Drug Development and Industrial Pharmacy, 2012, 1–19, Early Online

© 2012 Informa Healthcare USA, Inc.

ISSN 0363-9045 print/ISSN 1520-5762 online
DOI: 10.3109/03639045.2012.660949

REVIEW ARTICLE

Role of excipients in successful development of

self-emulsifying/microemulsifying drug delivery
system (SEDDS/SMEDDS)
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Md. Akhlaquer Rahman1, Arshad Hussain1, Md. Sarfaraj Hussain1, Mohd. Aamir Mirza2, and
Zeenat Iqbal2
1
Faculty of Pharmacy, Integral University, Lucknow, India and 2Department of Pharmaceutics, Faculty of Pharmacy,
Jamia Hamdard, New Delhi, India

Abstract
The oral delivery of hydrophobic drug presents a major challenge because of the low aqueous solubility of such
compounds. Self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS), which are isotropic mixtures
of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve
the oral absorption of highly lipophilic drug compounds. The efficiency of oral absorption of said drug from such type
of formulation depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant
For personal use only.

ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification
ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems.
With the growing interest in this field, there is an increasing need for guidelines in excipient selection to obtain
effective delivery system with improved bioavailability.
The aim of this review is to present the recent approaches in selecting the most appropriate lipid system(s); methods
for its characterization and role of various excipients for improved delivery of dosage form.
Keywords: Self-emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS), lipophilic drugs, excipient,
surfactant, P-glycoprotein (P-gp), oral delivery, oral bioavailability

Introduction compounds is not feasible and the synthesis of weak

Oral route has been the major route of drug delivery for acid and weak base salts may not always be practical.
the chronic treatment of many diseases. However, oral Moreover, the salts that are formed may convert back to
deliveries of 50% of the drug compounds are hampered their original acid or base forms and lead to aggregation in
because of the high lipophilicity of the drug itself. Nearly the gastrointestinal tract. Particle size reduction may not
40% of new drug candidates exhibit low solubility in water, be desirable in situations where handling difficulties and
which leads to poor oral bioavailability, high intra- and poor wettability are experienced for very fine powders4.
inter-subject variability and lack of dose proportional- To overcome these drawbacks, various other formulation
ity1. Thus, for such compounds, the absorption rate from strategies have been adopted including the use of cyclo-
the gastrointestinal (GI) lumen is controlled by dissolu- dextrins, nanoparticles, solid dispersions and inclusion of
tion2. Modification of the physicochemical properties, permeation enhancers1,5. Indeed, in some selected cases,
such as salt formation and particle size reduction of the these approaches have been successful. In recent years,
compound may be one approach to improve the dissolu- much attention has focused on lipid-based formulations
tion rate of the drug3. However, these methods have their to improve the oral bioavailability of poorly water soluble
own limitations. For instance, salt formation of neutral drug compounds. In fact, the most popular approach is

Address for Correspondence: Md. Akhlaquer Rahman, Faculty of Pharmacy, Integral University, Lucknow 226026, India.
Tel: +91 9565402042. Fax: +91 0522 2890809. E-mail: [email protected]
(Received 02 May 2011; revised 09 January 2012; accepted 20 January 2012)

1
 2 M.A. Rahman et al.
the incorporation of the drug compound into inert lipid Type II lipid formulations (typically referred to as
vehicles such as oils6, surfactant dispersions7,8, self-emul- self-emulsifying drug delivery system, SEDDS) are iso-
sifying formulations9–12, emulsions13–17 and liposomes18 tropic mixtures of lipids and lipophilic surfactants that
with particular emphasis on self-emulsifying/microemul- self-emulsify to form fine oil-in-water emulsions when
sifying drug delivery system (SEDDS/SMEDDS). introduced in aqueous media24. Self-emulsification is
generally obtained at surfactant contents above 25%
(w/w). However, at higher surfactant contents (greater
Self-emulsifying/microemulsifying drug than 50–60% (w/w) depending on the materials) the
delivery system progress of emulsification may be compromised by the
They are defined as isotropic mixtures of natural or syn- formation of viscous liquid crystalline gels at the oil/
thetic oils, solid or liquid surfactants, or alternatively, one or water interface25. Poorly water soluble drug (PWSD)
more hydrophilic solvents and co-solvents/surfactants19,20. can be dissolved in SEDDS and encapsulated in hard or
Upon mild agitation followed by dilution in aqueous media, soft gelatin capsules to produce convenient single unit
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such as GI fluids, these systems can form fine oil-in-water dosage forms. Type II lipid-based formulations pro-
(o/w) emulsions (10–1000 nm) or microemulsions (above vide the advantage of overcoming the slow dissolution
200 nm). They spread readily in the GI tract, and the diges- step typically observed with solid dosage forms and as
tive motility of the stomach and the intestine provide the described above, generate large interfacial areas which
agitation necessary for self-emulsification11. in turn allows efficient partitioning of drug between the
Due to the large number of possible excipient com- oil droplets and the aqueous phase from where absorp-
binations that may be used to assemble lipid based for- tion occurs26. The SEDDS formulation showed superior
mulations and self-emulsifying systems in particular, a in vivo performance with at least 3-fold higher Cmax and
classification system (Lipid Formulation Classification AUC when compared with the other dosage forms. Rapid
System-LFCS) was established by Pouton in 2000 and release of the drug and increased drug solubilization in
recently updated (2006) to help stratify formulations into the gastrointestinal lumen were suggested to be respon-
those with similar component parts21,22. The LFCS classi- sible for the improved drug bioavailability.
fies lipid-based formulations into four types according to Type III lipid based formulations, commonly
their composition and the possible effect of dilution and referred to as self-microemulsifying drug delivery
For personal use only.

digestion on their ability to prevent drug precipitation. system (SMEDDS), and are defined by the inclusion
Type I systems consist of formulations which comprise of hydrophilic surfactants and co-surfactant. Type III
drug in solution in triglycerides and/or mixed glycerides formulations can be further segregated (somewhat
or in an oil in water emulsion stabilized by low concentra- arbitrarily) into Type IIIA and Type IIIB formulations
tion of emulsifiers such as 1% (w/v) polysorbate 6023 and in order to identify more hydrophilic systems (Type
1.2% (w/v) lecithin15. Generally, these systems exhibit IIIB) where the content of hydrophilic surfactants and
poor initial aqueous dispersion and require digestion by co-surfactant increases and the lipid content reduces.
pancreatic lipase/co-lipase in the GIT to generate more Type IIIB formulations typically achieve greater disper-
amphiphilic lipid digestion products and promote drug sion rates when compared with Type IIIA although the
transfer into the colloidal aqueous phase. However, for risk of drug precipitation on dispersion of the formula-
readily digestable formulations this process is typically tion is higher given the lower lipid content. The distinc-
efficient and facile formulation dispersion and drug tion between SEDDS (Type II) and SMEDDS (Type III)
solubilization may be catalyzed by lipid digestion. Type I formulations is also commonly made on the particle
lipid formulations therefore represent a relatively simple size and optical clarity of the resultant dispersion27.
formulation option for potent drugs or highly lipophilic Types of oral lipid formulations, excipients used with
compounds where drug solubility in oil is sufficient to their advantages and limitations are also summarized
allow incorporation of the required payload (dose). in Table 1.

Table 1. Types of oral lipid formulations, their advantages and limitations.

