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Critical Reviews™ in Therapeutic Drug Carrier Systems, 26(5), 427–521 (2009)

Self-Emulsifying Drug Delivery Systems


(SEDDS): Formulation Development,
Characterization, and Applications
Bhupinder Singh,*1 Shantanu Bandopadhyay,1 Rishi Kapil,1
Ramandeep Singh,2 & O.P. Katare1
1University Institute of Pharmaceutical Sciences (UGC Centre of Advanced Studies),
Panjab University, Chandigarh 160 014, India; 2Cipla R & D Center, Vikhroli (W),
Mumbai 400 083, India

*Address all correspondence to Dr. Bhupinder Singh Bhoop, Professor of Pharmaceutics &
Pharmacokinetics, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced
Studies, Dean Alumni Relations, Panjab University, Chandigarh 160 014 India; Tel.: 91-172-
2534103; Fax: 91-172-2541142; bsbhoop@yahoo.com or bsbhoop@pu.ac.in.

ABSTRACT: Self-emulsifying drug delivery systems (SEDDS) possess unparalleled


potential in improving oral bioavailability of poorly water-soluble drugs. Following
their oral administration, these systems rapidly disperse in gastrointestinal fluids,
yielding micro- or nanoemulsions containing the solubilized drug. Owing to its min-
iscule globule size, the micro/nanoemulsified drug can easily be absorbed through
lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaus-
tive and updated account of numerous literature reports and patents on diverse
types of self-emulsifying drug formulations, with emphasis on their formulation,
characterization, and systematic optimization strategies. Recent advancements in
various methodologies employed to characterize their globule size and shape, ability
to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological
characteristics, and so forth, are discussed comprehensively to guide the formula-
tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive
review offers an explicit discussion on vital applications of the SEDDS in bioavail-
ability enhancement of various drugs, outlining an overview on myriad in vitro, in
situ, and ex vivo techniques to assess the absorption and/ or permeation potential of
drugs incorporated in the SEDDS in animal and cell line models, and the subsequent
absorption pathways followed by them. In short, the current article furnishes an
updated compilation of wide-ranging information on all the requisite vistas of the
self-emulsifying formulations, thus paving the way for accelerated progress into the
SEDDS application in pharmaceutical research.

KEY WORDS: self-emulsifying formulation, bioavailability enhancement, SNEDDS,


SMEDDS, hepatic first-pass effect, lipid-based drug delivery

ABBREVIATIONS

SEDDS self-emulsifying drug-delivery S-SEDDS supersaturable SEDDS


system

0743-4863/09 $35.00
© 2009 by Begell House, Inc. www.begellhouse.com
427
B. Singh et al.

DDS drug-delivery systems PPI polymeric precipitation


inhibitor
GI gastrointestinal HPMC hydroxypropyl methylcel-
lulose
P-gp P-glycoprotein GRAS Generally Recognized as Safe
SMEDDS self-microemulsified drug DoE Design of Experiments
delivery system
SNEDDS self-nanoemulsified drug DLS dynamic light scattering
delivery system
HLB hydrophilic-lipophilic balance MCT medium-chain triglyceride
PEG polyethylene glycol LCT long-chain triglyceride

I. INTRODUCTION

Oral intake has been the most sought-after route of drug delivery
by both patients and drug manufacturers for the treatment of most
pathological states. Despite tremendous strides made in novel non-
oral drug delivery systems (DDS) to date, the majority of the drugs
available commercially are oral formulations.1 Nevertheless, with
oral delivery, over one-half of the drug compounds are diminished
in the gastrointestinal (GI) tract because of their high lipophilicity
and consequently poor aqueous solubility. Oral bioavailability of such
drugs, being primarily a function of their solubility and dissolution,2,3
tends to exhibit inadequate magnitude with high intra- and inter-
subject variability. Further, oral bioavailability also depends upon
a multitude of other drug factors such as stability in GI fluids,2,3
intestinal permeability,4 resistance to metabolism by cytochrome
P450 family of enzymes present in gut enterocytes and liver hepa-
tocytes,5,6 and interactions with efflux transporter systems such as
P-glycoprotein (P-gp).7,8 Figure 1 illustrates the mechanisms of the
physiological pathways through which the bioavailability of a drug
from the conventional formulations tends to get impeded.
Several approaches have been employed to improve the oral
bioavailability of diverse drugs during formulation. Among these,
oral lipid-based drug-delivery systems (DDS) have shown immense
potential in improving the poor and inconsistent drug absorption of
many poorly water-soluble drugs, especially following their admin-
istration after meals.9,10 These approaches include various types of
lipid suspensions, solutions, and emulsions.11-14 With applications in
specific domains, lipidic formulations have therefore gained a signifi-
cant niche in oral drug delivery systems.

428
Self-Emulsifying Drug Delivery Systems

FIGURE 1. Physiological pathways leading to reduction in drug bioavailability through


oral conventional dosage forms.

Self-emulsifying drug delivery systems (SEDDS) are relatively


newer, lipid-based technological innovations with immense promise
in enhancing the oral bioavailability of drugs. These formulations
have been shown to reduce the slow and incomplete dissolution of
a drug, facilitate the formation of its solubilized phase, increase the
extent of its transportation via the intestinal lymphatic system, and
bypass the P-gp efflux, thereby augmenting drug absorption from the
GI tract.15,16 Figure 2 illustrates the lymphatic pathways through
which these self-emulsifying formulations are known to carry the
drug from the GI mucosa to systemic circulation. Recently, there
has been a dramatic increase in the reporting of such lipid-based
formulations in both published and patent literature worldwide.17-22
A quick glance at these reports affirms both the high versatility and
success rate of the novel technology of these systems.
Self-emulsifying formulations are isotropic mixtures of drug,
lipids (natural or synthetic oils), and emulsifiers (solid or liquid),
usually with one or more hydrophilic co-solvents/co-emulsifiers.17,23
SEDDS is a broad term encompassing emulsions with a droplet size
ranging from a few nanometers to several microns. Depending upon
the size of globules, these emulsions are characterized as concen-
trated microemulsions, nanoemulsions, or pre-concentrates.24 Self-

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B. Singh et al.

FIGURE 2. The self-emulsifying formulations enhancing the oral bioavailability of drugs


through lymphatic pathways bypassing the hepatic first-pass effect.

microemulsified drug delivery system (SMEDDS) are formulations


forming transparent microemulsions with an oil droplet size ranging
between 100 and 250 nm. Self-nanoemulsified drug delivery system
(SNEDDS) is relatively a recent term indicating formulations with a
globule size less than 100 nm. Although several reviews have been
written previously on the subject,23,25-29 the diversity of SEDDS and
the number of drugs encapsulated in these carriers have since been
augmented significantly, and this calls for an updated review.

I.A. Formulation Aspects

The SEDDS formulation forms a clear dispersion instantaneously


in the GI tract that remains stable on dilution.30 Such dispersions
are either micro- or nanoemulsions, depending upon the globule size
of the SEDDS formulation. A typical SEDDS formulation basically

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Self-Emulsifying Drug Delivery Systems

constitutes apt lipidic and emulsifying excipients having an inherent


ability to solubilize the drug.31 As the release of a drug compound
from SEDDS takes place in the GI tract, the hydrophobic agent should
remain solubilized for at least the time period relevant during GI
absorption. Therefore, a typical SEDDS formulation also contains
a co-emulsifier in addition to the essential lipid and emulsifier.32-34
Figure 3 illustrates the usual methodology pathways to prepare
SEDDS formulations and the eventual formation of the micro-/nano-
emulsions following their dilution. These SEDDS have to be ultimately
formulated as an oral solution in soft gelatin capsules or as solid dos-
age forms in hard gelatin capsules, depending on the final physical
nature of the system as liquid or semisolid/solid, respectively.

FIGURE 3. Schematic flowchart on the general strategy of formulating self-emulsifying


systems and their subsequent conversion to micro/nano emulsions.

Depending upon the relative proportions of lipidic triglycerides,


water-soluble or water-insoluble surfactant emulsifiers, and hydro-
phobic co-emulsifiers or co-solvents, the SEDDS have been classified
as Type I, II, IIIA, IIIB, and IV.27 Barring Type I, which contains

431
B. Singh et al.

only mixtures of lipidic constituents, but without surfactants and co-


surfactants, all of the SEDDS formulations tend to result in globule
size in the nanometer ranges. While Type I is devoid of surfactants
and co-surfactants, all of the rest of the categories contain different
percentages of each of these constituents. Table 1 outlines the key
features of each type of SEDDS. As is evident from the table, Type I
SEDDS have been found to be of limited utility, as the rate-governing
phenomenon in determining their efficacy is lipid digestibility. This is
particularly true when Type I SEDDS employ long-chain fatty acids.
Type II to IV SEDDS are therefore better suited for the formulation
of various kinds of drugs.

1. Lipids

Lipid is an essential component of SEDDS formulations. Not only can


lipids solubilize marked amounts of lipophilic drugs and facilitate self-
emulsification, but they also have the propensity to augment the fraction
of drug transported via intestinal lymphatic system, thereby increasing
its absorption from the GI tract.35 Natural edible oils, comprised of
medium-chain triglycerides are not usually used owing to their poor
ability to dissolve large amounts of lipophilic drugs. Modified long- and
medium-chain triglyceride oils, with varying degrees of saturation or
hydrolysis, have widely been used for the design and development of
SEDDS formulations. These oils offer distinct formulative and physi-
ological advantages, as their degradation products resemble that of the
natural end-products of intestinal digestion.23,36,37 Of the vast list of
these modified triglycerides, a list of the most important hydrogenated
vegetable oils is presented in Table 2, along with their fatty acid com-
position and molecular structural features. Most of the mono-, di-, and
triglycerides and their mixtures in varying proportions, with or without
the fatty acid esters of propylene glycol, are available commercially in
the purified form. Both unsaturated and saturated fatty acids have
been widely employed in the formulation of lipidic systems. However,
the SEDDS in particular are comprised of saturated fatty acids such
as caproic, caprylic, capric, lauric, and myristic acid. One can make the
appropriate choice of these by examining their composition, potential
utilities, physical state, and hydrophilic-lipophilic balance (HLB).
Table 3 provides a comprehensive account of most of such lipidic
constituents, along with their characteristics, as gathered from various
literature resources from journals and patents.42-44 These amphiphilic
excipients are progressively and effectively replacing the conventional

432
Table 1. Composition and Salient Features of Various Types of SEDDS Formulations23,38-41

Constituents/ Type I Type II Type IIIA Type IIIB Type IV


Attributes
Triglycerides or 100% 40%–80% 40%–80% <20% --
mixed glycerides
Water-insoluble -- 20%–60% -- -- 0%–20%
surfactants
Water soluble sur- -- -- 20%–40% 20%–50% 30%–80%
factants
Hydrophilic co- -- -- 0%–40% 20%–50% 0%–50%
solvents
Particle size of Coarse 100%–250% 100%–250% 50%–100% --
dispersion (nm)
Significance of Limited importance Solvent capacity Some loss of solvent Significant phase --
aqueous dispersion unaffected capacity changes and poten-

433
tial loss of solvent
capacity
Significance of Crucial requirement Not crucial, but is Not crucial, but may Not required, but is --
digestibility likely to occur be inhibited unlikely to occur
Characteristics Non-dispersing, SEDDS without SEDDS/ SMEDDS SMEDDS with water- Oil-free formulation
requires digestion water-soluble compo- with water-soluble soluble components based on surfactants
nents components and low oil content and co-solvents
Advantages GRAS status; simple; Unlikely to lose Clear to almost clear Clear dispersion; Good solvent capac-
excellent capsule solvent capacity on dispersion; drug drug absorption with- ity for many drugs;
compatibility dispersion absorption without out digestion disperses to micellar
digestion solution
Pitfalls Formulation has Turbid oil-in-water Possible loss of sol- Likely loss of solvent Loss of solvent capacity
poor solvent capacity (o/w) dispersion vent capacity on dis- capacity on disper- on dispersion; may not
unless drug is highly persion; less easily sion be digestible
lipophilic digested
Table 2. Fatty Acid Composition (Percent) of Vital Hydrogenated Vegetable Oils and Semi-Synthetic Triglycerides
Employed in SEDDS23,39,43,44

Fatty Acid

Caproic
Caprylic
Capric
Lauric
Myristic
Myristoleic
Pentadecanoic
Palmitic
Palmitoleic
Margaric
Margaroleic
Stearic
Oleic
Ricinoleic
Linoleic
Linolenic
Ecosanoic
Ecosenoic
Ecosadienoic
Behenic
Erucic
Tetracosanoic
Melting Point
(°C)

Oil
No. of Carbons 6 8 10 12 14 14 15 16 16 17 17 18 18 18 18 18 20 20 20 22 22 24
No. of Double 0 0 0 0 0 1/9 0 0 1/ 9 0 1 0 1 1 2 3 0 1 2 0 1 0
Bonds/ Position
Sunflower oil 0.1 7 0.1 0.1 5 19 68 0.8 0.4 0.1 0.7 –18

434
Castor oil 2 1 7 87 3 –12
Corn oil 0.1 11 0.2 0.1 2 25 60 1 0.4 0.1 –10
Olive oil (virgin) 9 0.6 3 80 6 0.7 0.4 –6
Peanut oil 0.1 11 0.2 0.1 0.1 2 47 32 1 2 3 1 –5
Cottonseed oil 0.1 0.7 22 0.6 0.1 0.1 3 19 54 0.7 0.3 0.2 0–5
Canola oil 0.1 4 0.3 0.1 2 61 21 9 0.7 1 0.3 0.7 0.2 17–22
Rapeseed oil 0.1 4 0.3 1 19 14 11 0.7 7 0.7 0.5 41 1 17–22
Coconut oil 0.5 7 6 47 19 9 3 7 2 0.1 0.1 21–27
Soybean oil 0.1 11 0.1 0.1 4 23 54 8 0.3 0.3 22–31
Palm oil 0.1 1 44 0.2 0.1 4 39 10 0.4 0.3 0.1 26–30
Palm kernel oil 0.2 3 3 48 16 8 3 15 2 0.1 0.1 26–30
Cocoa butter 0.1 26 0.4 0.3 34 34 3 1 0.1 0.2 30–35
Lard 0.1 0.1 2 0.1 26 3 0.4 0.2 14 44 10 0.4 0.2 0.7 0.1 36–42
Tallow 0.1 3 0.9 0.5 24 4 2 0.8 19 43 3 0.7 0.2 0.3 40–46

Table 3. Popular Lipidic Constituents Employed in the SEDDS Formulations and Their Vital Properties23,29,42,44

Excipient Chemical Composition Trade Name (Supplier) Melting HLB* Potential Use(s)
Point (°C)
Mono-, Di-, and Triglycerides

435
Glyceryl triacetate Tri-acetic acid (2:0) ester of Captex 500 P (Abitec Co) –78 Solubilizer, vehicle
(triacetin) glycerol Triacetic (Sigma-Aldrich)
Glyceryl mono-, di- Mono-, di-, and tri-docosanoic Compritol 888 ATO (Gat- 69–74 2 Controlled release tablet,
tribehenate acid (22:0) esters of glycerol tefosse) lubricant, binder
Glyceryl tribehenate Tri-docosanoic acid (22:0) Syncrowax HR-C (Croda) 78 Suspending agent, lubri-
Tribehenin (Sigma-Aldrich) cant, binder
Glyceryl tributyrate Tri-butyric acid (4:0) ester of Tributyrin (Sigma-Aldrich) –75 Solubilizer, vehicle
glycerol
Glyceryl mono- and Mono- and di-capric acid (10:0) Capmul MCM C-10 40–41 Solubilizer, emulsifier,
dicaprate esters of glycerol (Abitec Co) coemulsifier
Glyceryl tricaprate Tri-capric acid (10:0) ester of Captex 1000 (Abitec Co) 31–32 Solubilizer, vehicle
(tricaprin) glycerol Tricaprin (Sigma-Aldrich)

Continued on page 436


Table 3. (Continued)

