules present on the bioavailability, and decrease the gastric irritation of
surface. Grade A and Grade B formulation will remain as ketoprofen include preparation of matrix pellets of nano-
nanoemulsion when dispersed in GIT. While formulation crystalline ketoprofen,(8) sustained release ketoprofen
falling in Grade C could be recommend for SEDDS microparticles(9) and formulations(9), floating oral
formulation. (18) ketoprofen systems(10), and transdermal systems of
Turbidimetric Evaluation ketoprofen(11)
Nepheloturbidimetric evaluation is done to Protection against Biodegradation:The ability of self
monitor the growth of emulsification. Fixed quantity of emulsifying drug delivery system to reduce degradation as
Selfemulsifying system is added to fixed quantity of well as improve absorption may be especially useful for
suitable medium (0.1N hydrochloric acid) under drugs, for which both low solubility and degradation in the
continuous stirring (50 rpm) on magnetic plate at ambient GI tract contribute to a low oral bioavailability. Many drugs
temperature, and the increase in turbidity is measured are degraded in physiological system, may be because of
using a turbidimeter. However, since the time required for acidic PH in stomach, enzymatic degradation or hydrolytic
complete emulsification is too short, it is not possible to degradation etc
monitor the rate of change of turbidity (rate of
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