Formulation type Excipients Characteristics Advantages Limitations
Type I Oils without surfactants Non-dispersing, requires GRAS, simple, good capsule Poor solvent capacity unless
(e.g., tri-, di-, and digestion compatibility drug highly lipophilic
monoglycerides)
Type II Oils and water-insoluble SEDDS formed without Unlikely to loose solvent Rather coarse o/w dispersion,
surfactants water-soluble components capacity on dispersion digestion likely but not crucial
Type III Oils, surfactants and SEDDS/SMEDDS formed Clear or almost clear Possible loss of solvent capacity
co-solvents (both water with water-soluble dispersion; digestion not on dispersion and/or digestion
soluble and insoluble components necessary for absorption
excipients)
Type IV Water-soluble Typically disperses to form a Formulation has good Likely loss of solvent capacity
surfactants only or with micellar solution solvent capacity for many when dispersed, digestible
co-solvents (no oils) drugs

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 3

Solid self-emulsifying/microemulsifying Self-emulsification depends on the nature of the

drug delivery system oil/surfactant pair, surfactant concentration and oil/
surfactant ratio, and the temperature at which self-
Self-emulsifying/microemulsifying drug delivery sys- emulsification occurs. Only very specific pharmaceutical
tems require incorporation into capsules directly, or excipients combinations lead to efficient self-emulsifying
transformed into granules, pellets, and powders for dry systems (SES). The efficiency of drug incorporation into a
filled capsules as well as tablet preparations. The latter SEDDS is dependent upon the particular physicochemi-
are possible by innovative adaptations of conventional cal compatibility of the drug/system19. So, pre-formula-
equipment with relative ease and process simplicity, tion solubility and phase diagram studies are required in
using methods like melt granulation, melt extrusion, order to obtain an optimal formulation design. Although
adsorption on solid support, spray cooling, spray dry- incompletely understood, the currently accepted view is
ing, supercritical fluid based methods and high pressure that lipids may enhance bioavailability via a number of
homogenization28. Recently, pellets containing self- potential mechanisms, including33.
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emulsifying mixtures were prepared by extrusion-spher- Alterations (reduction) in gastric transit: Alterations
onization technique29. (reduction) in gastric transit slow down the delivery sys-
A high content of liquid formulation can be loaded tem to the absorption site and increases the time avail-
(upto 70%) onto a carrier, which not only maintains good able for dissolution33.
flowability but also enables the production of tablets with Increases in effective lumenal drug solubility: The
good cohesive properties and good content uniformity in presence of lipids in the GI tract stimulates an increase
both capsules and tablets. This clearly expands the options in the secretion of bile salts (BS) and endogenous biliary
available to the formulator. In addition to providing the lipids including phospholipid (PL) and cholesterol (CH),
obvious in vivo benefits of the delivery system in tablet leading to the formation of BS/PL/CH intestinal mixed
dosage form (improved drug absorption, and so on), the micelles and an increase in the solubilization capacity
benefits of developing a solid dosages forms are that a of the GI tract. However, intercalation of administered
high content of liquid formulation can be loaded onto a (exogenous) lipids into these BS structures either directly
carrier and the process gives good content uniformity. In (if sufficiently polar), or secondary to digestion, leads to
terms of functionality and performance, the solubilizing swelling of the micellar structures and a further increase
For personal use only.

properties of the final solid dosage form should remain in solubilization capacity33.
unaffected by both the adsorption of the liquid formula- Stimulation of intestinal lymphatic transport: For
tion onto a carrier and the state of the drug in the lipid highly lipophilic drugs, lipids may enhance the extent of
formulation. The formulation and process is remarkably lymphatic transport and increase bioavailability directly
straightforward and few challenges can be envisaged at or indirectly via a reduction in first-pass metabolism34.
the industrial scale. This technique offers formulators Changes in the biochemical barrier function of the GI
an additional option in the quest to achieve product tract: It is clear that certain lipids and surfactants may
performance, product design and manufacturability30,31. attenuate the activity of intestinal efflux transporters, as
Details of the formulation techniques are excluded from indicated by the p-glycoprotein efflux pump, and may also
this review. reduce the extent of enterocyte-based metabolism35.
Changes in the physical barrier function of the GI tract:
Various combinations of lipids, lipid digestion products
Biopharmaceutical issues
and surfactants have been shown to have permeability
It is important to note that lipids (e.g., triglycerides) enhancing properties36. For the most part, however, pas-
affect the oral bioavailability of drugs by changing sive intestinal permeability is not thought to be a major
biopharmaceutical properties, such as increasing dis- barrier to the bioavailability of the majority of poorly
solution rate and solubility in the intestinal fluid, pro- water-soluble, and in particular, lipophilic drugs.
tecting the drug from chemical as well as enzymatic
degradation in the oil droplets and the formation of Excipient selection
lipoproteins promoting lymphatic transport of highly Self-emulsification has been shown to be specific to the
lipophilic drugs32. nature of the oil/surfactant pair; the surfactant concen-
The absorption profile and the blood/lymph distri- tration and oil/surfactant ratio; and the temperature
bution of the drug depend on the chain length of the at which self-emulsification occurs. In support of these
triglyceride, saturation degree, and volume of the lipid facts, it has also been demonstrated that only very
administered. Drugs processed by the intestinal lymph specific pharmaceutical excipient combinations could
are generally transported to the systemic circulation in lead to efficient self-emulsifying systems10,11. Once a list
association with the lipid core of lipoproteins. In addition of suitable excipients is identified, a binary drug-excip-
to the stimulation of lymphatic transport, administration ient screening for solubility, compatibility, and stabil-
of lipophilic drugs with lipids may enhance drug absorp- ity should follow in order to identify the lipid system(s)
tion into the portal blood compared with non-lipid most appropriate for the drug in question. For design
formulations. of SEDDS/SMEDDS, which require multiple excipients,

© 2012 Informa Healthcare USA, Inc.

 4 M.A. Rahman et al.
although it is necessary to assess the relative solubility any safety issues and generally regarded as safe (GRAS).
and affinity of the drug for each component, the focus Vegetable oils are glyceride esters of mixed unsaturated
should be the overall solubilizing power of the system and long-chain fatty acids, commonly known as long-chain
not so much as the solubility of the drug in the individual triglycerides (LCT). Oils from different vegetable sources
components. These components are oily phase, surfac- have different proportions of fatty acids, the details of
tant and co-surfactant may be natural, semi-synthetic which are listed in Table 2. The fatty acid compositions
and synthetic. of coconut and palm kernel oils are noteworthy in that
The components are selected with objectives, such as: they are unusually rich in saturated medium-chain oils
(particularly C12). Coconut oil is distilled to produce the
• To achieve maximal drug loading; generic product ‘medium-chain triglycerides’ (MCT)
• To achieve minimal self-emulsification time and (also known as glyceryl tricaprylate/caprate) which is
droplet size in the gastric milieu for maximal available from several suppliers and commonly com-
absorption; prises glyceryl esters with predominantly saturated C8
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• To reduce variation in the emulsion droplet size as a (50–80%) and C10 (20–45%) fatty acids. Triglycerides are
function of pH and electrolyte content of the aque- highly lipophilic and their solvent capacity for drugs is
ous medium; commonly a function of the effective concentration of the
• To prevent/minimize drug degradation/metabolism ester groups, thus on a weight basis MCT generally has
in physiological milieu. higher solvent capacity than LCT39,40. In addition MCT is
not subject to oxidation, so is a popular choice for use in
Natural lipid lipid-based products.
A number of natural product oils, derived primarily from
plant sources and processed to remove impurities or to Semi-synthetic and synthetic lipid
isolate various fractions of the original product, are avail- Several liquid and thermo-softening (semisolid) excipi-
able and suitable for use in encapsulated oral formulation ents, most commonly prepared by chemically combin-
products. Naturally occurring oils and fats are comprised ing medium-chain saturated fatty acids or glycerides
of mixtures of triglycerides which contain fatty acids of derived from natural product plant oils, with one or more
varying chain lengths and degrees of unsaturation. The hydrophilic chemical entities are currently available as
For personal use only.

melting point of particular oil increases in proportion to pharmaceutical excipients for oral formulation develop-
the fatty acid chain lengths and decreases with increasing ment41. These excipients find application as drug-solu-
degree of unsaturation, which also increases the relative bilizing vehicles, surfactants and wetting agents and as
susceptibility to oxidation. Triglycerides may be syntheti- emulsifiers and co-emulsifiers in SEDDS and SMEDDS.
cally hydrogenated to decrease the degree of unsaturation, They are generally well-suited for filling into both soft and
thereby conferring resistance to oxidative degradation. hard gelatin or into HPMC capsules. Thermo-softening
Separation of natural product oils into their component excipients, which melt in the range of 26–70°C and exist
glyceride fractions is used to prepare excipients that max- as waxy semi-solids at ambient room temperature, are
imize desirable physical and drug absorption-promoting typically filled into capsules in the molten state, with the
properties, while minimizing such issues as susceptibil- excipient melting temperature limiting their use to hard
ity to oxidation37,38. Triglyceride vegetable oils have many gelatin capsules.
advantages as the foundation of self-emulsifying drug Partial glycerides are product of glycerolysis, a
delivery systems. They are commonly ingested in food, transesterification reaction of triglycerides with glyc-
fully digested and absorbed, and therefore do not present erol under heating with an alkaline catalyst in order

Table 2. Fatty acid composition of natural product oils.