Glyceryl mono- and Mono- and di-caprylic acid Capmul MCM C-8 (Abitec -- -- Solubilizer, emulsifier,
dicaprylate (8:0) esters of glycerol Co) 30–34 6 coemulsifier
Imwitor 742 (Sasol) 20–25 3–4
Glyceryl tricaprylate Tri-caprylic acid (8:0) ester of Captex 8000 (Abitec Co) 9–10 Solubilizer, vehicle
(tricaprylin) glycerol Neobee 895 (Stepan)
Tricaprylin (Sigma-Aldrich)
Glyceryl mono- and Mono- and di-caprylic acid (8:0) Capmul MCM (Abitec Co) 25–30 3–4 Solubilizer, vehicle, emulsi-
dicaprylate/caprate and capric acid (10:0) esters of Imwitor 742 (Sasol) fier, co-emulsifier
glycerol
Glyceryl tricaprylate/ Tri-caprylic (8:0) and capric Migloyl 810 (Sasol) –5 1 Solubilizer, vehicle for cap-
caprate (10:0) esters of glycerol Migloyl 812N (Sasol) sule formulations
(medium-chain Neobee 1053 (Stepan)
triglycerides) Neobee M5 (Stepan)

436
Captex 300 (Abitec Co)
Captex 355 (Abitec Co)
Crodamol GTCC (Croda)
Labrafac CC (Gattefosse)
Labrafac Lipophile (Gat-
tefosse)
Estasan GT8-60 3575
(Uniqema)
Estasan GT-65 3577
(Uniqema)
Estasan GT8-70 3579
(Uniqema)
Glyceryl tricaprylate/ Tri-caprylic acid (8:0), capric Captex 350 (Abitec Co) Liquid Solubilizer, vehicle
caprate/ laurate acid (10:0) and lauric acid
(12:0) esters of glycerol
Glyceryl tricaprylate/ Tri-caprylic acid (8:0), capric Captex 810D (Abitec Co) Liquid Solubilizer
caprate/ linoleate acid (10:0) and lauric acid Miglyol 818 (Sasol)
(18:2) esters of glycerol
Glyceryl tricaprylate/ Tri-caprylic acid (8:0), capric Softisan 378 (Sasol) 39–42 Solubilizer
caprate/ stearate acid (10:0) and stearic acid
(18:0) esters of glycerol
Glyceryl tricaprylate/ Tri-caprylic acid (8:0), capric Miglyol 829 (Sasol) Liquid Solubilizer
caprate/ succinate acid (10:0) and succinic acid
esters of glycerol
Glyceryl monolaure- Mono-lauric acid (12:0) ester of Stepan GML (Stepan) 56–60 3–4 Solubilizer, emulsifier for
ate glycerol Imwitor 312 (Sasol) w/o emulsions
Glyceryl dilaurate Do-decanoic acid (12:0) diester Stepan GDL (Stepan) 30 4 Solubilizer, emulsifier
of glycerol
Glyceryl trilaurate Tri-lauric acid (12:0) ester of Dynasan 112 (Sasol) 45–47 Solubilizer, vehicle,
(trilaurin) glycerol Trilaurin (Sigma-Aldrich) lubricant, controlled

437
release agent
Glyceryl monolinole- Mono-octadecadienoic (18:2) Maisine 35-1 (Gattefosse) Liquid 3 Solubilizer, vehicle for cap-
ate acid esters of glycerol sule formulations
Glyceryl trimyristate Tri-myristic acid (14:0) esters Dynasan 114 (Sasol) 56–57 Solubilizer, vehicle,
(trimyristin) of glycerol Trimysitin (Sigma-Aldrich) lubricant, controlled
release agent
Glyceryl monoleate Mono-oleic acid (18:1) esters Capmul GMO (Abitec Co) 24 3 Emulsifier, solubilizer, wet-
of glycerol Peceol (Gattefosse) ting agent, vehicle for cap-
Drewmulse GMO (Stepan) sule formulations

Glyceryl mono- and Mono- and di-oleic acid (18:1) Capmul GMO-50 14–19 Solubilizer, emulsifier
dioleate esters of glycerol (Abitec Co)
Capmul GMO-K/
(Abitec Co)
Continued on page 438
Table 3. (Continued)

Glyceryl trioleate Tri-oleic acid (18:1) Emerest 2423 (Cogins) –4 to –5 Solubilizer, lubricant
(triolein) ester of glycerol Triolein (Sigma-Aldrich)
Glyceryl trip Tri-palmitic acid (16:0) ester of Dynasan 116 (Sasol) 66 Solubilizer, lubricant,
releasesalmitate glycerol Tripalmitin (Sigma-Aldrich) controlled
(tripalmitin)
Glyceryl palmitostea- Mixture of mono-, di, and tri- Pericol ATO 5 (Gattefosse) 53–57 2 Lubricant, controlled
rate palmitic acid (16:0) and stearic release, thickener,
acid (18:0) esters of glycerol suspending agent

Glyceryl mono- Mono stearic acid (18:0) ester Campul GMS-50K 57 3-4 Solubilizer, emulsifier, con-
stearate of glycerol (Abitec Co) trolled release,
Imwitor 491 (Sasol)
Geleol (Gattefosse)

438
Stepan GMS 63F
(Stepan)
Glyceryl distearate Octa-decanoic acid (18:0) dies- Stepan GDS 386F 54 2 Emulsifier,
terof glycerol (Stepan) co-emulsifier,
wetting agent, lubricant
Glyceryl mono-, di-, Mono-, di- and tri-stearic acid Imwitor 900 (Sasol) 54–64 3 Solubilizer, emulsifier,
and tristearate (18:0) esters of glycerol coemulsifier, lubricant
Glyceryl triundecano- Tri-undecanoic acid (11:1) Captex 8227 (Abitec Co) 25–29 Solubilizer, vehicle,
ate (triundecanoin) ester of glycerol Tri-undecanoin (Sigma- lubricant
Aldrich)
Hard fat Glycerol esters of saturated Gleurice 33/01 (Gattefosse) 33–37 1 Vehicle for capsule formula-
C8-C18 fatty acids Gleurice 33/01 (Gattefosse) 37–42 tions, controlled release
Glycerol esters of saturated Gleurice 43/01 (Gattefosse) 42–46
C12-C18 fatty acids
Mixtures of Mono-, Di-, and Triglycerides with Fatty Acid Esters of Polyethylene Glycols

PEG-4 glyceryl Caprylic acid (C8:0) and capric Labrafac HydroWL Liquid 5 Vehicle, surfactant,
caprylate/ caprate acid (C10:0) esters of glycerol 1219 (Gattefosse) solubilizer
and PEG 200
PEG-6 glyceryl Caprylic acid (C8:0) and capric Softigen 767 (Sasol) Liquid 18 Vehicle, water soluble sur-
caprylate/ caprate acid (C10:0) esters of glycerol Acconon CC-6 (Abitec factant, solubilizer,
and PEG 300 Co) coemulsifier
PEG-6 glyceryl lino- Mono-, di-, and tri-linoleic acid Labrafil M 2125 CS Liquid 3–4 Vehicle, solubilizer, vehicle
leate (C18:2) esters of glycerol and (Gattefosse) for softgels, coemulsifier,
mono and diesters of PEG 300 lipid phase or cosurfactant
in microemulsions
PEG-8 glyceryl Mono-, di- and tri-caprylic acid Labrasol (Gattefosse) Liquid 14 Vehicle, solubilizer,
caprylate/ caprate (C8:0) and capric acid (C10:0) Acconon MC-8 (Abitec Co) surfactant for
esters of glycerol and monoand microemulsions

439
di-esters of PEG 400
PEG-32 Glyceryl Mono-, di- and tri-caprylic acid Gleurice 44/14 (Gatte- 42–48 14 Solubilizer, semisolid
laureate C8:0) and capric acid (C10:0) fosse) matrix capsule vehicle,
esters of glycerol and monoand Acconon C-44/ (Abitec emulsifier for semisolid
di- fatty acid esters of PEG- Co) SMEDDS
1500; may contain some free
PEG and glycerol
PEG-32 glyceryl Mono-, di- and tri-palmitic Gleurice 50/13 46–51 13 Vehicle, solubilizer,
palmitostrearate acid (C16:0) and stearic acid (Gattefosse) emulsifier
(C18:0) esters of glycerol plus
mono- and di- fatty acid esters
of PEG-1500; may contain
some free PEG and glycerol

Continued on page 440


Table 3. (Continued)

PEG-35 castor oil Mixture of glyceryl PEG ricin- Cremophor EL (BASF) Liquid 12–14 Water soluble nonionic sur-
(polyoxyl 35 oleate (35 moles of ethylene Etocas 35 NF (Croda) factant, vehicle, solubilizer,
castor oil, USP/NF) oxide per mole of castor oil) emulsifier
with fatty acid esters of PEG,
free PEGs and ethoxylated
glycerol
PEG-40 castor oil Glyceryl PEG ricinoleate with Marlower R40 (Sasol) Liquid 13 Vehicle, solubilizer,
40 moles of ethylene oxide per emulsifier
mole of castor oil
PEG-40 hydro- Hydrogenated glyceryl PEG Cremophor RH-40 16–26 14–16 Solubilizer, water soluble
genated castor oil ricinoleate with 40 moles of (BASF) nonionic surfactant, emulsi-
ethylene oxide per mole of fier, wetting agent
castor oil

440
Polyglycerol Fatty Acid Esters

Polyglycerol-3 oleate Mono-oleic acid [18:1(9)] Caprol 3GO (Abitec Co) Liquid 6.5 Surfactant, solubilizer,
ester of a 3 glycerol unit chain vehicle, emulsifier
Polyglyceryl-3 Di-oleic acid [18:1(9)] ester of Plurol oleique Liquid 6 Surfactant, solubilizer,
dioleate a 3 glycerol unit chain CC497 (Gattefosse) vehicle, emulsifier, vehicle
for capsules
Polyglyceryl-3 Mono-stearic acid (18:0) ester Caprol 3GS (Abitec Co) Solid 7 Surfactant, solubilizer,
stearate of a 3 glycerol unit chain emulsifier
Polyglycerl-3 Di-isostearic acid (18:0) ester Plurol oleique CC 497 Liquid 6–7 Surfactant, solubilizer,
diisostearate of a 3 glycerol unit chain (Gattefosse) vehicle, emulsifier
Polyglyceryl-6 Di-oleic acid [18:1(9)] ester of Caprol MPGO (Abitec Co) Liquid 10 Surfactant, solubilizer, vehi-
dioleate a 6 glyceryl unit chain Plurol Oleique (Gattefosse) cle, emulsifier, lubricant,
crystallization inhibitor
Polyglyceryl-6 Octa-stearic acid (18:0) ester Caprol ET (Abitec Co) 38 2.5 Surfactant, solubilizer,
octastearate of 6 glycerol unit chain crystallization inhibitor
Polyglyceryl-10 Mono- and di- oleic acid Caprol PGE 860 (Abitec Liquid 11 Surfactant, solubilizer,
mono, dioleate [18:1(9)] esters of a 10 glyceryl Co) vehicle, emulsifier
unit chain

441
Polyglyceryl-10 Deca-oleic acid [18:1(9)] ester Caprol 10G10O (Abitec Liquid 3 Surfactant, solubilizer, vehi-
decaoleate of a 10 glycerol unit chain Co) cle, emulsifier, lubricant,
crystallization inhibitor
*HLB, hydrophilic-lipophilic balance
B. Singh et al.

(i.e., natural) medium-chain triglyceride oils in SEDDS systems.45


As shown in the table, the lipidic constituents in all of the SEDDS
formulations have invariably been the mono-, di-, or triglyceryl deriva-
tives with HLB values ranging between 1 and 6, and melting points
ranging between –78°C to +78°C. Apart from this, the mixtures of
mono-, di-, and triglycerides with fatty acid esters of polyethylene
glycol (PEG) having HLB values ranging between 3 and 18, have
also been employed.46 The semisynthetic derivatives are known to
form good emulsification systems when used in conjunction with a
large number of solubility-enhancing surfactants approved for oral
administration.45,47,48

2. Emulsifiers

Next to the lipids, the other most vital component of the SEDDS is
an emulsifier. An emulsifier, invariably a surfactant, is obligatory to
provide the essential emulsifying characteristics. Surfactants, being
amphiphilic in nature, can dissolve (or solubilize) relatively high
amounts of hydrophobic drug compounds. Emulsifiers from natural
sources are regarded as much safer than synthetic ones. However,
as the former possess only limited self-emulsification capacities,
these are seldom employed for the formulation of SEDDS. The twin
issues that govern the selection of a surfactant are its HLB and
safety. The HLB of a surfactant provides important information on
its potential utility in the formation of SEDDS. For imparting high
self-emulsifying properties to the SEDDS formulation, the emulsi-
fier should have a relatively high HLB (i.e., high hydrophilicity) for
immediate formation of o/w droplets, and/or rapid spreading of the
formulation in the aqueous media.26,49-51 This will keep the drug at
the site of absorption for a relatively prolonged period of time for
effective absorption, because the precipitation of drug compound
within the GI lumen can be prevented.52,53
The most widely recommended emulsifiers, which include non-
ionic surfactants with relatively high HLB values such as solid or
liquid ethoxylated polyglycolyzed glycerides, polyoxyethylene (20)
sorbitan monooleate (i.e., Tween 80), and poly(ethylene oxide)-
poly(propylene oxide), block copolymers such as Pluronic F127.54-56
Nonionic surfactants are also considered to be safer than the ionic
ones.54,57-60 Nonetheless, the former may cause reversible change(s)
in the permeability of intestinal lumen. Following the selection of
safe and effective surfactants, it becomes important to explore their

442
Self-Emulsifying Drug Delivery Systems

Table 4. Popular Emulsifiers Employed in SEDDS Formulations With Their


HLB Values23,29,39,40

Chemical Name HLB* Commercial/ Manufacturer/


Brand Name Supplier
PEG-4 lauryl ether 9.7 Brij-30 Atlas/ ICI
PEG-6 corn oil 4 Labrafil M 2125 CS Gattefosse
PEG-6 apricot kernel oil 4 Labrafil M1944CS Gattefosse
PEG-8 caprylic/capric glycerides 14 Labrasol Gattefosse
PEG-8 caprylic/capric glycerides >10 Labrafac CM 10 Gattefosse
Polyoxyethylene-polyoxypropylene 18–23 Pluronic F 127 BASF
copolymers
PEG-8 corn oil 6–7 Labrafil WL 2609 BS Gattefosse
L-a-Phosphatidylcholine 4–9 Lecithin  Alfa Aesar
PEG-20 sorbitan monooleate 15 Tween-80 Atlas/ ICI
PEG-20 sorbitan trioleate 11 Tween-85 Atlas/ ICI
PEG-20 sorbitan monolaurate 17 Tween20 Atlas/ ICI
PEG-20 sorbitan tristearate 11 Tween 65 Atlas/ ICI
PEG-25 hydrogenated castor oil 11 Simulsol 1292 Seppic
PEG-25 hydrogenated castor oil 11 Cerex ELS 250 Auschem SpA
PEG-25 trioleate 11 Tagat TO Goldschmidt
PEG-35 castor oil 12–14 Cremophor-EL BASF
Cremophor-ELP
PEG-35 hydrogenated castor oil 13 Cremophor RH40 BASF
PEG-35 castor oil 12–14 Cremophor EL BASF
Cremophor EL-P
PEG-40 hydrogenated castor oil 13 Cremophor RH40 BASF
Sorbitan monooleate 4.3 Span 80 Atlas/ ICI
(tocophersolan, D-α-tocopheryl 13 TPGS Eastman
PEG-1000 succinate)
Polyoxyl-40-hydrogenated castor 13 Cremophor RH 40 BASF
oil
Polyoxyethylene hydrogenated cas-
13 HCO-40 Nikkol
tor oil 40
Methyl-oxirane polymer with oxi-
12–18 Pluronic L-64 BASF
rane
Glyceryl monooleate 3–4 Peceol Gattefosse
Ethoxylated castor oil 12–15 Emulphor El-620 Rhodia

* HLB, hydrophilic-lipophilic balance

443
B. Singh et al.

pragmatic concentration ranges. Because at times, high amounts


of hydrophobic drugs need to be dissolved, the formulation of an
effective SEDDS usually requires quite high concentrations of an
emulsifying surfactant. For forming stable SEDDS, the surfactant
concentration usually should range between 30% and 60% w/w,
as higher concentrations may be irritating to the GI mucosa. An
inverse relationship between the droplet size and the concentration
of the surfactant has been reported.61-63 This phenomenon could be
attributed to the stabilization of the oil droplets as a consequence
of the localization of the surfactant molecules at the oil-water inter-
face. However, in some cases, the droplet size tends to augment
after attaining a critical concentration.55,64,65 This is amenable to
the interfacial disruption caused by enhanced water penetration
into the oil droplets, which is mediated by the increased surfactant
concentration, thus leading ultimately to the ejection of oil droplets
into the aqueous phase.65
Some popular emulsifier surfactants include PEG, polyoxyethylene,
ethoxyl esters, fatty acids, and lecithins. Table 4 summarizes com-
mercially available emulsifiers with high potential to be employed
in the SEDDS formulations. The majority of these are derivatives of
PEG with HLB values ranging between 4 and 14.