Oil C8 C10 C12 C14 C16 C18 C18:1 C18:1-OH C18:2 C18:3
Apricot kernel – – – – – 1.0 64.2 – 28.3 0.2
Canola – – – – 4.7 2.0 60.0 – 21.7 9.1
Castor – – – – 2.0 1.0 7.0 87 3.0 –
Coconut 2.4 2.7 44.4 16.6 9.6 2.8 17.8 – 3.1 0
Corn – – – – 10.7 1.6 24.5 – 10.7 1.1
Olive – – – – 12.9 71.2 71.2 – 10.0 0.9
Palm – – – 1.0 45.0 40.0 40.0 – 2.0 –
Palm kernel – 4.0 48.0 16.0 8.0 15.0 15.0 – 36.0 –
Peanut – – – – 12.0 48.0 48.0 – 36.0 0
Safflower – – – – 5.5 11.1 11.1 – 81.4 0.4
Sesame – – – – 9.0 41.0 41.0 – 45.0 –
Soybean – – – – 10.4 21.5 21.5 – 51.5 7.8
Sunflower – – – – 6.2 20.7 20.7 – 67.9 0.2

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 5
to increase the hydrophilicity of vegetable oils. Partial definition these materials can only be used in Type III or
glycerides may also be obtained by either interesterifi- Type IV formulations. Above their critical micelle con-
cation or direct esterification of glycerol with selected centration these materials dissolve in pure water at low
lipids. Commonly known excipients that fall under this concentrations to form micellar solutions. This implies
category are glyceryl monocaprylocaprate (Capmul® an HLB value of approximately 12 or greater47. The fatty
MCM); glyceryl monostearate (Geleol™, Imwitor® acid components can be either unsaturated or saturated.
191, Cutina™ GMS or Tegin™); glyceryl distearate The popular castor oil derivative Cremophor® RH40, is a
(Precirol™ ATO 5); glyceryl monooleate (Peceol™); typical example of a product with saturated alkyl chains
glyceryl monolinoleate (Maisine™ 35-1); glyceryl resulting from hydrogenation of materials derived from
dibehenate (Compritol®888 ATO). Monoglycerides a vegetable oil. Its close relative Cremophor® EL, which
can also be acetylated on their two free hydroxyl groups has also been used widely, has a slightly lower degree
(Myvacet® 9-45)42. Polyoxylglycerides (also named of ethoxylation but is not hydrogenated and is therefore
macrogolglycerides by the European Pharmacopoeia) unsaturated. Relatively few of the available water-soluble
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are a well established class of pharmaceutical excipi- ester surfactants have been used in pharmaceutical prod-
ents for solubility and bioavailability enhancement43–45. ucts. This is a function of their proven safety profile rather
They are obtained by polyglycolysis of vegetable oils than particular advantages they offer in physicochemical
(hydrogenated or not) with polyoxyethyleneglycols performance.
(PEG) of certain molecular weight (varying from 200 to Polyalcohol esters of edible fatty acids are the last
2000 g/mol) under heating and in presence of an alka- and the largest family of vegetable oil derivatives. The
line catalyst. Each polyoxylglyceride is composed of a alcohols may be polyglycerol (polyglyceryl oleate:
defined mixture of mono-, di-, and triglycerides and Plurol™ Oleique CC497); propylene glycol (propylene
mono- and diesters of PEG. This composition renders glycol monocaprylate: Capryol™ 90, propylene glycol
them readily dispersible in water. Depending on the monolaurate: Lauroglycol™ 90); polyoxyethylene-gly-
distribution of their components, excipients belonging cols (PEG-8 stearate: Mirj® 45, PEG-40 stearate: Mirj®
to this category may take various physical forms rang- 52, PEG-15 hydroxystearate: Solutol® HS15), sorbi-
ing from viscous liquids to solids at room temperature. tan or monoanhydrosorbitol (sorbitan monooleate:
They may be composed of unsaturated long chain fatty Span® 80, polyoxyethylene-20 sorbitan monooleate
For personal use only.

acids (LCFA) like oleyl polyoxylglycerides (Labrafil® or polysorbate 80: Tween® 80). These esters are
M1944CS, synthesized by an alcoholysis/esterifica- amphiphilic compounds with medium to high HLB
tion reaction using apricot kernel oil and PEG 300) and depending on the type of alcohols used and the degree
linoleyl polyoxylglycerides (Labrafil® M2125CS, syn- of esterification48,49. They may be used as solubilizers,
thesized by an alcoholysis/esterification reaction using or as components of self-emulsifying systems in bio-
corn oil and PEG 300), saturated medium chain fatty availability enhancement.
acid esters like lauroyl polyoxylglycerides (Gelucire®
44/14, synthesized by an alcoholysis/esterification Co-surfactant
reaction using palm kernel oil and PEG 1500). Transient negative interfacial tension is rarely achieved
by the use of single surfactant, usually necessitating
Surfactant the addition of a co-surfactant. Fluid interfacial film is
The surfactant chosen must be able to lower the inter- again achieved by the addition of a co-surfactant. In the
facial tension to a very small value which facilitates dis- absence of co-surfactant, a highly rigid film is formed by
persion process during the preparation of SEDDS and the surfactant and thus produces microemulsion over
provide a flexible film that can readily deform around only a very limited range of concentration. The presence
the droplets and be of the appropriate lipophilic char- of co-surfactants allows the interfacial film sufficient
acter to provide the correct curvature at the interfacial flexibility to take up different curvatures required to
region. Surfactants are quite useful excipients when form microemulsion over a wide range of composition.
used correctly. Medium chain length alcohols (C3–C8), which are com-
The usual surfactant concentration in self-emulsifying monly added as co-surfactants, have the effect of further
formulations required to form and maintain an emulsion reducing the interfacial tension, whilst increasing the
state in the GI tract ranged from 30 to 60% w/w of the for- fluidity of the interface thereby increasing the entropy of
mulation. A large quantity of surfactant may irritate the GI the system50.
tract. Thus, the safety aspect of the surfactant should be
carefully considered in each case. The high HLB and sub-
Recently marketed excipients and their
sequent hydrophilicity of surfactants is necessary for the
regulatory status
immediate formation of o/w droplets and/or rapid spread-
ing of the formulation in the aqueous environment, pro- In a recently published survey by Strickley, it has deter-
viding a good dispersing/self-emulsifying performance. mined that oral lipid-based formulations have been
The most commonly used surfactants for self-emul- marketed for over 2 decades and currently comprise
sifying formulation are water-soluble22,46, though by an estimated 2–4% of the commercially available drug

© 2012 Informa Healthcare USA, Inc.

 6 M.A. Rahman et al.
products surveyed in 3 markets worldwide51. These single melting point. Differential Scanning Calorimetry
products accounted for approximately 2% (21 products (DSC) permits study of the thermal behavior of excipi-
total) of marketed drug products in the United Kingdom, ents: melting, crystallization, solid-to-solid transition
3% (27 products total) in the United States of America, temperatures and determination of the solid fat content
and 4% (8 products total) in Japan. Strickley’s survey of the excipient versus temperature (which can also be
revealed that the most frequently chosen excipients for assessed by Nuclear Magnetic Resonance, NMR). DSC
preparing oral formulations were dietary oils composed allows repeated heating/cooling cycles close to the ther-
of medium- (e.g., coconut or palm seed oil) or long-chain mal treatment; the excipients are exposed during process-
triglycerides (e.g., corn, olive, peanut, rapeseed, sesame, ing. In addition, microscopic methods such as hot-stage
or soybean oils, including hydrogenated soybean or microscopy (HSM) can be used to assess the organization
vegetable oils), lipid soluble solvents (e.g., polyethylene of the lipid excipient during heating or cooling. Nearly
glycol 400, ethanol, propylene glycol, glycerin). all lipid excipients exist under various polymorphs. For
Now, Polyglycolyzed glycerides (PGG) with varying glycerides the main crystalline structures determined by
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fatty acid and polyethylene glycol (PEG) chain lengths X-Ray Diffraction (XRD) are hexagonal (α), orthorhom-
giving them a varied HLB value, in combination with veg- bic (β′) and triclinic (β). These structures differ by their
etable oils have been used to solubilize poorly water-sol- thermal properties (transition and melting temperature
uble drugs and improve their bioavailability11. According for example), and depend on the thermal history of the
to the manufacturer, these products are derived from excipient. As a rule, polymorphic changes have little or no
selected, high purity; food-grade vegetable oils which are effect on the functionality of self-emulsifying systems that
reacted with pharmaceutical grade PEG and therefore are readily dispersible in aqueous or physiological media.
expected to be well tolerated by the body19. Ethoxylated If on the other hand the formulation matrix is slow or inca-
lipids are derived from castor oil that is rich in ricinoleic pable of erosion in the dissolution media, polymorphism
acid. Due to the presence of a hydroxyl group on the can significantly affect the drug release properties53–55.
twelfth carbon of ricinoleic acid, glycerides containing However, changes in lipid crystallinity can be controlled
this fatty acid can also be ethoxylated (reaction of etheri- by adapted means: tempering at a temperature close to
fication) to increase their hydrophilicity. They are widely the melting point of the excipient56, controlling the crys-
used as surfactants to enhance bioavailability of poorly- tallization rate57, adding some crystallization seeds to
For personal use only.

soluble drugs. Three main products representing this cat- promote the crystallization of one chosen polymorph; or
egory are: ethoxylated castor oil (Cremophor® EL) and even by adding other excipients such as cellulose ethers
ethoxylated hydrogenated castor oil (Cremophor® RH40 or polysorbates to the lipid excipient54–58.
and Cremophor® RH60). Examples of some new surfac-
tant, co-surfactant and oils (Lipid ingredients) available Chemical analysis
in Gattefosse, Abitech, BASF, and Sasol Chemicals with The exact composition of lipid-based excipients in terms
their regulatory status are mentioned in Table 3. of esters, ethers and fatty acid distribution can be assayed
Recently, the emulsification and solubilization proper- by established HPLC and GC methods. Also, quick tests
ties of polyglycolyzed glyceride-based oils, in self-emul- for excipient characterization are available as chemical
sifying formulations have been investigated using Tween indices like: Saponification Value relating to the molecular
80 and Tween 20 as surfactants52. Danazol, a poorly water- weight of the fatty acid chains; Iodine Value as a measure
soluble compound with an estimated aqueous solubility of of the saturation of hydrocarbon chains; Hydroxyl Value
<1 g/mL and log P = 4.2 and mefenamic acid, a non-steroi- to determine the quantity of free hydroxyl groups from
dal anti-inflammatory drug with an aqueous solubility of free glycerol, mono and diglycerides combined; Peroxide
40 g/mL and log P = 5.3 were selected as the model drugs. Value to quantify and monitor oxidative changes; and
The more hydrophilic oil-surfactant mixtures showed Acid Value for measuring the quantity of free (unest-
greater emulsification ability and a smaller particle size. erified) fatty acids. Regular testing for Peroxide Value
A linear relationship was observed between the HLB of and Acid Value can help assess oxidative stability and
the mix and the solubility of both danazol and mefenamic potential for hydrolysis of the sensitive bonds in storage
acid, with more hydrophilic mixtures producing greater or during processing. Analysis for moisture content may
drug solubility52 (Figure 1). These results should serve as a also be considered especially for hygroscopic/high HLB
useful guide to the proper selection of PGG for SEDDS. excipients. Complete set of analytical methods are avail-
able from USP/NF, EP and may also be obtained from the
manufacturer of the excipient28.
Quality control test for lipid excipients
Physical analysis
Dissolution and dispersion testing in
Since lipid based excipients are often processed near
appropriate media
or above their melting points, analysis of their thermal
behavior at varying stages of formulation is of prime The conventional USP dissolution testing is required
importance. Lipids possess complex chemical composi- by the FDA as a quality control tool and is rarely an
tions that lead to broad melting ranges as opposed to a indication of the in vivo dissolution behavior of

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 7

Table 3. Examples of lipid ingredients available in the market and their regulatory status.
Excipients Description/Main fatty acid Composition HLB Regulatory Status
Labrafac® Lipophile WL Medium chain triglycerides [Caprylic (C8) 50–80%, Capric 2 JPED, USP-NF, JSFA
1349 (C10) 20–50%]
Labrafac® PG Propylene glycol dicaprylocarate 2 USFA, E477, USP-NF Pending
Labrafil® M 1944 CS Oleoyl polyoxyl-6 Glycerides [Oleic (C18:1) 58–68%, 4 USP-NF, EP
Linoleic (C18:2) 22–32%]
Labrafil® M 2125 CS Linoleoyl polyoxyl-6 glycerides [Oleic (C18:1) 24–34%, 4 USP-NF, EP
Linoleic (C18:2) 53–63%]
Labrafil® M 2130 CS Lauroyl polyoxyl-6 glycerides 4 EP
Labrafac® CM 10 C8–C10 polyglycolized glycerides [Caprylic (C8) 50%, 10 –
Capric (C10) 50%]
Labrafil® WL 2609 BS Linoleoyl macrogol glycerides [Oleic (C18:1) 24–34%, 6 –
Linoleic (C18:2) 53–63%]
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

Labrasol® caprylocaproyl macrogol-8-glycerides [Caprylic (C8) 14 USP-NF, EP

50–80%, Capric (C10) 20–50%]
Lauroglycol™ 90 Propylene glycol monolaurate Type II [monoesters > 90%, 5 EP
C12 (lauric acid) > 95%]
Lauroglycol™ FCC Propylene glycol laurate Type I [monoesters 45–70%, 4 EP
30–55% Diester >95% C12]
Maisine™ 35-1 Glyceryl monolinoleate [C18:2 >50% max; C18:1 10–35%; 4 USP-NF, EP, FCC, GRAS, E471, JSFA
C18:0 <6%; C16 4–20%]
Cremophore® EL Polyoxy-35-castor oil 12–14 USP
Cremophore® RH40 Polyoxy-40-hydrogenated castor oil 14–16 FDA inactive ingredients
Cremophor® A25 Macrogol 25 cetostearyl ether [Stearic (C18) and Cetyl 15–17 –
(C16)]
Capryol™ 90 Propylene Glycol Monocaprylate [>90% Monoester of C8 6 USFA, JSFA, FCC, USP-NF
(caprylic acid)]
For personal use only.

Capryol™ PGMC 90 Propylene glycol monocaprylate; >60% Monoester >90% 5 USP 31-NF 26 Supp 1
C8
Peceol™ Glyceryl mono-oleate [C18:1 > 60%; C18:2 < 35%; 3.3 USP-NF, EP, FCC, GRAS, E471, JSFA
C18:0 < 6%; C16 < 12% 0–5%]
Plurol oleique® CC497 Polyglyceryl-3 dioleate 6 FCC, USFA, E471, JSFA
Plurol® Diisostearate Triglycerol diisostearate – EP
Transcutol® HP Diethylene glycol monoethyl ether (>99.9%) – USP-NF, EP, USIFA
Transcutol® P Diethylene glycol monoethyl ether – IIG, USP-NF, EP, USIFA
Vitamin E® TPGS Vit E d-α-tocopheryl polyethylene glycol 1000 succinate 13 USP
Gelucire® 44/14 Lauroyl polyoxylglycerides [C12 (40–50%); C14 (14–24%); 14 USP 29-NF 24 IIG/EP
C8 (4–10%), C10 (3–9%), C16 (4–14%), C18 (5–5%)]
Gelucire® 50/13 Stearoyl polyoxyl-32 glycerides [C16 (40−50%); 13 IIG, USP-NF, EP, USFA
C18 (48 – 58%); C16 + 18 > 90%]
Acconon® CC-6 PEG-6 Caprylic / Capric Glycerides 12.5 EP, USP, NF
Captex® 355 Caprylic/Capric Triglyceride – USP
Captex® 200 Propylene Glycol Dicaprylate/Dicaprate – –
Migliol® 810 Medium chain fatty acids [C8 (65–80%); C10 (–20–35%) – USP, NF, BP
Migliol® 812 Medium chain fatty acids [C8 (50–65%); C10 (30–45%) – USP, NF, BP
Migliol® 840 Medium chain diesters of propylene glycols – Ph. Eur., JCIC, USP-NF
Miglyol® 818 Medium chain fatty acids [C8 (45–65%); C10 (30–45%); – –
C18:2 (2–5%)]
Capmul® MCM Glyceryl monocaprylate [(58% MG, 36% DG, 5% TG; 80% 5–6 EP
C8, 20% C10)]
Capmul® MCM C8 Glyceryl monocaprylate[(68% MG, 27% DG, 3% TG; >95% 5–6 EP
C8, 3% C10)]
Capmul® MCM C10 Glyceryl monocaprylate [(>45% MG; >45% C10)] 5–6 EP
Imwitor® 742 MG/DG/TG of C8 and C10 Fatty Acid [45–55% MG] – USP/NF
Imwitor® 928 MG/DG/TG of saturated FA of coconut oil [40% MG] – USP/NF
Myrj® 45 PEG 400 monostearate Polyoxy 8 stearate [Stearic (C18) 11.1 –
acid]
Brij® 97 Polyoxyl 10 oleyl ether Oleth 10 PEG monooleyl ether 12.4 –
[Oleyl (C18:1)]

© 2012 Informa Healthcare USA, Inc.