3. Co-solvents

Co-solvents, such as ethanol, propylene glycol, and PEG, are also


commonly required to enable the dissolution of a large quantity of
hydrophilic surfactant(s) in SEDDS. Table 5 lists co-emulsifiers/
co-solvents commonly employed in SEDDS formulations. Lipid mix-
tures with higher surfactant/oil or co-surfactant/oil ratios lead to
the formation of SMEDDS.45,66 However, co-solvents have a serious
limitation of becoming evaporated from the shells of sealed gelatin
capsules, leading eventually to the precipitation of drug inside the
shell. Newer co-solvents such as Transcutol™ and Glycofurol™ have
several stellar advantages over traditional ones, including better
stability and less volatility.67,68
Table 6 provides a list of various SEDDS formulations in commercial
circulation, along with their excipient composition, drug solubility, final
dosage form(s), and storage recommendations. Drugs of choice in such
marketed delivery systems have been poorly soluble drugs including
antiretrovirals such as lopinavir, saquinavir, ritonavir, tipranavir, and
amprenavir; immunosuppressants such as cyclosporine A; NSAIDs

444
Self-Emulsifying Drug Delivery Systems

Table 5. Popular Co-emulsifiers Employed in the SEDDS Formulations


with Their HLB Values23,29 39 40

Chemical Name HLB* Brand Name Manufacturer/


Supplier
Polyglyceryl-6 dioleate 6 Plurol Oleique CC 497 Gattefosse
Caprol® 6G20 Abitec Co
Hodag PGO-62 Calgene
Sorbitan monooleate 4.3 Span 80 Atlas/ ICI
Propylene glycol monolaurate 5 Lauroglycol 90 Gattefosse
Propylene glycol monolaurate 4 Lauroglycol FCC Gattefosse
PEG-60 hydrogenated castor oil 14 HCO-60 Nikko
Sodium lauryl sulfate 40 SLS Canadian Alcolac
Block copolymer of ethylene 12–18 Pluronic L44 BASF
oxide and propylene oxide
Diethylene glycol mono ethyl ether -- Transcutol P Gattefosse
Glyceryl caprylate 5–6 Capmul MCM-C8 ABITEC
PEG-6 apricot kernel oil 4 Labrafil 1944 Gattefosse
Di-methyl isosorbide -- Arlasolve DMI Atlas/ ICI
Methyl-oxirane polymer with 12–18 Pluronic L64 BASF
oxirane
Caprylic/ capric glycerides 5–6 Akoline MCM Aarhuskarlshamn
Polaxomer 188 29 Lutrol F 68 BASF
Diethylene glycol monoethyl -- Carbitol Dow Chemicals
ether

* HLB, hydrophilic-lipophilic balance

such as ibuprofen and indomethacin; hypolipidemic agents such as


fenofibrate; and flavonoids such as isotretinoin.

I.B. Mechanism of Self-Emulsification

The mechanism through which self-emulsification occurs has not


yet been thoroughly elucidated. Nevertheless, it has been suggested
that self-emulsification takes place when the entropy change favor-
ing dispersion is greater than the energy required to increase the
surface area of the dispersion.69,70 The free energy of a conventional
emulsion formulation is a direct function of the energy required to
create a new surface between the oil and water phases. The ther-
modynamic relationship for the net free energy change is described
by Equation 1:

445
Table 6. Key Instances of Marketed Pharmaceutical Products Formulated as Self-Emulsifying Systems18,44

Trade Name Drug Aqueous Type of Excipients Storage


(Company) Molecule Solubility Formulation
Neoral® Cyclosporine A 0.00953 mg/mL Soft gelatin capsule dl-α-tocopherol, corn oil-mono-di-tri- RT*
(Novartis) (10, 25, 50, 100 mg) glycerides, polyoxyl 40 hydrogenated
castor oil (Cremophore RH 40)
Oral solution dl-α-tocopherol, corn oil-mono-di-tri-
(100 mg/ml) glycerides, polyoxyl 40 hydrogenated
castor oil (Cremophore RH 40)
Sandimmune® Cyclosporine A Soft gelatin capsule Corn oil, polyoxyethylated linoleic RT
(Novartis) (10, 25, 50, 100 mg) glycerides (Labrafil M 2125 CS)
Oral solution Olive oil, polyoxyethylated oleic glyc-
(100 mg/ml) erides (Labrafil
M 1944 CS)
Gengraf® Cyclosporine A Soft gelatin capsule Polyoxyl 35 castor oil (Cremophor RT

446
(Abbott) (25, 100 mg) EL), polysorbate 80
Cyclosporine Cap- Cyclosporine A Soft gelatin capsule Caprylic/capric triglycerides (Labra- RT
sules® (Sidmak) (100 mg) fac), dl-α-tocopherol, glyceryl capry-
late, PEG-8 caprylic/capric glycerides
(Labrasol), PEG-35 castor oil (Cremo-
phore EL)
Kaletra® Lopinavir Lopinavir Soft gelatin capsule Oleic acid, polyoxyl 35 castor oil (Cre- 2°C–8°C, or
(Abbott) & Ritonavir (0.00192 mg/mL) lopinavir (133.3 mg) & mophor EL) RT for <2
Ritonavir ritonavir (33.3 mg) months
(0.00126 mg/mL) Oral solution Polyoxoy hydrogenated castor oil
lopinavir (Cremophor RH 40), peppermint oil
(80 mg/ml) &
ritonavir (20 mg/ml)
Norvir® Ritonavir 0.00126 mg/mL Soft gelatin capsule Oleic acid, polyoxyl 35 castor oil (Cre- 2°C–8°C, or
(Abbott) (100 mg) mophor EL) RT for <2
months
Fortovase® Saquinavir 0.00247 mg/mL Soft gelatin capsule Medium-chain mono- and diglycerides, 2°C–8°C, or
(Roche) (200 mg) dl-α-tocopherol RT for <2
months
Aptivus® Tipranavir 0.000207 mg/mL Soft gelatin capsule Polyoxyl 35 castor oil (Cremophor 2°C–8°C prior
(Boehringer Ingel- (200 mg) EL), medium-chain mono- and di- to opening the
heim) glycerides bottle, RT for
<60 d
Fenogal® Fenofibrate 0.000707 mg/mL Hard gelatin capsule Lauryl macrogol-glycerides (Gelucire RT
(Genus) (200 mg) 44/14)
Lipirex® Fenofibrate Hard gelatin capsule Lauryl macrogol-glycerides (Gelucire RT

447
(Sanofi-Aventis) 44/14), PEG 20000
Polyoxoy 60 hydrogenated castor oil RT
Infree® Soft gelatin capsule
Indomethacin 0.00240 mg/mL (Cremophor RH 60), hydrogenated oil,
(Eisai Co.) (200 mg)
glyceryl monooleate
Agenerase® TPGS (12%), PEG 400 (17%), Propyl- RT
Amprenavir 0.0491 mg/mL Soft gelatin capsule
(GaxoSmithKline) ene glycol (55%), Sodium chloride
Solufen® Lauryl macrogol-glycerides (Gelucire RT
Ibuprofen 0.0684 mg/mL Hard gelatin capsule
(Sanofi-Aventis) 44/14)
Accutane® Isotretinoin 0.00477 mg/mL Soft gelatin capsule Beeswax, BHA, EDTA, hydrogenated RT
(Roche) (10, 20, 40 mg) soybean oil flakes, hydrogenated veg-
etable oils, soybean oil
*RT, room temperature
B. Singh et al.

(1)
where ΔG is the free energy associated with the process, ri is the radius of
the droplets, Ni is the number of droplets, and σ is the interfacial energy.
The two phases of the emulsion tend to separate with time to reduce
the interfacial area and thus minimize the free energy of the system(s).
Conventional emulsifying agents stabilize emulsions resulting from
aqueous dilution by forming a monolayer around the emulsion droplets,
reducing the interfacial energy and forming a barrier to coalescence. On
the other hand, emulsification occurs spontaneously with SEDDS, as the
free energy required to form the emulsion is low, whether positive or
negative.45 For emulsification to take place, it is vital for the interfacial
structure to offer negligible or no resistance against surface shearing.71
The ease of emulsification has been suggested to be related to the ease
of water penetration into various liquid crystals or gel phases formed on
the surface of the droplet.55,60 The interface between the oil and aque-
ous continuous phases is formed upon addition of a binary mixture (oil/
non-ionic surfactant) to water.55 This is followed by solubilization within
the oil phase as a result of aqueous penetration through the interface.
This occurs until the solubilization limit is attained close to the inter-
phase. Further, aqueous penetration will lead to the formation of the
dispersed liquid crystal phase. Ultimately, everything that is in close
proximity to the interface will be liquid crystal, the actual amount of
which depends upon the emulsifier concentration in the binary mixture.
Therefore, following gentle agitation of the self-emulsifying system,
water rapidly penetrates into the aqueous cores, leading to interface
disruption and droplet formation. As a result of the liquid crystal inter-
face formation surrounding the oil droplets, the SEDDS become quite
stable to coalescence. Moreover, the presence of the drug compound
may alter the emulsion characteristics, possibly by interacting with the
liquid crystal phase. Nevertheless, the correlation between liquid crystal
formation and spontaneous emulsification has still not been properly
established.26,72,73

I.C. Liquid SEDDS Formulations: A Literature Update

An exhaustive study was undertaken to review numerous literature


reports on the formulation of SEDDS. Table 7 presents an updated
comprehensive account of the SEDDS formulations of various drugs
along with their excipient composition. The table affirms the utility
and popularity of SEDDS formulations for scores of drugs varying

448
Self-Emulsifying Drug Delivery Systems

Table 7. Literature Update on Various Reports on Self-Emulsifying


Systems along with the Excipients Employed

Composition
Co-
Drug(s) Lipid(s) Emulsifier(s) emulsfier(s) Ref No.
9-Nitrocamptothecin Maisine 35-1 C-EL, Labrasol Transcutol P 84
All-trans-retinol Capmul MCM-
Soybean oil C-EL 85
acetate C8
Alpha-Asarone EO T 80 PEG 400 86
Amphotericin B Peceol, DSPE PEG 2000 87
Atorvastatin Labrafil C-RH 40 PG 88
BCNU (1,3-bis(2-
chloroethyl)-1-nitro- Tributyrin C-RH 40 Labrafil 1944 89
sourea)
Beta-lactamase Lauroglycol FCC C-EL Transcutol 90,91
Carvedilol -- -- Lutrol F 68 92
Carvedilol Capmul MCM Nikkol HCO 50 Transcutol HP 93
Carvedilol Medium-chain Nikkol HCO 50 Transcutol HP 94
triglyceride
CDA Capryol 90, Cap- Solutol HS 15, T Ethanol, Trans- 95
mul MCM, olive 80, C-EL cutol P
oil, Miglyol 812,
Lecithin SPL
Cefpodoxime Prox-
Capryol 90 C-EL Akoline MCM 96
etil
Tween 20 and
PEG-8 caprylic/
Celecoxib PGmonocaprylic -- 97
capric glycerides
ester
Myvacet 9-45, Labrafac CM-10,
Coenzyme Q10 Lauroglycol 65
Captex-200 Labrasol
Coenzyme Q10 R and S enantio- -- -- 98
mers of limonene
Coenzyme Q10 Labrafil M 1944, Labrasol Lauroglycol 99
Labrafil M 2125 FCC, Capryol
90
Coenzyme Q10 Acetylated mono- T 20 Propylene gly- 100
glyceride col laurate
Cyclosporine Sweet orange oil Emulphor EL-620 Capmul MCM- 101
C8
Cyclosporine Medim Chain Fractionated -- 102
Monoglycerides
oat oil, Galactolipid
Cyclosporine A EO T 80, Oleylamine Benzyl alcohol 63

Continued on page 450

449
B. Singh et al.

Table 7. (Continued)
Cyclosporine A Labrafil M 2125 C-RH40 Propylene 103
CS glycol, ethanol
anhydrous
Danazol Captex 355, Soy- Lecithin Capmul MCM 104
bean oil, Maisine
35-1
Danazol, Halofan- A mixture of long C-RH 40 Ethanol 105
trine, and Probucol chain mono-, di-,
and triacylglyc-
erides (Maisine
35-1 and sesame
oil)
DDB (Biphenyl Triacetin Labrasol Transcutol, 106
di-Me dicarboxy- Cremophor
late ) RH 40, Plurol
Oleique CC
497
Dexibuprofen Capryol 90 Labrasol, Labrafil M 107
1944 CS
Diazepam Cithrol GMS Solutol HS 15 -- 108
Diclofenac Goat fat T 65 -- 109
Felodipine Miglyol® 840, C-EL -- 110
Capmul® MCM
Fenofibrate PEG-8-caprylic/ PEG-4 lauryl ether PEG-400 111
capric glyceride
Fenofibrate Miglyol 812, T 80, T 85 Propylene 112
Imwitor 988 glycol
Flurbiprofen Capmul PG8 T 20 or C-EL - 58
GBE50 IPM C-EL 1,2-propanediol  113
Gentamicin - Labrasol - 114
Glyburide Capryol 90 T 20 Transcutol P 115

Halofantrine Structured triglyc- Maisine 35−1, C-EL Ethanol 116


erides
Hippophae rham- Miglyol 812 N C-EL 1,2-Propylene 117
noides (total fla- glycol
vones)
Ibuprofen Labrafil M1944CS C-RH 40 Carbitol 32
Ibuprofen Caprylocaproyl Polyoxyl castor oils PG derivatives 118
macroglycerides
Idebenone Labrafil 2609 Plurol oleique WL Labrasol contg. 119
1173 80% Transcutol
Indomethacin EO T 85 120
Indomethacin Castor oil C-RH40 Capmul MCM- 121
C8
Indomethacin   Ethyl oleate S 20, T 80 122

450
Self-Emulsifying Drug Delivery Systems

Itraconazole Transcutol ace- Pluronic L-64 Transcutol 123


tate
Ketoprofen -- Gelucire® 44/14 -- 124
Lovastatin Capmul MCM Nikkol HCO-50 Lutrol F 127 125
Metronidazole Homolipid from T 65 -- 126

Capra hircus
Naproxen Gelucire®44/14 -- 127
Nilvadipine Sefsol 218 Nikkol HCO-50, Ethanol 128
Labrasol
Nimesulide Mono and diglyc- Polysorbate 80 -- 129
eride
Nimodipine MCT 3 C-RH40, Labrasol -- 67
Paclitaxel GDO C-EL, PEG 400 Ethanol 75
Paclitaxel -- C-EL Dehydrated 130
ethanol
Paclitaxel dl-Alpha tocoph- TPGS, tyloxapol Ethanol 131
erol
DOC-Na
Paclitaxel Vitamin E TPGS, C-RH 40 DOC-Na, PG 7
Paclitaxel Vitamin E TPGS, Tyloxapol Ethanol 132
Paclitaxel Tetraglycol, C-ELP -- 133
Labrafil 1944
Paclitaxel   Benzyl alcohol, Phosphatidylcho- -- 134
2-Phenylethanol line, T 80, S 80  
benzyl benzoate
and Tributyrin
Penclomedine Miglyol 812 TPGS -- 2
Piroxicam Homolipid from T 65 -- 126,135

Capra hircus
Piroxicam Labrafil M C-EL Transcutol P 136
1944CS
Probucol Maisine 35-1, C-RH 40 -- 137
Sesame oil
Progesterone EO T 80 and oleyl- Benzyl alcohol 138
amine
Progesterone Inwitor 742 Polysorbate 80 -- 139
Puerarin Oleic acid T 80 Propylene gly- 140
col
Puerarin Ethyl oleate T 80 Glycerinum 141
Raloxifene hydro- Capmul MCM T 80 Transcutol HP, 142
chloride ethanol
Seocalcitol Viscoleo, sesame C-RH 40 Akoline MCM, 143
oil peceol

Continued on page 452

451
B. Singh et al.

Table 7. (Continued)
Seocalcitol MCT C-RH 40 Akoline MCM 144
Simvastatin Capryol 90 C-EL Carbitol, PEG 145
400
Tacrolimus Ethyl oleate Solutol HS 15 Glycofurol 68
Tamoxifen citrate Maisine 35-1, C-RH 40 Propylene gly- 146
Caproyl 90 col
Tocotrienols , Soyabein oil, Labrasol , T 80 -- 62
Vitamin A,D and K Palm olein
Ubiquinone Lemon oil C-EL Capmul MCM- 70,147
C8
UC781 Simulsol 1292 T 80, C-RH 40 Ethanol 148
Vinpocetine Labrafac, oleic C-EL Transcutol P 149
acid
Vitamin E Palm oil T 80 S 80 150
Vitamin E -- Tyloxapol, Polyoxyl PG, ethanol, 151
hydrogeneated cas- Bile salts,
tor oil TPGS
Xibornol Labrafil M1944, Labrasol and Transcutol 152
Labrafil M2125 Labrafac PG
and Labrafac CC
GDO, glycerol dioleate; GMO, glycerol monooleate; DGMO-C, diglyceryl monooleate; C-EL, Cre-
mophor EL; C-RH 40, Cremophor RH 40; T 80, Tween 80; T 65, Tween 65; S 80, Span 80; S
20, Span 20; IPM, Isopropyl myristate; EO, ethyl oleate; MCT, medium-chain triglyceride; PG,
propylene glycol; PEG, polyethylene glycol; TPGS, tocophersolan; D-α-tocopheryl polyethyl-
eneglycol 1000 succinate; DSPE, distearoylphosphatidylethanolamine; C-ELP, Cremophor ELP

widely in their physicochemical behavior and therapeutic indications.