 8 M.A. Rahman et al.

Analysis of physiological effects of excipients

Lipid-based excipients can influence oral absorption
via various physiological effects such as retarded gastric
emptying69, stimulating bile flow and secretion of pan-
creatic juice70, increasing the membrane lipid fluidity or
acting directly onto enterocytes-based drug transport
and disposition71, opening of tight junctions, inhibiting
efflux transporters like p-glycoprotein (P-gp), inhibiting
pre-systemic metabolism or promoting the lymphatic
pathway to avoid the first pass metabolism. Many in vitro
models are available to assess these effects (Caco-2 cells,
intestinal microsomes, precise slice of intestine72, Ussing
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

chamber, and everted gut sac) as well as in vivo models

(in situ perfusion).
Figure 1. Relationship between the solubility of mefenamic acid
and danazol in Labrafils and Labrafil/surfactant mixes and HLB
value of the solvent. Figures modified from Reference (52).
Formulation
l­ ipid-based formulations. Lipids and lipid-based The method of making self-emulsifying drug delivery
excipients are subject to digestive processes occurring system for increasing the bioavailability of a drug and/or
in the gastro-intestinal tract. Gastric and pancreatic pharmaceutical ingredient by emulsifying the drug with
lipases can lipolyze glycerides59,60 as well as other excipients includes various steps as described below;
esters of fatty acids and alcohols such as PEG esters
contained in polyoxyl glycerides61. Lipases may also 1) Preparation of phase diagram.
impact the emulsification/dispersion properties of 2) Solubilizing a poorly water-soluble drug and/or
fatty acid esters, hence altering their solubilization pharmaceutical ingredient, in a mixture of surfac-
capacity in vivo. Thus digestibility of the excipients tant, co-surfactant and solvent. Now mixing the oil
For personal use only.

should be taken into account during the development phase suitably prepared, if necessary, by heating or
of lipid-based formulations52,62–65. Dissolution test- other preparatory means, to the solubilized drug.
ing in bio-relevant media can help the formulator to 3) The emulsion, then be added to a suitable dosage
assess such effects and to predict the in vivo behavior form such as soft or hard-filled gelatin capsules and
of lipid-based formulations. allowed to cool.
Dispersion testing, i.e. emulsification capacity and
analysis of particle size distribution is often used to
assess the effectiveness of self-emulsifying formulations. In vitro characterization
Emulsification capacity is generally evaluated visually66 Determination of self-emulsification time
and particle size distribution can be measured either Pouton et al. quantified the efficiency of emulsification
by optical microscopy, laser light diffraction or Photon of various compositions of the Tween 85/medium-chain
Correlation Spectroscopy (PCS) depending on the fine- triglyceride systems using a rotating paddle to promote
ness of the dispersion. emulsification in a crude nephelometer24. This enabled
According to Reiss, self-emulsification occurs when an estimation of the time taken for emulsification. Once
the entropy changes that favors dispersion is greater than emulsification was complete, samples were taken for par-
the energy required to increase the surface area of the ticle sizing by photon correlation spectroscopy, and self-
dispersion67. The free energy of the conventional emul- emulsified systems were compared with homogenized
sion is a direct function of the energy required to create a systems. The process of self-emulsification was observed
new surface between the oil and water phases and can be using light microscopy. It was clear that the mechanism
described by the equation: of emulsification involved erosion of a fine cloud of small
particles from the surface of large droplets, rather than a
∆G = ∑ i ( N i 4 ∏ ri 2σ ) progressive reduction in droplet size.

where ΔG is the free energy associated with the pro- Turbidity measurement
cess, N is the number of droplets of radius r, and σ is This identifies efficient self-emulsification by establish-
the interfacial energy. The two phases of emulsion tend ing whether the dispersion reaches equilibrium rapidly
to separate with time to reduce the interfacial area and, and in a reproducible time73. These measurements are
subsequently, the emulsion is stabilized by emulsifying carried out using turbiditymeters, most commonly
agents, which form a monolayer of emulsion droplets, used are the Hach turbidity meter and the Orbeco-
and hence reduces the interfacial energy, as well as pro- Helle turbidity meter74. This apparatus is connected to
viding a barrier to prevent coalescence68. dissolution apparatus and optical clarity of formulation

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 9
is observed every 15 sec to determine clarity of micro- diffusion coefficients of many components. Self diffusion
emulsion formed. Turbidity can also be observed by coefficient (D) can be calculated using Stokes-Einstein
spectroscopic characterization of microemulsion (i.e. equation:
absorbance of suitably diluted aqueous dispersion at
suitable wavelength75. D = KT / 6πη r
where; K = Boltzmann constant, T = Absolute tem-
Droplet size perature, η = Viscosity of the medium, r = radius of the
Common techniques used to determine the droplet droplet.
size distributions of the resultant emulsions include
photon correlation spectroscopy, laser diffraction
and coulter counter. Photon correlation spectroscopy Electron microscopic studies
is sensitive to particles within a diameter range from Freeze fracture transmission electron microscopy
3 nm to 3 µm. Laser diffraction is effective in detecting (FFTEM) and Transmission electron microscopy (TEM)
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

droplets within a diameter range from 0.5 nm to 200 are the most important technique for the study of micro-
µm. A Coulter counter measures the change in the structures because it directly produces images at high
electrical resistance induced by the droplets of the resolution and it can capture any coexistent structure
sample flowing through a pinhole. A 30 µm pinhole and microstructure transitions83. However, extremely
is suitable for measuring the diameter of droplets rapid cooling of the sample is required in order to main-
within the size range of 1.5 µm to 10 µm. The advan- tain structure and minimize the possibility of artifacts in
tage of this technique is that it provides an absolute FFTEM studies.
droplet count within a specified size range, which is Recent developments in the cryofixation technique
in contrast to the relative count provided by laser dif- have overcome many problems associated with artifact
fraction76. Freeze-fracture electron microscopy has formation in early studies. A complementary technique is
been used to study surface characteristics of such of direct imaging, in which thin portions of the specimen
dispersed systems 77. Because of the high lability of are directly investigated in the frozen hydrated state by
the samples and the possibility of artifacts, electron using a cryostage in the TEM. The development of glass
microscopy is considered a somewhat misleading
For personal use only.

forming microemulsions that do not breakdown during

technique. Particle size analysis and low-frequency cooling and in which neither disperse nor matrix phase
dielectric spectroscopy have been used to examine crystallizes during the cooling process, has provided a
the self-emulsifying properties of Imwitor® 742 and way for direct studies of microemulsion and microemul-
Tween® 8078. sion structures84.
Zeta potential measurement
This is used to identify the charge of the droplets. In con- Scattering techniques
ventional SEDDS, the charge on an oil droplet is negative
because of the presence of free fatty acids79. Scattering method that has been employed in the study
of microemulsions include Small angle X-ray scatter-
Liquefaction time ing (SAXS)85,86, Small angle neutron scattering (SANS),
This test is designed to estimate the time required by Dynamic light scattering (DLS), Photon correlation spec-
solid SEDDS to melt in vivo in the absence of agitation troscopy (PCS)87. SAXS is capable of delivering structural
to simulated GI conditions. Dosage form is covered in information of macromolecules between 5 and 25 nm,
a transparent polyethylene film and tied to the bulb of of repeat distances in partially ordered systems of up to
a thermometer by means of a thread. The thermometer 150 nm. It is used for the determination of the microscale
with attached dosage form is placed in a round bottom or nanoscale structure of particle systems in terms of
flask containing 250 mL of simulated gastric fluid without such parameters as averaged particle sizes, shapes,
pepsin maintained at 37°C80. The time taken for liquefac- distribution and surface-to-volume ratio. SANS can be
tion is subsequently noted. used to obtain information on the size and shape of the
droplets. The term ‘droplet’ is used to describe micelles,
mixed micelles and oil-swollen micelles throughout the
Nuclear magnetic resonance (NMR) studies present work. Small-angle neutron scattering experi-
The structure and dynamics of microemulsions can be ments use the interference effect of wavelets scattered
studied by NMR techniques. Self diffusion measure- from different materials in a sample (different scattering-
ments using different tracer techniques, generally length densities).
radio labeling, supply information on the mobility and The major drawback of these techniques is the dilu-
microenvironment of the components81,82. The Fourier tion of the sample required for the reduction of inter-
transform pulsed-gradient spin-echo (FT-PGSE) tech- particular interactions. This dilution can modify the
niques use the magnetic gradient on the samples and it structure and the composition of the pseudo ternary
allows simultaneous and rapid determination of the self phases. Nevertheless, successful determination has been

© 2012 Informa Healthcare USA, Inc.

 10 M.A. Rahman et al.
carried out using a dilution technique that maintains the traditional medicine (TM) has been reported in author’s
identity of the droplets. published article93.
SANS allows selective enhancement of the scattering
power of different microemulsion pseudo phases using
Role of excipients in bioavailability
protonated or deuterated molecules. Dynamic light scat-
enhancement
tering, Photon correlation spectroscopy is used to ana-
lyze the fluctuations in the intensity of the scattering by In applying lipid-based drug delivery system (LBDD)
the droplets due to Brownian motion. the most common questions formulators face are: what
type of lipid(s) to use? Which formulation technique to
apply? How to develop and manufacture the formula-
Improvement of oral absorption by tion? Since the rationale for LBDD is to take advantage of
SEDDS/SMEDDS the influence lipids may have on processes that inhibit or
The release of drug from delivery system takes place promote drug absorption, it is essential to initially define
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

upon its partitioning into the intestinal fluids during the formulation objective(s). A first step in defining the
droplet transport and disintegration along the GI tract. It formulation needs may lie in the Biopharmaceutics Drug
was proposed that two main factors, small particle size Disposition Classification System (BDDCS) that allows
and polarity of the resulting oil droplets determine the general predictions pertaining to the biopharmaceutical
efficient release of the drug from formulation11. In o/w disposition of drugs based on their solubility and metab-
microemulsions, however, the impact of the polarity of olism. By definition, a type II BDDCS (low solubility,
the oil droplets is not very significant because the drug intense metabolism) drug needs solubility enhancers.
compound reaches the capillaries incorporated within For a type IV BDDCS (low solubility, low metabolism)
the oil droplets88,89. Owing to its miniscule globule size, drug however, the formulation may require the presence
the micro-emulsifed drug can easily be absorbed through of lipid-based excipients that facilitate permeation in
lymphatic pathways, by passing the hepatic first-pass addition to solubilization.
effect90.
Many studies carried out in animals for the assess-
Role of lipids
ment of the oral bioavailability of hydrophobic drugs
For personal use only.

formulated in o/w emulsions indicated better absorp- Lipids are found to have an important impact on the oral
tion profiles91, but the use of these systems is limited due bioavailability of PWSD. There are several complex pos-
to their poor physical stability and the large volumes sible mechanisms that can lead to alteration in the bio-
needed. Thus, SEDDS may be a promising alternative to pharmaceutical properties of the drug, like increase in
orally administered emulsions because of their relatively dissolution rate, increase in solubility in the GI fluid and
high physical stability and ability to be delivered in stan- protection of the drug from chemical as well as enzymatic
dard soft gelatin capsules. degradation in the oil droplets109–112 and the formation of
A higher bioavailability of hydrophobic drugs incor- lipoproteins promoting the lymphatic transport of highly
porated in SEDDS was reported earlier41. A study car- lipophilic drugs20. The absorption profile and distribu-
ried out in non-fasting dogs for the assessment of the tion of the drug compound into blood/lymphatic system
oral bioavailability of a lipophilic naphthalene deriva- are affected by the acid chain length of the triglyceride,
tive formulated in SEDDS demonstrated three-fold saturation degree, and volume of the lipid administered.
higher values in Cmax and AUC as compared to other Generally, compounds processed by the intestinal
dosage forms11. In another study done on rats, the oral lymph are transported to the systemic circulation in
bioavailability of the anti-inflammatory drug ontazolast association with the lipid core of lipoproteins113, and as
was substantially improved when this lipophilic drug such require co-administered lipid to stimulate lipo-
was administered in a lipid-based formulation, such as protein formation. Short and medium chain fatty acids
emulsion, glyceryl oleate (Peceol) solution, and SEDDS (with a carbon chain length shorter than 12 carbon
in comparison to the suspension formulation34. A mul- atom) are transported to the systemic circulation by the
tiple dosage study was conducted on humans diag- portal blood and are not incorporated to a great extent in
nosed with HIV infection who were given orally an HIV chylomicrons114.
protease inhibitor either as a SEDDS or as an elixir92. In contrast, long chain fatty acids and monoglycer-
Greater AUC values in addition to higher Cmax and Cmin ides are re-esterified to triglycerides within the intestinal
values were reported for patients given the SEDDS as cell, incorporated into chylomicrons and secreted from
compared to the ones given the elixir. Examples of bio- the intestinal cell by exocytosis into the lymph vessels.
availability enhancement of PWSD after administration Besides stimulation of the lymphatic transport, lipophilic
of SEDDS and MEDDS formulations and some of the drugs when administered along with lipids may enhance
marketed formulations are mentioned in Table 4 and drug absorption into the portal blood when compared
5 respectively. The application of lipid based formula- to non-lipid formulations115. Bile salts, monoglycerides,
tions (SEDDS/SMEDDS) as a promising system for cholesterol, lecithin and lysolecithin further emulsify the
the oral delivery of many therapeutic agents including large fat droplets upon their entry to the intestine, and

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 11

Table 4. Examples of bioavailability enhancement of PWSD after administration of SEDDS and MEDDS formulations.
Compound Category Formulation(s) Study design/Observations Ref
Cyclosporin Anticancer Sandimmune (SEDDS: Corn oil Relative BA in humans/Increased (94)
and Ethanol) or BA and Cmax and reduced Tmax from
Neoral (SMEDDS: SMEDDS
Corn oil glycerides,
Cremophor®
RH40, PG, DL-α-
tocopherol and
Ethanol)
Sandimmune (SEDDS) or Relative BA in humans/Increased Cmax, (95)
Neoral (SMEDDS) AUC and dose linearity and reduced
food effect from SMEDDS
Sandimmune (SEDDS) or Relative BA in humans/Reduced (96)
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

Neoral (SMEDDS) intra-and inter-subject variability from

SMEDDS
Halofantrine Antimalarial MCT SEDDS (47% Captex® 355, 23% Capmul® Relative BA in dogs/Trend to higher (97)
MCM, 15% Cremophor® EL and Ethanol).MCT BA from LCT SMEDDS
SMEDDS (33% Captex® 355, 17% Capmul® MCM,
35% Cremophor® EL and Ethanol),LCT SMEDDS
(29% Soybean oil, 29% Maisine™ 35-1, 30%
Cremophor® EL and 7% Ethanol)
Ontazolast Antiarrhythmic SEDDS (Gelucrie® 44/14 and Peceol™ in the ratios Absolute BA in rats/BA increases of at (32)
50:50 and 80:20) least 10-fold from all formulations
Vitamin E Nutritional LCT SEDDS (Tween® 80:Span® 80:Palm oil in a Relative BA in humans/BA 3-fold (98)
supplement ratio of 4:2:4) higher from SEDDS
Coenzyme Q10 Antooxidant SMEDDS (40% Myvacet® 9–45, 50% Labrasol® and Relative BA in dogs/BA 2-fold higher (42)
10% Lauroglycol™) from SEDDS
Simvastatin Antihyperlipidimic SMEDDS (37% Capryol™ 90, 28% Cremophor® EL, Relative BA in dogs/BA 1.5-fold higher (99)
For personal use only.