Albeit Pouton was the first to report development of the SEDDS in
1985,51 but most of the work in the domain has been reported in the
last decade. Further, these reports are an explicit testimony to the
fact that the bioavailability enhancement potential of SEDDS has not
only been restricted to the Biopharmaceutical Classification Scheme
(BCS) class II drugs, but has also been extended to BCS class III, and
even to BCS class IV drugs such as cyclosporine A.
Along with the exhaustive literature search, an extensive search
into the patent literature was also undertaken to compile the informa-
tion shown in Table 8. Several patents granted by key governmental
intellectual property rights (IPR) agencies from the United Nations
(i.e., the World Intellectual Property Organization, WIPO), and in
the US, Canada, Europe, and Asia support the evolving significance
of the SEDDS formulations in the industrial milieu, as reflected in
the recent literature.

452
Table 8. Various Patents on Self-Emulsifying Drug Delivery Formulations

Title/Year Patent Number Inventors Company


Method for designing formulation of self-emulsi- US2009124670  (A1) Sakai Kenichi
fying preparation (2009)
Self-emulsifying pharmaceutical compositions of WO2009040776  (A1) Nakhat Premchand and Mand- Wockhardt Research
rhein or diacerein (2009) aogade Prashant Centre, India
Self-emulsifying formulations of CETP inhibitors US/2009/0186926 Laman L. Alani, Soumojeet Merck and Co., US
(2009) Ghosh, Bhagwant Rege,  Agam R.
Sheth, Maria T. Cruanes and Craig
A. Mckelvey
Process for dosing self-emulsifying drug delivery WO2008128960 (A1) Schwarz, Franz, Xaver Sandoz, Switzerland
systems  (2008)
Butylphthalide self-emulsifying drug delivery  HK1111299  (A2) Zhenato Liu and Liying Yang   Shijiazhuang Pharma

453
system, its preparation method, and application Group, Canada
(2008)
Delivery of tetrahydro cannabinol: a self-emulsi- US20070104741 Ram B. Murty, K.Y. Lexington, and Murty Pharmaceuticals,
fying drug delivery system to improve dissolution, Santos B. Murty Inc., US
stability, and bioavailability of drug compounds of
dronabinol or other cannabinoids (2007)
Soft gelatin capsule and injection of ibuprofen KR20020071037 (A)   Baek Kwang Seok and Choi Young
using SMEDDS as solubilization method Wook  
Self-microemulsifying drug delivery systems of a US 2007/0104740 A1 Jody Firmin Marceline Voorspoels
HIV protease inhibitor (2007)
Highly concentrated, self-emulsifying prepara- US2007012895 (A1) Bernhard Sandner, Cristina Stanica,
tions containing organopolysiloxanes and alkyl and Longying Jiang
ammonium compounds and their use in aque-
ous systems  (2007)
Continued on page 454
Table 8. (Continued)

Self-emulsifying formulations of cholesteryl ester US 2006/0014788 A1 Michael J. Gumkowski, Lombardo Pfizer Inc., US
transfer protein inhibitors CETP inhibitors have Franco, Sharad B. Murdande, and
improved solubility and bioavailability in a lipo- Michael E. Perlman
philic vehicle comprising a digestible oil, a lipo-
philic solvent, or a surfactant (2006)
Self-emulsifying formulations of fenofibrate and/ US 7022337 Likan Liang, Amir H. Shojaei, Scott Shire Laboratories Inc.,
or fenofibrate derivatives with improved oral bio- A. Ibrahim, and Beth A. Burnside US
availability and/or reduced food effect (2006)
Delivery of reactive agents via self emulsifica- US 2002/0131945 A1 Robert Wayne Glenn, James
tion for use in shelf-stable product (2006) Charles Dunbar, and Tharwat Tadros
Self-nanoemulsifying oily formulation for the US/2006/0292186 Jean-Sebastien Garrigue, Gregory
administration of poorly water-soluble drugs Lambert, Alain Razafindratsita,
(2006) Simon Benita, Shicheng Yang, and

454
Neslihan Gursoy
Method for designing formulation of self-emulsi- WO /2006/112541 A1 Kenichi Sakai Darby & Darby Pharma-
fying preparation (2006) ceutical Co.
Butylbenzene phthalein self emulsifying drug CA 2578130 Zhentao Liu, Liying Yang, Hanyu Shijiazhuang Pharma,
delivery system, its preparation method and MX2007002335 (A) Yang, Yuqing Gao, Dongmin Shen, China
application (2006,2007) Wenmin Guo, Xiaolong Feng, and
Jia Zheng
Galenic applications of self-emulsifying mixtures CA 2579449 Jean Pachot Aventis Pharma, France
of lipidic excipients (2006)
Self-emulsifying formulations of fenofibrate and/ US7022337B2 Likan Liang, Amir H. Shojaei, Scott Shire Laboratories Inc.,
or fenofibrate derivatives with improved oral bio- A. Ibrahim, and Beth A. Burnside US
availability and/or reduced food effect (2006)
Self-emulsifying drug delivery systems for hydro- WO/2005/037251 John Ong, Gregg Stetsko, Amylin Pharmaceuticals
phobic therapeutic compounds (2005) Odile Esther Levy, and S.S. Ghosh Inc., US
Self-emulsifying drug delivery systems for poorly US2005232952 (A1) Alain Razafindratsita, Gregory Lam- Novagali Pharma, SA
soluble drugs (2005) AU2003214538 bert, Jean-Sebastien Garrigue, Nes-
CA2003 2478424 lihan Gursoy, Shicheng Yang, and
Simon Benita
Pharmaceutical composition for hyperlipidemia KR20050011323  (A) Cho Sun Hang and Jeong Sang Korea Research Institute
treatment of self-emulsifying drug delivery sys- Young of Chemical Technology
tem to increase bioabsorption and improve sta-
bility of active ingredient (2005)
Self-emulsifying and self-microemulsifying for- US 2005/0025792 A1 Maria-Teresa Peracchia, Sophie Aventis Pharma, France
mulations for the oral administration of taxoids Cote, and Gilbert Gaudel
Self-emulsifying drug delivery system (2004) US2004248974 (A1) Christina Holmberg
Self-emulsifying drug delivery system, wherein SI1267832  (T1) Christina Holmberg and Britta Siek- Astra Zeneca
the fatty agent is optional (2004) mann
Self-emulsifying drug delivery system (2004, US20040048934 Rajeev D. Gokhale, Martin J. Griffin, G.D. Searle & Co., US

455
2007) US20077226932 James E. Truelove, James C. Stol-
zenbach, Aziz Karim, and Ajit K. Roy
Self-emulsifying compositions, methods of use, US 2004/0185068 A1 Zhi-Jian Yua and Stan Huth
and preparation (2004)
Oral dosage self-emulsifying formulations of US6555558 Shirlynn Chen and Jocelyn A. Gunn Boehringer Ingelheim
pyranone protease inhibitors (2003) Pharmaceuticals Inc.
Self emulsifying drug delivery systems for poorly EP1340497 (A1) Lambert Gregory and Razafind- Novagali SAS, France
soluble drugs (2003) CA 2003/2478424 ratsita Alain

Self-emulsifying drug delivery systems for US2002119198  (A1) Ping Gao, Walter Morozowich, and Pharmacia & Upjohn
extremely water-insoluble lipophilic drugs (2002, AU2001277099  (B2) Narmada Shenoy Company, US
2001, 2002) CA 20022410683

Continued on page 456


Table 8. (Continued)

Self-emulsifying drug delivery system for fat- EP1170003  (A1) Ho Sue San David and Yuen Kah Hovid Sdn Bhd
soluble drugs (2002) Hay
Self-emulsifying systems containing anticancer US 6316497 Rong Ron Liu and Zheng Wang Abbott Laboratories, US
medicament; the present invention relates
to a stabilized self-emulsifying system, com-
prising a therapeutically effective amount of
o-(chloroacetylcarbamoyl) fumigillol, a pharma-
ceutically acceptable carrier (2001)
Self-emulsifying ibuprofen solution and soft US 6221391 Mark T. Rouffer Accucaps Industries
gelatin capsule for use therewith this invention Limited, Canada
relates to a self-emulsifying solution of ibupro-
fen suitable for encapsulation into a soft gelatin
capsule (2001)

456
A pharmaceutical composition of concentrates WO0066140 (A1)   Mulye Nirmal   Pharmasolutions Inc, US
for microemulsion and self-emulsifying drug
delivery system (2000)
Self-emulsifiable formulation and oil-in-water US 5965160 Simon Benita, Jackie Kleinstern, and Yissum Research Devel-
emulsion (1999) Tatyana Gershanik opment Company of the
Hebrew University of
Jerusalem
Polymeric micromulsions (novel self-emulsifying US20060034797 Johnson & Johnson
diblock copolymer)
Pharmaceutical composition comprising cyclo- US2000/6057289 Nirmal Mulye Pharmasolutions, Inc.,
sporin in association with a carrier in a self- US
emulsifying drug delivery system (2000)
Delivery systems for hydrophobic drugs US6,096,338 Jonathan E. Lacy, Jonathan K.
Embleton. and Elizabeth A. Perry
Supersaturated cationic self-emulsified drug deliv- CN101057829  (A)   Gong Mingtao Chen Shanghai Inst Pharm
ery system and its preparation method (2007) Industry, China
Hemlock parsley oil self-emulsifiable oral CN101229205  (A) Qin Cai and Long Liang Sichuan Pearl Pharma-
medicine delivery system and preparing method ceutical, China
thereof (2008)
Solid self-emulsifying controlled release drug US2002103139  (A1) M. Weisspapir and J. Schwarz
delivery system composition for enhanced deliv-
ery of water-insoluble phytosterols and other
hydrophobic natural compounds for body weight
and cholesterol level control
Spheronized self-emulsifying system for hydro- US2003/6630150 Steven William Booth and John Merck Sharp & Dohme
phobic and water-sensitive agents (2003) Michael Limited, UK
Liquid phase remedy for impotence prepared KR2000/0022734  (A) Lee Sang Soon and Choi Yeong Guju Pharm Co Ltd
into self-emulsifying drug delivery system Wook  

457
Pharmaceutical solid self-emulsifying composition US 2002/0102301 A1 Joseph Schwarz
for sustained delivery of biologically active com-
pound and the process for preparation thereof 
Self-emulsifying active substance formulation US 2004/0013697 A1 Gunther Berndl, Jorg Breitenbach,
and use of this formulation Robert Heger, Michael Stadler, Peter
Wilke, and Jorg Rosenberg
Self-emulsifying drug delivery system, wherein SI1267832  (T1) Christina Holmberg and Britta Siek- Astrazeneca Ab
the fatty agent is optional (2004) mann
Self-emulsifying drug delivery systems for WO2005037250  (A1)  John Ong and Gregg Stetsko  Amylin Pharmaceuticals
hydrophobic therapeutic compounds Inc, US
Self-emulsifying pigments;  this invention relates US7276113 Mark G. Le Page, William Zava- U.S. Cosmetics Corpo-
to a surface-modified pigment having at least doski, Shigeru Kishida, and Yoshiaki ration, US
two surface-active agents chemically immobi- Kawasaki
lized onto the surface of the pigment
Continued on page 458
Table 8. (Continued)

New self-emulsifying drug delivery system CA200124018 Christina Holmberg and Britta Siek- Astrazeneca, Sweden
US20030077303 mann
AU2002329149
New self-emulsifying drug delivery system AU2001237876  (B2)  Britta Siekmann and Christina Hol- Nicox Sa
US 2003/0077303 mberg
AU2001237875
SI1267831  (T1)

Self-emulsifying drug delivery systems for AU2001277099  (B2) Ping Gao and Narmada Shenoy   Pharmacia and Upjohn
extremely water-insoluble, lipophilic drugs Company
Eutectic-based self-nanoemulsified drug delivery US 2003/0147927 A1 Mansoor A. Khan and Sami Nazzal

458
system
Self-emulsifying compositions for drugs poorly US6436430 Nirmal Mulye Pharmasolutions, Inc.
soluble in water (2002)
Formulation for self-emulsifying matrix type KR20010093728  (A) Hong Cheong Il and Ki Min Hyo   Chong Kun Dang Pharm
mucosal and transdermal absorbent Corp, Korea
Vinpocetine oral self-micro-emulsification med- CN101103962  (A) Gao Li and Ying Chen Tongji Medical College
icine-releasing system and preparation method of Huaz, China
thereof
Self-emulsifying matrix type transdermal prepa- US 2003/0129219 A1 Chung Il Hong, Hee Jong Shin, Min
ration Hyo Ki, Seok Kyu Lee, and Don Sun
Kweon
Self-Emulsifying Drug Delivery Systems

II. SPECIAL TYPES OF SEDDS FORMULATION

II.A. Supersaturable SEDDS

The high levels of surfactant typically present in SEDDS formulations


can lead to severe GI side-effects. Therefore, a new class of SEDDS
formulations, supersaturable SEDDS (S-SEDDS) has been designed
to reduce the amount of surfactant by incorporating a water-soluble
polymeric precipitation inhibitor (PPI).74 Such formulations have
been developed specifically to reduce the surfactant side-effects and
achieve rapid absorption of poorly soluble drugs.75-77 The system is
intended to generate and maintain a metastable supersaturated
state in vivo by preventing or minimizing the precipitation of the
drug through the use of a suitable PPI. Supersaturation is intended
to increase the thermodynamic activity to the drug beyond its solu-
bility limit, resulting in an increased driving force for transit into
and across the biological barrier.78 The S-SEDDS formulations have
been demonstrated to improve both the rate and extent of the oral
absorption of poorly water-soluble drugs quite effectively.74,79,80 The
inclusion of cellulosic polymers in the S-SEDDS formulation tends
to effectively suppress the precipitation of drugs.75 Various viscosity
grades of hydroxypropyl methylcellulose (HPMC) are well-recognized
for their ability to inhibit crystallization, and thereby their ability
to generate and maintain their supersaturated state for extended
time periods.81-83
In vitro dilution of the S-SEDDS formulation results in the for-
mation of a microemulsion, followed by slow crystallization of the
drug on standing, indicating that the supersaturated state of the
system is prolonged by HPMC in the formulations. In the absence of
HPMC, the SEDDS formulation undergoes rapid precipitation, yield-
ing a lower drug concentration.74 The comparative in vitro studies153
have indicated that the presence of a small amount HPMC in the
formulation is critical to achieving a stabilized supersaturated state
of drug upon mixing with water. Applying the S-SEDDS approach,
a reduced amount of surfactant is deliberately used with HPMC in
order to produce a temporarily supersaturated state with reduced
solubilization.74 This is done to obtain a high free drug concentration
through generating and maintaining a supersaturated state in vivo
and to increase the driving force for absorption.77
It is worth emphasizing that the significantly reduced amount of
surfactant used in the S-SEDDS formulation approach significantly

459
B. Singh et al.

Table 9. Literature Update on Various Reports on Supersaturable SEDDS

Drug Lipids/Oils Surfactants/Co- Polymeric Ref


surfactants Precipitation No.
Inhibitor
AMG 517 Capmul MCM Cremophor EL, Plu- PVP 12PF and K30 & 153
ronic F108, Tween HPMC E4M, E50, E5,
80 & PEG 400 K100 and K3
Paclitaxel Glycerol dioleate Cremophor EL & HPMC 2910 E5LV 75
PEG 400
PNU 91325 Mount olive, glyc- Cremophor EL, PEG HPMC 2910 E5LV and 77
erol monooleate & 400, Propylene gly- E50LV
glycerol dioleate col, Dimethyl acet-
amide, Pluronic L44
& Tween 80
Simvastatin Capmul PG 8, ethyl Tween 80, Cremo- HPMC E50LV, E5LV, 170
oleate phor EL, Transcutol and K4M
HP
HPMC, hydroxypropyl methylcellulose; PVP, povidone; PEG, polyethylene glycol

reduces toxicity and improves the safety profile over the conven-
tional SEDDS formulations. However, the mechanism underlying
the inhibited crystal growth and stabilized supersaturation using
these polymers is still poorly understood, even though several studies
have been carried out to investigate this process.154-156 Table 9 lists
various studies reported in the literature about S-SEDDS formula-
tions and their respective compositions. Methyl cellulose derivatives
such as HPMC have usually been used as PPIs in such formulations;
polymers such as polyvinylpyrrolidine have also been used.