28% Carbitol) from SMEDDS

Atorvastatin Three SMEDDS (Cremophor® RH40, Propylene Relative BA in dogs/BA significantly (100)
glycol and Labrafil®, estol or Labrafac®) increased from all SMEDDS
formulations
Indomethacin Analgesic SEDDS (70% Ethyl oleate and 30% Tween® 85) Relative BA in rats/BA significantly (101)
increased from SEDDS
Progesterone Hormones SEDDS (mono-di-glycerides: Polysorbate® 80, Relative BA in dogs/BA 9-fold higher (102)
50/50 w/w) from SEDDS
Tocotrienols Antioxidant Two SEDDS (Tween® 80 and Labrasol®) Relative BA in humans /BA 2 to 3-fold (64)
higher from SEDDS
Danazol Steroid LCT SMEDDS (Long chain lipids, Cremophor® EL Relative BA in dogs/BA of LCT (103)
and Ethanol),MCT SMEDDS (Medium chain lipids, SMEDDS 6-fold higher than that from
Cremophor® EL and Ethanol) MCT SMEDDS
Carvedilol Antihypertensive SEDDS (Labrafil® M1944CS, Tween® 80 and Relative BA in dogs/BA 4-fold higher (104)
Transcutol®) from SEDDS
Silymarin Antidiabetic, SMEDDS (Tween® 80, Ethyl alcohol and Ethyl Relative BA in rabbits/BA (105)
Anticancer, linoleate) approximately 2-fold higher from
SMEDDS
Itraconazole Antifungal SEDDS (Transcutol®, Pluronic® L64 and Relative BA in rats/Increased BA and (106)
Tocopherol acetate) reduced food effect from SEDDS
Atovaquone Antimalarial Two SMEDDS (Long chain lipids, Ethanol and Relative BA in dogs/BA 3-fold higher (107)
Cremophor® EL or Pluronic® L121) from SMEDDS
Seocalcitol Antineoplastic LCT SMEDDS (Sesame oil, Peceol™, Cremophor® Absolute BA in rats/BA of LCT (108)
RH40) versus MCT-SMEDDS (Vicscoleo, Akoline SMEDDS = MCT SMEDDS
and Cremophor® RH40)

smaller droplets of 0.5−1 µm mean diameter are formed. compound then reaches the systemic circulation via
Pancreatic lipase then catalyzes the metabolism of these the portal vein or lymphatic system. The effect of struc-
droplets20, which later on form mixed micelles with bile tured triglycerides with varying intra-molecular struc-
salts19. tures and chain lengths incorporated into a SMEDDS
Following their penetration through the aqueous on the intestinal lymphatic transport and absorption
layer and mucin, mixed micelles and microemulsions of halofantrine into the blood was investigated116. The
are absorbed through different mechanism either SMEDDS formulation included 29% w/w structured
by pinocytosis, diffusion or endocytosis. The drug triglyceride designated as LLL, LML, or MLM (L: long

© 2012 Informa Healthcare USA, Inc.

 12 M.A. Rahman et al.

Table 5. Formulations available in the market.

Active moiety Trade name Dosages form and strength Company
Tretinoin Vesanoid® Soft gelatin capsule, 10 mg Roche
Isotretinoin Accutane® Soft gelatin capsule, 10, 20 and 40 mg Roche
Cyclosporine Panimum bioral® Capsule, 50 and 100 mg Panacea Biotech
Cyclosporin A Gengraf® Hard gelatin capsule, 25 and 100 mg Abbott
Cyclosporin A Sandimmune® Soft gelatin capsule, 25, 50 and 100 mg Novartis
Lopinavir and Ritonavir Kaletra® Soft gelatin capsule, Lopinavir 133.33 mg and Abbott
Ritonavir 33.3 mg
Saquinavir Fortovase® Soft gelatin capsule, 200 mg Roche
Tipranavir Aptivus® Soft gelatin capsule, 250 mg Boehringer Ingelheim
Amprenavir Agenerase® Soft gelatin capsule, 50 mg GSK
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

chain fatty acid, C18; M: medium chain fatty acid, investigated the effects of a range of lipid-based for-
C8-10). The MLM and LML microemulsions had a mulations on the bioavailability and lymphatic trans-
similar droplet size of 50 nm. The lymphatic transport port of ontazolast, following oral administration to
of halofantrine, expressed as the cumulative percent- conscious rats. This drug undergoes extensive hepatic
age of the administered dose, after 12 h (mean % dose ± first-pass metabolism and it has solubility in soybean
S.E.) was 27.4 ± 1.3 after administration in the LML and oil of 55 mg/mL, and a log P of 4. The formulations of
17.9 ± 1.3 in the MLM. SMEDDS was comparable to that ontazolast investigated included a suspension (lipid-
previously reported117. free control), a 20% soybean o/w emulsion, two SEDDS
It was therefore hypothesized that medium chain fatty containing Gelucire® 44/14 and Peceol™ in the ratios
acid enhanced the absorption into the systemic blood 50:50 and 80:20, respectively, and a solution of the drug
circulation whereas long chain fatty acid enhanced the in Peceol alone. All the lipid formulations increased
lymphatic transport. Thus, the absorption profile of a the bioavailability of ontazolast relative to the control
drug formulated into a SMEDDS could be manipulated suspension, while the SEDDS promoted more rapid
For personal use only.

by varying the medium and long chain triglyceride con- absorption. Maximum lymphatic transport occurred
tent in the formulation in order to improve the oral bio- with the emulsion and the Peceol solution. The emul-
availability of highly lipophilic drugs. sion prolonged lymphatic transport and this may be
Charman et al proposed that drug candidates for lym- related to the need for pre-absorptive lipolysis of the
phatic transport should have a log P > 5 and, in addition, triglyceride vehicle and an associated slower gastric
a triglyceride solubility >50 mg/mL. The importance of emptying time. The Peceol solution provided the high-
lipid solubility was illustrated by comparing the lym- est rate of lymphatic triglyceride transport thus result-
phatic transport of DDT (log P 6.19) with hexachlo- ing in greater partitioning of the drug into the lymph.
robenzene (HCB, log P 6.53). While both compounds The SEDDS formulations resulted in the highest con-
have similar log P values, the difference in lymphatic centration of ontazolast in the chylomicron triglyceride.
transport on administration in oleic acid, 33.5% of the The authors suggest that SEDDS, which promote more
dose in the case of DDT in triglyceride solubility118. rapid absorption of ontazolast, could produce higher
However, combination of a high log P and high triglyc- concentrations of the drug in the enterocytes during
eride solubility does not always guarantee significant absorption and hence improve lymphatic drug trans-
lymphatic transport. Penclomedine, an experimental port by a concentration-partitioning phenomenon32.
cytotoxic agent with a log P of 5.48 and a triglyceride In order to evaluate and predict the effect of different
solubility of 175 mg/mL, was poorly transported in the lipid combinations in SEDDS on the oral bioavailability
intestinal lymph, ~3% of the dose119. Khoo et al. showed of Cyclosporin A (CsA), a statistical experimental design
significant lymphatic transport of the poorly lipid and multivariate optimization strategy was utilized121.
soluble (~1 mg/mL) HCl salt of halofantrine (Hf-HCl), The SEDDS containing lipid vehicle, galactolipids (GL)
following oral post-prandial administration to dogs. exhibits good self-emulsifying properties and because it is
The authors suggest that the high level of lymphatic non-ionic unlike phospholipids, which are charged, con-
transport of Hf-HCl (43.7% of dose), which was similar sidered to be safer for the long term use121. Increasing the
to that of the lipid soluble Hf base, was due to conver- drug content from 12.5 to 30% in formulation containing
sion of Hf-HCl in the intestinal lumen, during lipolysis, GL, medium chain triglycerides (MCT) and monoglycer-
to the more lipophilic free base, which then becomes ides (MCM) led to an approximately two-fold decrease in
associated with chylomicron production120. Although bioavailability121.
enhanced lymphatic transport has been suggested as a It is understood that droplet size distribution known
potential mechanism of enhanced bioavailability, few to have important influence on the rate and extent of
studies have investigated the lymphotropic potential drug release and absorption, appeared to have signifi-
of SEDDS90. However, one such study by Hauss et al. cant effect on bioavailability. However, in the case of