II.B. Solid SEDDS

SEDDS are usually prepared in liquid form, and therefore have to be


administered in a soft gelatin capsules, resulting in higher production
costs and lower stability, lower portability, and lower drug loading.157
This problem led to the development of solid SEDDS, which combine
the advantages of conventional SEDDS (i.e., enhanced solubility and
bioavailability) with those of solid dosage forms (e.g., low production cost,
convenience of process control, high stability and reproducibility, and
better patient compliance). The solid SEDDS focus on the incorporation
of liquid/semisolid ingredients into powders, employing diverse solidi-
fication techniques such as spray drying,158,159 melt granulation,160,161
molding,109 melt extrusion,162,163 and nanoparticle technology.126 The

460
Self-Emulsifying Drug Delivery Systems

powders can then be formulated as solid dosage forms28,164 such as


self-emulsifying tablets109,147,165 and self-emulsifying pellets.108,163,166
Alternative approaches for the development of solid SEDDS include
adsorption by solid carriers such as microcrystalline cellulose,108,158 col-
loidal silica,167 and various viscosity grades of HPMC,168,169 and the use
of high-melting-point solid excipients such as Lutrol® and Gelucire®.46
The idea of blending the advantages of SEDDS with those of pel-
lets through the inclusion of a self-emulsifying mixture into micro-
crystalline cellulose, and the production of pellets using extrusion-
spheronization, was first introduced by Newton et al. in 2001.171
Table 10 lists various studies on solid SEDDS formulations and their
respective compositions. Postulating it as a platform technology for
poorly soluble drugs, Bansal et al. in 2008172 highlighted various
aspects of solid SEDDS, especially their formulation constituents.
As melt extrusion/extrusion spheronization is a solvent-free process
allowing high drug loading and content uniformity, it has been most
extensively employed for solidification of SEDDS. Lesser used methods
include spray drying and molding.

II.C. SEDDS for Traditional Herbal Medicine

Long well-accepted in the mainstream of medical care throughout the


Asian continent, traditional herbal drugs are now considered as alter-
native medicines in much of the western world too. The concepts
of herbal medicines are well-defined in “Ayurveda,”173,174 Chinese
practice,175,176 and “Unani” systems of medicine. Nevertheless, the
absorption of many active phytochemical constituents from these
traditional herbs, such as Cardus marianus (silybin) and Curcuma
zedoaria (turmeric), have been reported to be ineffective. Therefore,
several studies have been undertaken to formulate the self-emulsifying
systems of vital constituents of such herbs to attain the desired objec-
tives. Table 11 provides a brief account of these reports.

II.D. Positively Charged SEDDS

Many physiological studies have proven that the apical potential


of absorptive cells, as well as that of all other cells in the body,
is negatively charged with respect to the mucosal solution in the
lumen.63,177-179 The drug exposure of the positively charged SEDDS has
been found to be higher than conventional formulations, especially for
bioavailability enhancement. More recently, it has been shown that

461
B. Singh et al.

Table 10. Literature Reports on Various Solid SEDDS

Drug Oils/Lipids Surfactants/ Other Vital Technique for Ref


Co-surfactants Excipients Solidification No.

Candesartan Miglyol 812 Labrasol Colloidal silicon Adsorption on 180


cilexetil Tween 80 dioxide solid carriers
Microcrystalline
cellulose
Carvedilol Capmul MCM HCO 50 -- -- 93
Lutrol F 68
Diazepam Cithrol GMS Solutol HS 15 Avicel PH 101 Extrusion/sphe- 108
ronization
Diclofenac Goat fat Tween 65 - Moulding 109
Ezetimibe Capryol 90 Cr-EL Aerosil 200 Mixing 167
Loratadine Captex 200 Cr-EL Porous polysty- Beads formation 181
and rene by evaporation
Capmul MCM
Lovastatin Capmul MCM HCO 50 -- -- 125
Lutrol F 68
Methyl para- Imwitor 742 Tween 80 Avicel PH101 Extrusion/sphe- 182
ben & propyl ronization
paraben
Nimesulide Cithrol GMO Tween 80 Microcel 101 Spray drying 129
Nimodipine Ethyl oleate Labrasol Dextran 40 Spray drying 159
(SMEDDS) Cr RH 40
Nimodipine Ethyl oleate Labrasol Methocel® Spray drying 169
(SEF) Cr RH 40 K4M Premium
CR EP, K15M
Premium CR
EP, and K100M
Premium CR
EP)
Nitrendipine Miglyol 812 Cr RH 40 Syloid 244 FP Extrusion/sphe- 183
Tween 80 Kollidon CL-SF ronization
Trancutol P Flowlac 100
Avicel PH 101
Progesterone Captex 355 Solutol HS 15 Avicel PH 101 Extrusion/sphe- 139,
EP/NF Cap- ronization 158
mul MCM
Vinpocetine Akoline MCM, Polysorbate 80 Microcel 101 Extrusion/sphe- 163
peanut oil Ac-Di-Sol ronization
Vitamin A Soybean Cr-EL Avicel Mixing and com- 184
acetate oil, Capmul pression into
MCM-C8 tablets

MCC, microcrystalline cellulose; Cr-EL, Cremophore EL; Cr RH 40, Cremophor RH 40

462
Self-Emulsifying Drug Delivery Systems

Table 11. Literature Reports on Self-Emulsifying Formulations of


Traditional Herbal Medicines

Drug(s) Lipid(s) Emulsifier(s) Co-emulsfier(s) Ref


No.
Curcuma oil EO T 85 -- 185
Emulsifier OP,
Curcumin EO PEG 400 186
C-EL 40
Miglyol 812,
Ginkgo biloba extracts T80, C-EL 35 1,2-Propanediol 33
Ethyl oleate
Jiaotai Pill actives
(Berberine hydrochlo- Cinnamon oil OP Propanediol 187
ride)
Ligusticum chuanxiong Nonionic sur- 188,
Chuanxiong oil ---
(a volatile oil) factant 189
Nobiletin Cradamol GTCC T80, C-EL 35 PEG 400 190
Maisine 35-1,
Oridonin C-EL Transcutol P 191
Labrafac CC
Pueraria Lobata Iso-
EO T80 Transcutol P 192
flavone
Puerarin Oleic acid T80 -- 193
Puerarin Oleic acid T80 Propylene glycol 194
Silymarin Ethyl linoleate T80 Ethanol 195
Polysorbate 20
Silymarin GMO Transcutol 196
and HCO-50
Zedoary turmeric oil EO T 85 -- 197
N-LCT, Caproyl
Plurol oleique CC
β-Artemether 90, Gelucire C-EL, T80 198
97
44/14
GMO, glycerol monooleate; C-EL, Cremophor EL; C-RH 40, Cremophor RH 40; C-EL 35, Cre-
mophor EL 35; T 80, Tween 80; T 85, Tween 85; EO, ethyl oleate; LCT, light-chain triglyceride;
PEG, polyethylene glycol

the enhanced electrostatic interactions of positively charged droplets


with the mucosal surface of the everted rat intestine are mainly
responsible for the preferential uptake of the drugs.63 The binding of
the cationic SEDDS has been found to be much higher compared with
the anionically charged formulation, suggesting increased adhesion
of the droplets to the cell surface due to electrostatic attraction.15,201
Therefore, studies on the successful formulation of some cationic
SEDDS have been undertaken. Table 12 lists studies on positively
charged SEDDS formulations and their compositions. Ethyl oleate
has been utilized as the lipidic carrier in almost all of the formula-

463
B. Singh et al.

Table 12. Literature Updates on Positively Charged SEDDS

Drug Oils/Lipid used Surfactants/Co- Positive Charge Ref


surfactants used Inducer No.
Carvedilol Lauroglycol Gelucire 44/14, Oleylamine 199
Tween 20
Cyclosporine A EO T 80, Dithiotreitol & Oleylamine 63
Ethanol
Fluorescent dye EO Polysorbate 80 Oleylamine 15
DiIC18
Lovastatin Gelucire 50/13 C-EL Oleylamine 200
Progesterone EO T 80, PEG 300 Oleylamine 179
Vinpocetine Labrafac & Oleic C-EL & Transcutol P Oleylamine 149
(SMEDDS) acid

C-EL, Cremophor EL; T 80, Tween 80; T 85, Tween 85; EO, ethyl oleate; PEG, polyethylene glycol

tions, while oleylamine has remained as the positive charge-inducer


of choice in all of these reported studies.
Olelylamine, a Generally Recognized as Safe (GRAS)-approved
excipient, has been preferred for SEDDS formulation primarily owing
to its resemblance to the hydrocarbon chain length of oleic acid, a
known biodegradable fusogenic agent.202 Further, oleylamine induces
charge in the range of 30 to 35 mV, which is vital for an efficient and
stable emulsion/microemulsion system. In addition to oleylamine, other
agents such as stearylamine and chitosan have also been employed
for inducing cationic charge in various lipid-based drug-delivery sys-
tems. Stearylamine-coated emulsions produce globules having zeta
potential in the range of 22 to 26 mV, whereas chitosan-coated ones
generate potential in the range of 20 to 23 mV. However, the use of
stearylamine in drug delivery is restricted to a concentration of 0.5%
w/w because of its reported cytotoxicity. Chitosan, on the other hand,
has been reported to be effective as a charge inducer in lipidic drug
delivery systems up to a concentration of 0.5% w/w, after which it
has virtually no effect on the charge or the globule size.203

II.E. Systematic Optimization Studies on SEDDS


Formulations

Owing to the diversity of their constitution, formulation optimization


of the SEDDS has been a tedious process. Accordingly, the modern

464
Self-Emulsifying Drug Delivery Systems

formulation optimization approaches, employing systematic Design


of Experiments (DoE), have been extensively practiced in the devel-
opment of variegated self-emulsifying delivery devices. These DoE
methodologies are well-known to improve the irregularities of one
variable at a time methods, with distinct advantages in terms of
economics of time, money, and effort; flexibility to fix errors; and pro-
nounced predictability.204,205 Numerous types of experimental designs
employed in drug-delivery optimization have been reviewed previ-
ously.206, 207 Table 13 provides a concise account of various literature
reports on DoE optimization of several self-emulsifying formulations
and their solid dosage forms such as tablets and pellets. The experi-
mental designs that have been successfully employed include central
composite design, Box-Benkhen design, simplex mixture design, and
D-Optimal design. The influential factors have invariably been the
SEDDS constituents. The response variables that have been employed
for optimization include emulsion droplet size, drug release profiles,
emulsification rate, intestinal absorption rate, extrusion force, and
compression force.

III. CHARACTERIZATION OF SEDDS FORMULATIONS

These multicomponent lipidic formulations have to be evaluated and


characterized using diverse in vitro, ex vivo, and in vivo procedures.
A number of techniques have been employed to characterize SEDDS
and determine the feasibility of their formulation process.208

III.A. Equilibrium Phase Behavior

Although self-emulsification is a dynamic, non-equilibrium process


involving interfacial phenomena, the information about the process
can be obtained using equilibrium-phase behavior. Equilibrium-phase-
behavior studies cannot reveal the true nature of the interfacial dis-
ruption that gives rise to spontaneous emulsification, but can at least
enable the prediction of the phases that are likely to be formed on
dilution of SEDDS with water.49,55 There appears to be a correlation
between emulsification efficiency and the region of enhanced water
solubilization (i.e., a typical characteristic of nonionic surfactant sys-
tem) and phase inversion region and the formation of lamellar liquid
crystalline dispersion phase on further incorporation of water.26,51
This method also allows comparison among different surfactants
and their synergy with the chosen co-solvent(s) or co-surfactant(s).

465
Table 13. Literature Reports on Various Self-Emulsified Formulations Optimized using “Design of
Experiments”

Drug (Delivery Ref


Type of Design Factors Employed Response Variables
System) No.
All-trans-retinol BBD (3 factors, 3 levels) Amount of added oil, surfac- Particle size, turbidity, and cumulative 209
acetate tant, and cosurfactant  amount of the active ingredient emulsi-
fied after 10 and 30 min 
Carvedilol CCD (2 factors, 3 levels) Capmul MCM, Nikkol HCO 50 Droplet size, emulsification time, lique- 93
& Transcutol faction time intestinal absorption rate
CoQ10 Face-Centered Cubic design Lemon oil, Cremophor EL & Amount of silicone dioxide, magnesium 165
(SNEDDS) (3 factors, 3 levels) Capmul MCM C8 stearate mixing time, compression force,
hardness, Carr’s flow index, friability,
cumulative percentage at different peri-
ods of time
CoQ10 BBD (3 factors, 3 levels) R-(+)-limonene, Cremophor EL cumulative percentage of drug released 210

466
(SNEDDS) & Capmul GMO 550 after 5 minutes, turbidity, particle size,
and zeta potential
Curcumin SLD (3 factors, 4 levels) Ethyl oleate, Emulsifier OP, Solubility of drug in SMEDDS, the mean 186
(SMEDDS) Cremophor EL & PEG 400 particle size of micro-emulsification
Cyclosporine A BBD (3 factors, 3 levels) Orange oil, Emulphor EL 620 Particle size, turbidity, cumulative per- 101
(SNEDDS) & Capmul MCM C8 cent of drug released after 5 min, emul-
sification rate (10 min), lag time
Genistein  BBD (3 factors, 3 levels) Maisine 35-1 and Labrafac Droplet size, turbidity, dissolution per- 211
Lipophile WL 1349, Cremophor centage
EL and Labrasol, and Trans-
cutol P
Ketoprofen FD (2 factors, 3 levels) Capmul MCM and Silicon diox- Droplet size, in vitro drug diffusion 212
ide
Lovastatin CCD (2 factors, 3 levels) Capmul MCM, Nikkol HCO 50 Amount permeated in 45 min, percent 125
& Lutrol F 127 dissolution efficiency in 15 min, mean
dissolution time, liquefaction time emulsi-
fication time
Lu 28-179, crystalline D-OD Akoline MCM, medium-chain Droplet size, solubility, weight change at 213
free base (SEDDS & triglyceride, Cremophor EL, the two storage conditions below 3%
SMEDDS) Tween 80 & PEG 200
Model drug A MD (3 factors, 2 levels) PEG 400, Cremophor EL, and Dispersion performance, droplet density 214
a mixture of glycerol dioleate,
and glycerol monooleate
Nimesulide MD (5 factors, 2 levels) Mono- and di-glycerides, Poly- Median diameter of pellets, percentage 166
(SEDDS) sorbate 80 in modal fraction
Oridonin CCD (2 factors, 5 levels) Maisine 35-1 & Labrafac CC, Droplet size, polydispersity, equilibrium 215
(SMEDDS) Cremophor EL & Transcutol P solubility, intestinal absorption rate
Raloxifene hydrochlo- D-OD (2 factors, 3 levels) Capmul MCM, Tween 80, Percent release in 10 min, percent dis- 142
ride transcutol HP propylene glycol solution efficiency in 15 min, mean dis-
& ethanol solution time, permeation in 30 min
Self emulsifying pellets CCD (2 factors, 5 levels) Mono- and diglycerides, Ratio of lactose to MCC, ratio of MP to 129
Polysorbate 80 water, extrusion force; and median size,

467
size spread, disintegration time, tensile
strength, shape, surface roughness of
the pellets.
Simvastatin MD (3 factors, 2 levels) Labrafac CC & Cremophor EL Amount of simulated gastrointestinal 216
(SMEDDS) fluid, oil and surfactant
Simvastatin CCD (2 factors, 3 levels) Capmul PG 8, ethyl oleate, Percent dissolution efficiency in 15 min, 170
Tween 80, transcutol HP & mean dissolution time, liquefaction time
Cremophor EL emulsification time
Ubiquinone BBD (3 factors, 3 levels) Lemon oil, Cremophor EL and Amounts of copolyvidone, maltodextrin 217,
(SNEDDS/ Tablets) Capmul MCM-C8 microcrystalline cellulose, cumulative per- 218
cent of Ubiquinone emulsified in 45 min
CCD, central composite design; BBD, Box-Behnken design; MD, mixture design; SLD, simplex lattice design; D-OD, D-optimal design; FD, factorial
design; SNCDF, self-nano-emulsified capsule dosage form
B. Singh et al.

The boundaries of the monophasic region can be easily demarcated


by visual observation of the samples. Phase behavior of the three-
component system can be represented pictorially by a ternary phase
diagram, which can be computed manually or derived using software
such as PCP Disso 3.0219 or Tri Plot 1.4.111

1. Phase-Solubility Studies

For solubility studies,18,28 the ratios of oil to the surfactant/co-sur-


factant mixture are varied, usually from 1:9 to 9:1 (w/w). Water is
added dropwise to the mixture under vigorous stirring until a clear
and transparent micro-/nano-emulsion is formed.

2. Pseudo-Ternary Phase Diagram Study

The pseudo-ternary phase diagrams of oil, surfactant/cosurfactant,


and water are developed using the water titration method. The
mixtures of oil and surfactant, usually accompanied by a cosurfac-
tant, at certain weight ratios are diluted with water in a dropwise
manner. For each phase diagram at a specific ratio, a transparent
and homogenous mixture of oil and drug gets formed under mixing
by magnetic stirring. Subsequently, each mixture is titrated with
water and visually observed for phase clarity and flowability. After
identification of the microemulsion region in the phase diagrams, the
microemulsion formulations are selected at the desired component
ratios.12 Figure 4 depicts a typical ternary plot showing the distinct
presence of the desirable microemulsion region.125

III.B. Phase Separation and Clarity Studies

The chemical and physical stability of micro-/nano-emulsions contain-


ing a drug can be studied via clarity and phase separation.54,158,192
The centrifuge tests are carried out to assess the physical stability
of such micro-/nano-emulsions. The emulsions are centrifuged (usu-
ally between 13,000 and 15,000 rpm) for a specified time period and
subsequently stored at different temperatures (e.g., at 5°C, 15°C,
25°C, and 37°C). At certain temperatures such as 15°C, 25°C and
37°C, emulsions generally fail to exhibit any appreciable change in
clarity and phase behavior. The drug levels also tend to remain nearly
constant, obviously connoting little degradation. Phase separation
and turbidity, however, are observed at lower temperature such as

468
Self-Emulsifying Drug Delivery Systems

FIGURE 4. A typical pseudo-ternary phase diagram obtained during formulation develop-


ment of the SEDDS. The figure evidently depicts the predominance of microemulsion
region over microgel region employing Capmul MCM as the lipid, Nikkol HCO 50 as
the surfactant and Lutrol F 127 as the co-surfactant.

5°C. Coagulation of the internal phase might lead to this instability.


Accordingly, micro-/nano-emulsions should be kept at a temperature
of 15°C or higher.

III.C. Self-Emulsification Characterization

1. Dispersibility Test

The efficiency of self-emulsification of oral micro-/nano-emulsions


is assessed using a standard USP dissolution apparatus.12,51,139
One milliliter of each formulation is added to 500 mL of water at
37 ± 0.5°C. A standard stainless steel dissolution paddle rotating
at 50 rpm provides gentle agitation. The in vitro performance of
the formulations is visually assessed from such a dispersion using
a suitable grading system.12 Grading systems can be based upon
the formation of a microemulsion (o/w or w/o), microemulsion gel,
emulsion, or emulgel. The schematic flow chart in Figure 5 illus-
trates the mode to characterize the type of formulation on the
basis of this grading system and the type of dispersion formed on
water dilution.

469
B. Singh et al.

2. Pellets

For preliminary assessment of the self-emulsifying properties of the


formulation, 0.1% Sudan Red is incorporated in the self-emulsifying
pellets.108 Pellets are then gently agitated in distilled water on a shak-
ing water bath at 37°C at about 50 oscillations per min. Aliquots of
samples are withdrawn periodically at short intervals of around 30
minutes for microscopic examination using a light microscope with
high optical zoom (e.g., 50 x/0.70) and a high-resolution eye piece
(e.g., 10 x 20).108,158,163

III.D. Size and Zeta Potential

A zetasizer uses light-scattering techniques to measure globule size,


zeta potential, and molecular weight of nanoparticulate systems. The
instrument measures the size and zeta-potential to optimize stability
and shelf life and speed up formulation development.61,62,64,72,220 The
electrophoretic mobility of the micelles and the nanoemulsion has
also been measured at 25°C with a zetasizer. The charge on the oil
droplets of SEDDS63 is another property that should be assessed. In
conventional SEDDS, the charge is negative due to the presence of
free fatty acids.138 However, incorporation of a cationic lipid such as
oleylamine will yield cationic SEDDS.35,63 The zeta potential of the
dispersions is calculated by the instrument according to the Helm-
holtz–Smoluchowski equation:

(2)
where U is the electrophoretic velocity, Ε is the permittivity, z is the
zeta potential, Ex is the axial electric field, and µ is the viscosity.
The value of the zeta potential, as well as the size of the droplets/
globules of the SEDDS formulation can be measured using diverse
techniques. A brief account of the methodologies is presented below.

1. Dynamic Light Scattering

Also called as photon correlation spectroscopy, the dynamic light-


scattering (DLS) technique is quite well-known. Briefly, the original
measurement is a time correlation function of the scattered intensity.
The instrument for DLS measurement is equipped with a He-Ne laser,
a digital correlator, and a single-photon detector module.

470
Self-Emulsifying Drug Delivery Systems

FIGURE 5. In vitro assessment of the formulation performance using the dispersibility


test depending upon the formation of microemulsion, microgel, emulsion and emulgel
in the decreasing order of emulsion stability.

471
B. Singh et al.

During DLS, the sample is illuminated with a laser beam, and


the intensity of the resulting scattered light produced by the particles
fluctuates at a rate that is dependent on the size of particles.74,79,221 The
globule size detection is carried out in a backscattering mode,220 with a
high scattering angle such as 173°. The reduction in this correlation func-
tion, namely scattered light intensity and particle size with displacement
time (called as “lag time”), can be used to extract information about the
diffusion coefficient of a particle or droplet in solution. The measured
diffusion coefficient can be used to calculate hydrodynamic radius (ρ) of
the droplet using the Stokes–Einstein equation:

(3)
where k is the Boltzmann constant, T is the absolute temperature,
η is the viscosity of the continuous phase, and D is the diffusion
coefficient.
Particle size data are first analyzed by cumulant analysis to obtain
an average diffusion coefficient, and subsequently by a constrained
inverse Laplace transform routine (i.e., CONTIN analysis)222 to obtain
information about the entire size distribution (i.e., monomodal or
multimodal). Two sets of data are obtained: one measurement is
usually carried out at least 4 hours after preparation of the sample,
while a second one is performed after 72 hours.220 The measure-
ment is intended to provide information on long-term stability of the
microemulsion.223,224

2. Static Light Scattering

In a typical small angle X-ray scattering technique (SAXS) experi-


ment, the Fourier transformation of the electron density fluctuations
in a sample is measured.225, 226 For the nanoemulsions, the electron
density is usually low in oil-cores and high in the surrounding water
phase. This is exploited to determine the shape and size of the nano-
emulsion droplets. More generally, the SAXS is used for investigating
structures on the 1-100 nm scale.43, 225 The instrument is optimized
for solution scattering and a specific q-range (e.g., between 0.009 and
0.281Å) covered with the applied setup. Measurements are gener-
ally performed on a photometer equipped with a He–Ne laser and
cylindrical cells immersed in a toluene-index matched container.
Intensities are recorded at different angles and normalized with
respect to toluene (θ=90o).

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Self-Emulsifying Drug Delivery Systems

3. Multi-Angle Light Scattering

Multi-angle light scattering experiments are usually performed on a


spectrometer equipped with a goniometer, a uniphase He–Ne laser,
an avalanche photodiode detector and a multi-angle tau correlator.220
The temperature can be controlled using an external water bath
circulator.

4. Emulsion Droplet Polarity

Emulsion droplet polarity is also a vital factor for characterizing


emulsification efficiency.53, 65 The HLB, chain length and degree of
unsaturation of the fatty acid, molecular weight of the hydrophilic
portion and the concentration of emulsifier have significant impact
on the polarity of the oil droplets.18 Polarity represents the affinity
of the drug compound for oil and/or water and the type of forces
formed. Rapid release of the drug into the aqueous phase is promoted
by drug polarity.127

5. Electron Microscopic Studies

Freeze-fracture electron microscopy has been used to study the surface


characteristics of the SEDDS. However, due to the high lability of
the samples and the possibility of artifacts, electron microscopy is, at
times, considered as a somewhat misleading technique. Particle size
analysis and low frequency dielectric spectroscopy have been utilized
to examine the self-emulsifying properties of a series of Imwitor 742
(i.e., a mixture of mono- and diglycerides of capric and caprylic acids)
and Tween 80 systems.64, 72

a. Scanning Electron Microscope (SEM)

In this technique, surface of the sample is scanned with a high-energy


beam of electrons in a raster scan pattern (i.e., a rectangular pattern
of image capture and reconstruction in television).227 The electrons
interact with the atoms that make up the sample producing signals
that contain information about the sample’s surface  topography,
composition and properties like electrical conductivity. This technique
is quite useful for determining the parameters like powder flow and
compaction which influences the production of solid dosage forms.124

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B. Singh et al.

b. Transmission Electron Microscopy (TEM)

In TEM, a beam of electrons is transmitted through a thin layer of


specimen. An image is formed from the interaction of the electrons
transmitted through the specimen; the image is magnified and
focused  onto an imaging device, such as a  fluorescent  screen, on
a layer of  photographic film, or to be detected by a sensor such as
a charge-coupled device (CCD) camera.228

c. Cryo-Transmission Electron Microscopy (Cryo-TEM Studies)

In Cryo-TEM studies, sometimes described as Electron cryo-micros-


copy  or cryo-electron microscopy, the sample is studied at  cryo-
genic temperatures, generally matching those of liquid nitrogen.229 The
important merit of such studies is that it allows the observation of
specimens that have not been stained or fixed in any way, showing
them in their native environment, which otherwise could lead to
undesirable conformational changes as in case of X-ray crystallog-
raphy. The samples for the Cryo-TEM studies are usually prepared
in a controlled environment vitrification system.230, 231

III.E. Turbidity Measurements

It is a relatively crude parameter for estimation of droplet size as well


as emulsification time. It is used to determine the rapid equilibrium
reached by the dispersion and the reproducibility of this process.130
Turbidity measurements are carried out on turbidity meters,85, 147
with the instrument connected to a dissolution apparatus. The opti-
cal density of the formulation is recorded periodically (say every 15
sec) to determine the clarity of microemulsion formed as well as the
emulsification time, i.e., time required by the formulation to emulsify
completely. Turbidity can also be observed in terms of spectroscopic
characterization of optical clarity, i.e., the absorbance of suitably
diluted aqueous dispersion.85

III.F. Rheological Studies

As a prelude to dissolution and permeation across GI lumen, drug


molecules form the SEDDS formulation have to undergo dilution in
the GI milieu to form nano/microemulsion. Accordingly, estimation
of their rheological behavior during this transition is quite vital,

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Self-Emulsifying Drug Delivery Systems

next only to the assessment of solubility and permeability across GI


tract.232 On dilution, the oil and emulsifier(s) present in SEDDS form
an interface with GI fluids, termed as intermediate liquid crystalline
phase. The rheological studies, consequently, focus on exploration
of the viscoelastic properties of this intermediate liquid crystalline
phase and to evaluate its effect on self-emulsification performance.233
Additionally, assessment of rheological properties of SEDDS is indis-
pensable to have better understanding of their phase behavior during
extreme conditions of temperature, humidity, transportation, etc.
Rheological behavior of micro/nanoemulsions formed after dilution
has been determined using digital instruments coupled with either cup
and bob or a co-axial measuring device. A rotational viscometer has
also been used for viscosity measurements on fresh microemulsions
and those stored for long periods.152 A typical rheometer test program
for rheological characterization (i.e., flow, thixotropy, static yield, creep
value) presents a data analysis for flow curves, quality control min/
max limits, mathematical models, data averaging and many more
analytical functions.233-235 Generally, viscosity measurements indicate
that on dilution with distilled water (e.g. 10 and 100 times), viscosity
of a formulation decreases,34 thus construing that the drug absorption
is likely to be faster from stomach. Besides, the effect of concentration
of excipients on the rheological profile of SEDDS can also be examined.

III.G. Stability Studies

1. Thermodynamic Stability Studies

The samples are subjected to a number of cycles, usually hexaplicate,


between temperatures of 4°C and 45°C.12 The formulations are then
centrifuged at 3500 rpm for 30 min. This is followed by freeze-thaw
cycles, usually triplicate, between -21°C and +25°C.12, 54 All the for-
mulations are kept at each temperature for not less than 48 h. The
formulation, that passes the thermodynamic stress tests, is further
taken for the dispersibility test for assessing the efficiency of self-
emulsification.115, 163, 236

2. Robustness to Dilution

Nanoemulsions, resulting from dilution with various dissolution


media, must be robust to all dilutions, and should not show any phase
separation or drug precipitation even after 12 h of storage.34, 96, 138, 237

475
B. Singh et al.

III.H. Liquefaction Time

This test is designed to estimate the time required by solid SEDDS


to melt in vivo in the absence of agitation in the simulated GI tract
conditions. One dosage form is wrapped in a transparent polyethylene
film and tied to the bulb of a thermometer by means of a thread.109
The thermometer with attached tablets is placed in a round bottom
flask containing simulated gastric fluid without pepsin maintained
at 37±1°C, by means of thermo-regulated heating mantle.

IV. PERMEATION STUDIES

The small intestine per se has two major functions. First, it is the
efficient absorption of nutrients, fluids, electrolytes and drugs.238 The
other one is the simultaneous exclusion of potentially antigenic or
toxic or inflammatory xenobiotics.239 Knowledge of the absorption and
metabolism of these substances at the intestinal mucosal level is of
particular importance, since the oral bioavailability of a drug is defined
as the fraction of an oral dose that reaches the systemic circulation.

IV.A. In Vitro/Ex Vivo Models

1. Isolated and Perfused Intestinal Segments

During the last decade, a wide range of isolated organ systems have been
developed for biomedical and pharmaceutical research. The availability
of sophisticated equipment, increased manual skills, and the routine use
and standardization of models and protocols, have led to the increased
reproducibility and validity of experimental results, virtually under “true-
to-life” circumstances. These methods contribute to the reduction of live
animal experimentation. The results are quite predictive of the in vivo
situation including absorption at the organ level.240, 241 Isolated perfused
organs have the distinct advantage that the scientist works with an intact
organ, where physiological cell-cell contacts and normal intracellular
matrixes are preserved.241 The major limitation, however, is the short
duration of the experiments, since changes tend to occur rapidly.

a. In Situ Single Pass Perfusion Technique (SPIP)

In this technique, perfusion solution is passed through the intesti-


nal segment (i.e., jejunum) by cannulating it at both the ends, and

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Self-Emulsifying Drug Delivery Systems

FIGURE 6. Schematic representation of single pass intestinal perfusion (SPIP) technique


as employed for the SEDDS formulation in rat.

various permeability parameters are calculated from amount of drug


unabsorbed from the intestine.190 Besides providing experimental
conditions closer to that occurring in vivo, this technique is also able
to predict the exact mechanism of absorption, i.e., passive absorption,
carrier mediated absorption or active transport.242 Figure 6 describes
the schematic representation of a typical SPIP technique in rat.
In this technique, the proximal part of the jejunum, 2-5 cm below
the ligament of Trietz is cannulated with a glass cannula and con-
nected to the reservoir.243 The intestine segment is perfused with blank
phosphate buffer (37± 1°C) until perfusate is clear. The intestine is

477
B. Singh et al.

subsequently perfused with drug solution maintained at 37± 1°C at a


perfusion rate of 0.2-0.3 ml/min. During the experiment, the animal
is kept under a heating lamp, and the exposed abdomen is covered
with a cotton pad to minimize dehydration. Steady state is usually
achieved within 30 min, following which 4-5 samples are obtained at
regular intervals of around 15 minutes. During the experiment, the
amount of water entering into the system and water leaving the system
is carefully recorded to calculate water flux.244 Effective permeability
(Peff) is calculated after correcting the outlet concentration for water
flux on the basis of ratio of weight of perfusion solution collected
and infused for each sampling points as mentioned in Equation 4.

(4)

where, Q is the flow rate, Cin and Cout are the respective inlet and
outlet concentration, r is the radius of the intestine, and l is the
length of the intestine measured after completion of perfusion. Aque-
ous permeability (Paq) was calculated using Equation 5:

(5)

where D is the diffusion coefficient, and the factor , known


as Graetz number (Gz), plays an important role in determining the
dimensionless quantity, A. Wall permeability (Pwall) is calculated
using Equation 6:

(6)

Dimensionless absorption number (An) is computed as the ratio of


the fundamental mass transfer process affecting drug removal from
intestine as shown in Equation 7:
(7)
where, SF is a scaling factor of 1.27 for complete radial mixing model.
The fraction of dose absorbed in rats using parameter determined
from perfusion experimental model is calculated using radial mixing
model as described in Equation 8:
(8)

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Self-Emulsifying Drug Delivery Systems

b. Everted Sac Technique

In this method, a 2 to 4 cm section of the intestine is tied off at one


end and everted using a glass rod or a thread. This method can be
used to determine kinetic parameters with high reliability and repro-
ducibility.245 Oxygenated tissue culture media and specific preparation
techniques ensure tissue viability for up to 2 hours. The technique
can be used to study drug transport across the intestine and into
the epithelial cells, provided that sensitive detection methods are
employed.246 Radiolabeled compounds are most appropriate for the
purpose. It is used mainly to quantify the paracellular transport of
hydrophilic molecules and to estimate the effects of potent enhancers
on their absorption. Molecules that cross the epithelial barrier by a
transcellular route have much higher permeability which can also
be accurately quantified using the everted sac system.
This kind of model is also suitable for measuring absorption at
different sites in the small intestine and for performing preliminary
experiments on the colon.245, 247 It is also useful for estimating the
first-pass metabolism of drugs in intestinal epithelial cells. Also, by
using this model (everted or not), it is convenient to study the effect
of Pgp on xenobiotic transport through the intestinal barrier. A poten-
tial disadvantage of this approach is the presence of the muscularis
mucosa, which is not usually removed from everted sac preparations.
Therefore, this model does not reflect the actual intestinal barrier,
because compounds under investigation pass from the lumen into
the lamina propria (where blood and lymph vessels are found) and
across the muscularis mucosa. Thus, the transport of compounds
with a propensity to bind to muscle cells might be underestimated.

c. Diffusion Cells Using Tissues

In this method, diffusion across a small section of intestine repre-


senting mucosal environment is studied into a system with specific
fluid pH, temperature, etc. representing secrosal environment. The
buffer solution at both sides of the membrane is gassed continuously
with carbogen.240 The same method can be used for tissues other than
intestinal tissue (e.g., buccal, esophageal, gastric, rectal, nasal, lung,
skin tissue, etc.). The usefulness of these cells for intestinal transport
studies has long been recognized. These cells have also been used
to study the intestinal metabolism of xenobiotics.240 In this system,
the drug can be exposed at either the mucosal level or the serosal

479
B. Singh et al.

level. The simplicity of these cells makes them an attractive in-vitro


model system for studying drug transport. This type of study may
provide additional information on the pharmacological behavior of
the test compound.

IV.B. Cell Models

1. Caco-2 Cells

Caco-2 cells are the most popular intestinal cellular model in stud-
ies on passage and transport. These cell lines are derived from
human colorectal adenocarcinoma.201 In culture, they differentiate
spontaneously into polarized intestinal cells possessing an apical
brush border and tight junctions between adjacent cells, and they
express hydrolases and typical microvillar transporters.6 Caco-2
cells, despite their colonic origin, express in culture the majority of
the morphological and functional characteristics of small intestinal
absorptive cells, including phase I and phase II enzymes, detected
either by measurement of their activities toward specific substrates,
or by immunological techniques.5, 201, 248

2. Brush Border Membrane Vesicles

In this approach, cell homogenates or intestinal pieces are treated by


calcium chloride precipitation method using centrifugation249. The final
pellet contains the luminal wall-bound proteins and phospholipids,
which contain most of the brush border enzymatic and carrier activ-
ity. Re-suspension of the pellet in buffer results in the formation of
vesicles. These vesicles are mixed with the permeant in buffer and
filtered after a fixed time, the amount of permeant taken up by the
vesicles is then determined. Typically, only the apical transcellular
transport is measured by this system. Despite drawbacks, like the
need for a radiolabeled compound and day-to-day variation in pre-
cipitation, this method is highly useful for mechanistic studies of the
drug absorption process.

3. Epithelial Cell Models

Uptake of a variety of substances is controlled by biological barriers


like epithelial tissues. Therefore, much attention is currently paid
to the use of epithelial cell cultures for studies of drug transport

480
Self-Emulsifying Drug Delivery Systems

mechanisms.250 Such studies are best performed in a model that


contains only absorptive cells, without the confounding contributions
of mucus, the lamina propria and/or the muscularis mucosa.

4. Isolated Intestinal Cells

These cells, obtained from the intestine of animal or human origin,


can be used as uptake systems in the assessment of oral bioavail-
ability. However, the use of isolated intestinal epithelial cells has
been relatively slow to gain popularity, because of the difficulty to
culture them and their limited viability.251, 252 Development of human
cell culture systems has been limited by the loss of important in-vivo
anatomical and biochemical features. Attention has, therefore, turned
to the use of human adenocarcinoma cell lines, such as HT-29 and
Caco-2, which reproducibly display a number of properties character-
istic of differentiated intestinal cells.253 They offer the advantage of
relative simplicity and suitability for automated procedures and HTS.
Nevertheless, the limitations of cell models must not be overlooked.
These cell lines originate from tumors, and out of the in-vivo physi-
ological environment. Therefore, extrapolation of the data to the in-
vivo situation may be difficult, as is true for most of in vitro systems.

5. Non-Intestinal Cell Systems

Madin Darby canine kidney (MDCK) cells have been isolated from
dog kidneys.254, 255 They are currently used to study the regulation
of cell growth, drug metabolism, toxicity and transport at the distal
renal tubule epithelial level.256, 257 MDCK cells have been shown to
differentiate into columnar epithelial cells and to form tight junctions
when cultured on semi-permeable membranes.258

V. BIOAVAILABILITY ENHANCEMENT

Drug absorption from an oral DDS can simplistically be considered


as a consecutive process of dissolution and permeation. Oral bio-
availability of a chemically stable drug is limited by its solubility
or permeability. Poor drug absorption, therefore, can be caused by
inadequate rate and extent of drug dissolution and/or low permeation.
Accordingly, as per the BCS,259 a drug can be classified in one of the
four possible categories, class I to IV based on these solubility and
permeability characteristics.

481
B. Singh et al.

The BCS class-I drugs, being highly soluble and permeable,


do not normally pose any problem of rate and extent of bioavail-
ability, with more than 90% drug absorption.260 Bioavailability of
poorly soluble BCS class-II drugs, on the other hand, is depen-
dent on their aqueous solubility/dissolution rate.41 Because these
drugs tend to exhibit dissolution-limited bioavailability, the in
vivo physiological performance correlates well with their in vitro
dissolution, resulting eventually in good in vitro/in vivo correla-
tions.261,262 Absorption of BCS class-III drugs is a distinct func-
tion of the permeability across GI barriers. BCS class-IV drug
compounds have neither sufficient solubility nor permeability for
oral absorption to be complete.259
For accomplishing better solubility or dissolution rate of BCS
class-II drugs, techniques such as micronization,263 co-solvents,264
micellar solubilization,265 solid dispersions,266 and complexation267
have been employed successfully. Diverse penetration or permeation
enhancers have been used to enhance drug absorption of BCS class-
III drugs effectively. The BCS class-IV drugs, on the other hand,
are considered problematic for product development pharmacists,
because it is difficult to improve the solubility and permeability of a
drug using conventional approaches. Self-emulsifying systems, in this
context, offer the unique feature of augmenting both the solubility
and permeability of diverse medicinal agents. Further, successful in
vitro/in vivo correlations have been established with poorly soluble
BCS class-II drugs such as probucol and carvedilol encapsulated
into SEDDS.93,268 Figure 7 diagrammatically outlines the potential of
SEDDS formulations for overcoming the problems of poor solubility
and/ or permeability of the BCS class-II to -IV drugs, leading eventu-
ally to enhanced bioavailability.

1. Mechanism of Drug Transport from SEDDS

The pathway of lipidic transport from the GI lumen to the systemic


circulation is of paramount significance for interpretation of the
biopharmaceutical properties of oral lipid-based formulations and
successful product development. On oral administration, the SEDDS
formulation undergoes digestive, absorptive, and circulatory phases.
Figure 8 presents a comprehensive pictorial view of such pathways
through which the drug molecules form self-emulsifying systems
and tend to get absorbed into the circulatory system. Understanding
the effect of lipid type and lipid digestion, in addition to drug load

482
483
FIGURE 7. Overcoming the problems of solubility and/ or intestinal permeability of Biopharmaceutical Classification System class II
to IV drugs employing SEDDS.
B. Singh et al.

FIGURE 8. Diagrammatic representation depicting the probable mechanistic pathways


for transportation of drugs across the GI lumen using SEDDS.

potential and the ease of dispersion of the SEDDS formulation, is


necessary to precisely predict and explain in vivo bioperformance. The
intraluminal processing of lipids prior to absorption (Fig. 8) dictates
the GI solubilization and bioavailability of the drug.

484
Self-Emulsifying Drug Delivery Systems

The combined effect of antral contraction, retropulsion, and gastric


emptying during the digestive phase disperses the lipidic formulation
into a coarse emulsion. This emulsion undergoes enzymatic hydroly-
sis at the oil/water interface, converting the digestion products into
an absorbable form. These dispersed lipid digestion products, along
with the undigested lipids, then empty into the duodenum,269 causing
the release of secretin from the duodenal mucosa, and this in turn
maximizes the activity of pancreatic lipase and co-lipase through the
secretion of bicarbonate.270 Digestion is completed by the action of these
interfacial enzymes that act on the surface of the emulsified triglyceride
droplets to quantitatively produce the corresponding 2-monoglyceride
and two fatty acids. The digestion phase terminates with the interac-
tion of fatty acids and monoglycerides with bile salts, resulting in the
formation of mixed micelles, while part of the triglycerides and fatty
acids may form vesicles after digestion in this preabsorptive phase. It
is at this phase that the drug released from the SEDDS due to either
precipitation or dissolution into the gastric media is resolubilized as
micelles or mixed micelles by emulsification.271
During the absorptive phase, these colloidal species produced as a
result of lipid digestion are taken up by passive diffusion, facilitated
diffusion, or active transport through the enterocyte membrane. In
the cytosol, a fatty acid-binding protein transports these micelles
through the apical membrane by a carrier-mediated transport pro-
cess.272 Alternatively, the absorbed free drug may be merged with
the chylomicrons (i.e., intestinal lipoproteins) within the enterocyte.
These chylomicrons are relatively large colloidal systems capable of
selective intestinal lymphatic transport of the lipophilic compounds.273
The endothelial architecture of the lymphatic vessels facilitates the
size-selective transport of chylomicrons for which simplistic access
across the blood capillary endothelium is restricted.274 Chylomicrons
travel through the lacteals to join lymphatic vessels from other parts of
the body, and enter the systemic circulation via the thoracic duct into
the subclavian vein, thus protecting the drug from hepatic first-pass
metabolism. During the circulatory phase, the blood-borne chylomicrons
rapidly disassemble, releasing the encapsulated drug. The residual
constituent lipids of SEDDS are utilized throughout the body.

2. Lymphatic Pathway

The lymphatic system is an extensive drainage network spread


throughout the body. It shadows the blood circulation system and

485
B. Singh et al.

functions mainly to return fluid that has leaked into the intersti-
tial space back to the blood. The intestinal lymphatics also play
an essential role in the absorption of products from lipid digestion,
e.g., long-chain fatty acids and lipid-soluble vitamins. Advantages of
drug delivery to the intestinal lymphatic system include avoidance
of hepatic first-pass metabolism and the potential to target specific
disease states known to spread via the lymphatics (e.g., certain
lymphomas, HIV, etc.). At the cellular level, three pathways have
been investigated to potentially target the drugs into the intestinal
lymphatics. The choice of pathway depends upon the physicochemical
properties of the drug candidate and the design of the drug-delivery
system.16,275-278
Possible mechanisms of drug transport through intestinal bar-
riers using the SEDDS include: an increase in membrane fluidity,
facilitating transcellular absorption; opening of the tight junction to
allow paracellular transport, mainly relevant for ionized drugs or
hydrophilic macromolecules; inhibition of P-gp and/or cytochrome
P450 to increase intracellular concentration and residence time; and
stimulation of lipoprotein/chylomicron production (Fig. 8). The latter
two mechanisms are potentially the most promising for intestinal
lymphatic drug targeting using lipid-based vehicles.276
Lipid-based vehicles and the presence of food often enhance
oral absorption, particularly of poorly water-soluble drugs. In some
instances, the lymphatic system plays a significant role in this
enhanced bioavailability. It seems quite likely, therefore, that the
physiological processes of lipid digestion and absorption are relevant
to this enhanced drug delivery. The lipid digestion and absorption
process, and its direct association with lymphatic transport of lipophilic
drugs, have already been extensively reviewed.15,275 Briefly, lingual
and gastric lipases279,280 initiate hydrolysis of a limited amount of
triglycerides, forming the corresponding diglyceride and fatty acids
within the stomach.23,62,275,281,282
Lipid vehicles may enhance lymphatic transport of lipophilic
compounds by stimulating the production of chylomicrons.116 Lipo-
philic drugs enter the lymphatic system in association with the tri-
glyceride core of the chylomicrons. Strong correlation, therefore, has
been established between the degree of lymphatic transport and the
triglyceride content of the lymph during the transport of a lipophilic
antimalarial drug.283

486
Self-Emulsifying Drug Delivery Systems

a. Paracellular Pathway

Firstly, absorption enhancers may open up the paracellular route,


resulting in increased absorption of hydrophilic macromolecules or
macromolecular conjugates.284 Due to the porous structure of the
lymphatic capillaries and the large size of the macromolecules, tar-
geting into the lymphatics may be possible.
Surfactant(s), one of the vital components of SEDDS, may open
up the paracellular route, resulting eventually in the increased per-
meability of hydrophilic molecule or macromolecule conjugate(s). Due
to the porous structure of the lymphatic capillaries, macromolecular
targeting may be possible. This route has an additional advantage
for the delivery of protein and peptide drugs owing to the existence
of lower enzymatic activity. Nevertheless, there are also certain
limitations. The transport capacity of this route is limited owing to
relatively low surface area and safety issues, especially due to chronic
use of absorption enhancers.

b. Gut Associated Lymphoid Tissues

Secondly, access to the lymphatics may be gained via gut-associated


lymphoid tissues. This route has been mainly explored in the deliv-
ery of particulates with significant potential for vaccine delivery.285

c. Transcellular Pathway

Intestinal lipid transport via the transcellular route is the third major
mechanism of delivery of lipophilic compounds when formulated as
lipid-based vehicles.16 The degree of lymphatic targeting via this route
has been shown to be influenced by the design of the lipid-based
vehicle(s). A range of different types of lipid-based formulations,
including triglyceride emulsions, micellar systems, and SEDDS, have
been studied for the purpose.
The precise mechanism of drug transport via the transcellular route
is not fully understood. At the cellular level, stimulation of chylomi-
cron production is a key factor in enhancing lymphatic transport of
lipophilic compounds. This can be attained through formulation design
and incorporation of excipients such as long-chain unsaturated fatty
acids to drive chylomicron production. Drug loading is influenced by
the physicochemical properties of the drug candidate, which ideally
should have a log P value of around 4 to 5 and triglyceride solubil-

487
B. Singh et al.

ity of around 50 mg mL–1.286 Pre-absorptive events in the gut lumen


have also been shown to influence the degree of lymphatic transport;
the physiological processes of lipid digestion and absorption play a
role in drug uptake and lymphatic transport.15

3. Effect of P-gp Inhibition

There may be other possible reasons for enhanced uptake of hydro-


phobic and/or lipophilic drugs formulated as SEDDS from the GI
tract, such as a decrease in the P-gp drug efflux.7,8 In addition to a
multi-drug efflux pump, phase I metabolism by intestinal cytochrome
P450s is now recognized as a significant factor in oral drug bioavail-
ability. In some cases, as shown recently, excipients incorporated in
SEDDS/SMEDDS can inhibit both pre-systemic drug metabolism
and intestinal efflux mediated by P-gp, resulting in an increased oral
absorption of cytotoxic drugs.287,288

4. Effect of Formulation Constituents on Bioavailability


Enhancement

Of all of the constituents of SEDDS formulation, the most notewor-


thy effect on the bioavailability of drug compounds is exerted by the
lipids.18 Lipids are primarily responsible for promoting the transport
of lipophilic drugs through the lymphatic system, thus bypassing the
hepatic first-pass.17,47 Furthermore, the drug, which has been encap-
sulated in oil droplets, is further protected from the harsh chemi-
cal and enzymatic environments of the GI tract.287,288 The mode of
transport of drugs through the lymphatic system, however, depends
upon the nature of the lipids. Therefore, the route and mechanism
of drug transport tends to be a function of the type of lipids used.
Lipids having a carbon chain length shorter than 12 atoms, popularly
designated as medium-chain triglycerides (MCTs), enter systemic cir-
culation through the portal blood.329 The MCTs have been preferred
in SEDDS due to better solubility, self-emulsification ability, and
fluidity, primarily due to the fact that MCTs are not incorporated
into chylomicrons through re-esterification to triglycerides within the
intestinal cells. On the contrary, the re-esterified fatty acids of long-
chain triglycerides (LCTs) are secreted from the intestinal cells by
exocytosis into the lymph vessels.16,36 Studies have been undertaken
to compare the influence of MCTs and LCTs in SEDDS formulations
using drugs such as halofantrine303 and danazol.330

488
Self-Emulsifying Drug Delivery Systems

Apart from lipids, surfactants also play a key role in augmenting the
bioavailability of drugs encapsulated in SEDDS. In addition to increas-
ing the dissolution rate of drugs, surfactants disrupt the phospholipid
bilayer of intestinal membranes, which along with the unstirred aque-
ous layer forms the rate-limiting barrier to the absorption of drugs.18, 331
Most studies aiming at investigating the bioavailability enhance-
ment effect of SEDDS have been carried out in laboratory animals;
only a few studies in healthy human volunteers have been carried
out (Table 14). In a clinical study of 32 healthy males, a single dose
of astaxanthin SEDDS was administered to observe the enhance-
ment of bioavailability in relation to pure drug. The researchers
concluded that the relative bioavailability of the food supplement
astaxanthin given as a high single dose could be enhanced by its
incorporation into lipid formulations of various compositions.291 In
another study, six groups of three healthy volunteers were admin-
istered self-emulsifying systems of cyclosporine (200 mg) varying
in their ratio of drug to lipid. The optimized formulation showed a
1.2-fold increase in bioavailability compared Sandimmune Neoral.102
Likewise, a 1.075-fold increase in the bioavailability of fenofibrate
SMEDDS compared with Tricor® tablets was observed when admin-
istered to 18 human subjects.302 Another single center, open label
study involving eight volunteers concluded a 2.5-fold increase in
bioavailability of itraconazole SEDDS compared with Sporanox®
capsules.306 Subramanian et al. reported a relative bioavailability
of 132% when celecoxib was administered as SMEDDS compared
with a conventional marketed brand.97
Apart from these literature reports, a few clinical studies have
also been carried out with marketed products. In a crossover study
for nodular acne patients, Accutane® (SEDDS of isotretinoin), showed
a 2-fold increase in bioavailability when administered with a stan-
dardized high-fat meal compared with administration during a fasted
condition.332 Another clinical trial was conducted on Agenerase®,
an antiretroviral SEDDS formulation of amprenavir. The relative
bioavailability of oral drug solution was 14% less than the SEDDS
capsules as assessed in human adults. The study further concluded
that the SEDDS formulation may be taken with or without food, but
should not be taken with a high-fat meal.333
Table 14 lists such literature reports on oral bioavailability
enhancement of drugs accomplished using SEDDS and SMEDDS. As
illustrated in the table, up to a 78-fold increase in the bioavailability
of the drugs has been achieved from the SEDDS compared with their

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B. Singh et al.

Table 14. Literature Updates on Various Reports of Bioavailability


Enhancement Using Self-Emulsifying Formulations

Drug Enhancement With Reference Species Ref


to to No.
Acyclovir 3.5-fold Pure drug solution Male albino rats 34
Acyclovir 12.78-fold Commercial tablet Albino SD rats 289
AMG 517 3-fold Aqueous suspension Cynomologus mon- 153
keys
Anethole trithione 2.5-fold Tablets Rabbits 290
Astaxanthin 1.7 to 3.7-fold Commercial formula- Humans (male) 291
tion (hard gelatin
capsules)
Atorvastatin 1.5-fold Conventional tablet Beagle dogs 292
Bicalutamide 2-fold Suspension Rats 293
Carvedilol 4.13-fold Commercial tablet Beagle dogs 92
Carvedilol 1.56-fold Luode (a commer- Beagle dogs 294
cial tablet)
Celecoxib 1.32-fold Conventional cap- Healthy adult males 97
sule
Chlorpropham 1.22-fold Oral suspension F344 rats 295
Coenzyme Q10 2-fold Powder formulation Dogs 65
Cyclosporine 1.2-fold Sandimmun Neoral Humans 102
Cyclosporine 4-fold Sandimmun capsule Beagle dogs 296
Danazol 1.28-fold Powder formulation Beagle dogs 297
Danazol 2-fold Pure surfactant solu- Beagle dogs 298
tion
Diisopyramide, Ibu- 1.5- to 78-fold -- SD rats and beagle 299,
profen, Ketoprofen, dogs 300
Tolbutamide,
Exemestane 2.9-fold Suspension Female Wistar rats 301
Fenofibrate 1.075-fold Tricor® tablets Humans 302
Gentamycin 5-fold i.v. saline Beagle dogs 114
Halofantrine 6- to 8-fold Solid halofantrine Male beagle dogs 303
hydrochloride tablets
Indomethacin 1.57-fold IDM suspended in Male SD rats 120
methyl cellulose
Insulin 1.15-fold Subcutaneous injec- Beagle dogs 304
tion

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Self-Emulsifying Drug Delivery Systems

Itraconazole 2.27-fold Solid dispersion Male SD rats 305


Itraconazole 2.8- to 3.7-fold Sporanox® capsules SD rats 123
Itraconazole 1.9- to 2.5-fold Sporanox® capsules Humans 306
Itraconazole 2-fold Solid dispersion Rats 305
Ketoconazole 2-fold Pure drug Rats 307
Ketoprofen 1.13-fold Pure drug Humans 308
L-683453 1.137-fold -- Beagle dogs 309
Matrine 3.4-fold Pure drug Male Wistar rats 310
Mitotane  3.4-fold Lysodren® Rabbits 311
Nimodipine 2.6- to 6.6-fold Conventional tablet New Zealand male 67
Rabbits
Nimodipine 4.6-fold Suspension Male rabbits 67
1.91-fold oily solution
1.53-fold micellar solution
Nitrendipine 3.2-fold (Liquid Conventional tablet Beagle dogs 183
SEDDS) &
2.44-fold (SE
pellets)
Nitrendipine   1.6-fold Conventional tablet Beagle dogs 312
Oleanolic acid 2.4-fold Tablet Rats 313
Ontazolast 13.49-fold Suspension Male Charles River 47
CD rats
Oridonin 2.2-fold Suspension Male SD rats 191

Pacitaxel 1.84 to 5-fold Taxol formulation Rats, SD rats 7,75


Pacitaxel 1.32-fold Taxol formulation Rats and guinea 314
pigs
Phenytoin 2.3-fold Dilatin® suspension Rats 315
PNU-91325 1.11-fold Tween formulation Dogs 77
Probucol 1.56-fold Powder formulation Gottingen minipigs 61
Probucol 2-fold Oily formulation Gottingen minipigs 268
Progesterone 2.75-fold Suspension Female Sabra rats 138
Protein drugs 1.3- to 2.7-fold Free solution Rats 316
(β-lactamase)

Pueraria lobata iso- 2.5-fold Yufengningxin tablet Beagle dogs 192,


flavone 317
Pueraria lobata iso- 1.82-fold Yufengningxin tablet Rats 318
flavone

Continued on page 492

491
B. Singh et al.

Table 14. (Continued)

Ramipril 2.29-fold Conventional cap- Male albino rats 12


5.39-fold sule Wistar rats
Drug suspension
RO 15-0778 (a 1.89-fold Drug solution in Dogs 29
naphthalene deriva- 11.08-fold PEG
tive) 22.61-fold Capsule
Tablet
SC-52151 -- Elixir Humans 319
Silymarin 3.6-fold Legalon® capsule Rats 196
Silymarin 1.88-fold PEG solution Male rabbit 195
48.82-fold PEG suspension
Simvastatin 1.5-fold Zocor® tablets Beagle dogs 145
Solvent Green 3 1.7-fold Soybean oil emul- Rats 320
sion
Tocopherol 2.22- to 4.1- Natopherol® soft Humans 150
fold gelatin capsules
Torcetrapib 2-fold Capsules Dogs 321

Tretinoin 1.67-fold Commercial capsule Beagle dogs 322


formulation
Vinpocetine 17.3-fold Crude powder -- 323
Vinpocetine 1.72-fold Conventional tablet Beagle dogs 324

Vinpocetine 1.89- to 1.91- Tablets and crude SD rats 149


fold powder suspension
Vinpocetine 2.4-fold Physical mixture Wistar rats 163

Vitamin A 2-fold Oily drug solution Rats 325

Vitamin A acetate 1.43-fold Solid-state vitamin A Rats 184


oily solution
Zedoary essential oil 2.5-fold Unformulated oil Rats 326
Zedoary turmeric oil 1.35-fold Conventional SES Rabbits 197,
327
Zedoary turmeric oil 1.7-fold Unformulated  Zedo- Rats 328
ary turmeric oil

SD, Sprague-Dawley; SES, self-emulsifying systems

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Self-Emulsifying Drug Delivery Systems

respective conventional formulations. Comparative bioavailability


studies have proved the bioequivalence of the self-emulsifying systems
in liquid form with that of the corresponding solid dosage forms.93,139
Once SEDDS are formulated, optimized, and characterized, apt
technological knowledge has to be accumulated.334 To accomplish this,
the technique and formula of the laboratory scale needs to be scaled
up to the production level. SEDDS, being stable and robust formula-
tions, are considered quite conducive for this kind of translation and
transformation to the industrial milieu.

VI. CONCLUSIONS

The prevalence of a strong relationship between the pharmacophore


lipophilicity and its pharmacodynamic activity has led to the discovery
of new chemical entities, most of which are inadequately soluble in
aqueous fluids. Continued reliance on combinatorial chemistry and
high-throughput processing is likely to bring forth majority of such
new chemical entities, which fail on solubility and/or dissolution fronts.
The standard formulation manipulations aiming at bioavailability
enhancement, such as inclusion complexes, supersaturated systems,
and micronization, have been usually found to be ineffective, not
pragmatic, or inadequate for the purpose. Self-emulsifying formula-
tions, which allow better formulation versatility and characterization
of lipidic excipients, offer a viable alternative to serve the desired
purpose through physicochemical and physiological mechanisms
controlling drug absorption.
In addition to enhancing the solubility of poorly soluble drugs,
SEDDS also improve drug bioavailability by a number of other
possible pathways; for example, bypassing the hepatic first-pass
effect, inhibition of P-gp efflux, and resistance to metabolism by the
cytochrome P450 family of enzymes within the gut and liver. The
miniscule globule size of SEDDS, coupled with their surface activity,
enables more efficient drug transport through the intestinal boundary
layer and absorptive brush border membranes, resulting eventually
in a more rapid onset and extended duration of therapeutic action.
Further, less susceptibility of SEDDS to gastric emptying delays
and lipolysis in the GI tract, as well as their high thermodynamic
stability and robustness to dilution, thus keeping the drug in a solu-
bilized state during the absorption phase, also reduces variability in
bioavailability. To date, no other DDS can match the bioavailability
enhancement potential of these self-emulsifying formulations.

493
B. Singh et al.

Apart from the technological versatility of the SEDDS in employ-


ing different drugs, processes, and excipients, these formulations are
also quite favorable for federal acceptance, because they qualify as
GRAS excipients during their manufacture. Furthermore, the ease
of their scale-up tends to reduce the burden of technology transfer
form laboratory to industry-sized batches.
Like any other drug-delivery technology, there have been barri-
ers to the practical applications of SEDDS formulations. Because of
these barriers, the so-called “improved bioavailability” drug-delivery
products that have been introduced into the market lately mostly
consist of conventional products rather than SEDDS. No doubt, the
number of publications, patents, and technologies on SEDDS are
increasing at a steady pace. However, considerable skepticism and
apathy tend to fuel the reluctance to undertake research into this
relatively novel and more useful SEDDS approach. Now is the most
opportune time to intensify research efforts on these promising drug-
delivery systems directed at surmounting the solubility and stability
issues, improving production methodologies on industrial scale, and
refinement of in vitro as well as in vivo models for more dependable
prognosis of formulation performance in humans.
This paper is an attempt by the authors to provide a holistic
overview of all of the vital characteristics of these self-emulsifying
formulations. It is hoped that this will provide the desired impetus
to product development scientists, facilitating further evolution of
SEDDS research and next-generation product launches. The day is
not far off when the benefits of these self-emulsifying formulations
will be realized and used by the drug industry and research groups
to their fullest advantage.

ACKNOWLEDGMENTS

Vital inputs from Mr. Lalit Kumar Khurana, Mr. Rattandeep Singh
Batra, Mr. Gajanand Sharma, Ms. Rajeshri Suther, Mr. Sandeep K.
Singh, and Ms. Sudha Dehal in the compilation of the current manu-
script are gratefully acknowledged. The authors are also thankful to
the University Grants Commission (UGC), New Delhi, India, and to
the All India Council of Technical Education (AICTE), New Delhi,
India, for providing financial assistance to conduct drug-delivery
research on SEDDS at the institute.

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Self-Emulsifying Drug Delivery Systems

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