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 13
CsA, the droplet size distribution has no effect on bio- possibly due to its high molecular weight and low aque-
availability. The type of lipid excipient and their ratio ous solubility128. The oil based and powder-filled capsule
within the SEDDS formulation were reported to have formulations of CoQ10 available in the market, exhibit
a significant impact on CsA oral bioavailability. For high variations in oral bioavailability129. Thus, a new
instance, the formulation containing sphingolipids, formulation of SEDDS was designed and optimized on
cholesterol and MCT was shown to result in almost no the basis of mean emulsion droplet diameter containing
absorption while the SEDDS comprising fractionated acetylated monoglycerides (Myvacet® 9-45), Labrafac®
oat oil (FOO) was reported to yield a bioavailability CM-10 and propylene glycol monolaurate (lauroglycol)
comparable to the reference product. A SEDDS formu- and evaluated for improved oral bioavailability. The bio-
lation including FOO contained 50% neutral lipids and availability studies were carried out on dogs resulted in a
50% polar lipids (mixed phospholipids and GL) and two-fold higher oral bioavailability with SEDDS formula-
MCM at a 1:1 ratio was developed. The drug content tion as compared to the powder formulation, containing
was 10% in the SEDDS formulation, which was shown sodium lauryl sulphate as the wetting agent and lactose
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

to be approximately bioequivalent to the reference as the bulking agent.

product, Sandimmune Neoral®121. Tipranavir (TPV), a new class of non peptidic protease
inhibitors (NPPIs), used as potent anti-HIV drug130, was
formulated into a new SEDDS filled into soft gelatin cap-
Role of surfactants sule and compared with the hard filled capsule (HFC)
The role of surfactants in bioavailability enhancement is formulation, led to an approximately two-fold higher
considered to the mechanism that it increases the per- bioavailability131. Another potent and well-tolerated
meability by interfering with the lipid bilayer of the single anti-HIV drug belonging to class protease inhibitor (PI),
layer of the epithelial cell membrane122, which with the Saquinavir (SQV) used in highly active antiretroviral
unstirred aqueous layer, forms the rate-limiting bar- therapy (HAART) regimens available in both hard gela-
rier to drug absorption/diffusion123,124. Therefore, most tin capsules (HGC; Invirase®) and soft gelatin capsules
drugs are absorbed via the passive transcellular route. (SGC; Fortovase®)132–134. The bioavailability after single
Surfactants partition into the cell membrane and change administration of 600 mg SQV in HGC was found to be
the structural organization of the lipid bilayer leading much lower than 600 mg SQV in SGC135,136. The significant
For personal use only.

to permeation enhancement. Another mechanism by improvement in bioavailability (331%) of SQV with SGC
which surfactant enhances absorption of the drug is by is attributed to capmul, a glyceride (medium chain mono
increasing the dissolution rate125. and diglycerides) type excipient used in the SGC for-
Cyclosporin A (CsA), a potent immunosuppressive mulation137. Capmul keep the drug in solubilized state
drug used in organ transplantation is a cyclic undeca- throughout GIT, which make the drug release rapid.
peptide with very poor aqueous solubility126. Various However, this excipient has adverse effects such as diar-
formulation strategies were applied to improve the rhea. Therefore, a new formulation approach has been
bioavailability of CsA, which eventually led to the dis- designed to keep the bioavailability of SQV high while
covery of Sandimmune® and Sandimmune Neoral® lowering the side effects of capmul. It has been shown
having better performance than previous one21. It was in healthy subjects boosted with SQV/ritonavir (RTV)
observed that a significant amount of dissolved CsA 1000 mg/10 mg BID that SQV in HGC could be absorbed
from Sandimmune® was in the undigested lipid phase well and tolerated better than SQV in SGC. On the other
whereas a mixed micellar phase was formed as a result hand, RTV may also lead to side effects since its formula-
of “in vitro pre-digestion” of the oily solution following tion contains polyoxyl 35 castor oil (Cremophor® EL)138.
the administration of Sandimmune Neoral®88. When It has also been shown that micellar solubilization of
in vivo study were carried out in order to compare blood lipophilic drugs with high concentrations of surfactants in
levels of two formulation on perfused rats, it was found the formulation significantly affected the amount of free
that CsA in positively charged SEDDS led to higher blood drug and extent of absorption139,140. The intestinal absorp-
levels as compared to the corresponding negatively tion of griseofulvin in rats was reported to decrease in the
charged SEDDS25. This was due to the interaction of posi- presence of 20 mM taurocholate as a result of micellar
tively charged oil droplets with the negatively charged solubilization139. In a study carried out on a formulation
surface components of the GIT. It is noteable point that of CsA containing surfactant such as Cremophor® EL
larger droplets in sizes of microns are less neutralized by or RH40 and TPGS at concentrations above 0.02% w/v,
mucin than smaller droplets in submicron sizes formed demonstrated a decrease in permeability of CsA, which
by the same formulation127. It is likely to prove that there was attributed to micellar solubilization140.
is a more complex correlation between droplet size and Digestability of the surfactant plays an important role
bioavailability in positively charged formulations. on in vitro and in vivo solubilization of self-emulsifying lip-
Coenzyme Q10 (CoQ10), a well known antioxidant id-based formulations and thus bioavailability of PWSD.
used in the treatment of cardiovascular disorders like It is expected that, all surfactants belonging to class fatty
angina pectoris, hypertension and congestive heart acid-ester were to a lesser or greater extent digestible.
failure was found to be poorly absorbed through GIT However, Cremophor® RH40 (polyoxyl 40 hydrogenated

© 2012 Informa Healthcare USA, Inc.

 14 M.A. Rahman et al.
castor oil) and Cremophor® EL (polyoxyl 35 castor oil)
are structurally similar surfactant but appeared to be
difference in digestibility behavior. Cremophor® RH40
is less readily digested than Cremophor® EL. Such dif-
ferences in the digestibility behavior of these two is not
clear at this time but it is assumed that differences in
the reactivity of the saturated (hydrogenated) castor oil
glyceride backbone in Cremophor® RH40 leading to the
generation of slightly different reaction products with
polyethylene oxide, when compared with Cremophor®
EL (which is generated by polyethoxylation of unsatu-
rated castor oil).
In an experiment, self-microemulsifying formulations
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

of danazol comprising of 55% w/w long chain lipid (1:1 Figure 2. In vitro digestion study of two self-microemulsifying
w/w blend of soybean oil/maisine™), 7.5% w/w ethanol drug delivery system (SMEDDS). One incorporating the less
and 37.5% of either Cremophor® RH40 or Cremophor® readily digestible surfactant Cremophor® RH 40 (Cremophor RH
40 SMEDDS) and the other based on the more readily digestible
EL was prepared and in vitro digestion study was con- Cremophor® EL (Cremophor EL SMEDDS). Figures modified
ducted. A marked difference in in vitro solubilization from Reference (25).
capacity was observed and it was found that the formu-
lation containing less readily digestible Cremophor®
RH40 was more resistant to precipitation on digestion25
(Figure 2). Two microemulsifying formulation containing
Cremophor® RH40 and Cremophor® EL was adminis-
tered in beagle dogs confirmed the in vitro solubilization
patterns and 3-fold higher bioavailability with formula-
tion containing surfactant Cremophor® EL25 (Figure 3).
For personal use only.

Inhibition of P-glycoprotein (P-gp)

Appropriate excipient selection is vital to successful
formulation design. It is no longer sufficient to consider
only the traditional roles, such as solubilization capacity
in the case of a surfactant, but the increasing evidence
of the bioactive nature of many excipients must also Figure 3. Plasma profiles obtained after administration of each of
be evaluated. This bioactivity has received significant the formulations (800 mg) to fasted beagle dogs. Figures modified
from Reference (25).
attention in the recent past and is a rapidly growing
area of research. Excipients such as Cremophor® and
Tween® 80 are known modulators of P-gp and their both P-gp and cytochrome P450 (CYP3A4)144,145. Thus,
potential to influence other transporters has yet to be extensive efforts have been devoted towards the design
fully investigated. and development of a new formulation of paclitaxel
Decrease in the P-gp drug efflux may be other pos- for oral administration with improved bioavailability.
sible reasons for increased uptake of PWSD formulated Recently, a supersaturable SEDDS (S-SEDDS) was
as SEDDS from the GIT141,142. Multidrug efflux pump and developed for the oral delivery of paclitaxel146. The fact
phase I metabolism by the intestinal cytochrome P450s that high content of surfactants in orally administered
is now becoming recognized as a significant factor in SEDDS could lead to adverse effects at the GIT and a
oral drug bioavailability143. Recently, in some case, it has decrease in intestinal absorption of the drug as a result
been observed that, SEDDS/SMEDDS excipients itself of a decrease in free drug, led to the development of this
can inhibit both pre-systemic metabolism and intestinal new SEDDS in which the surfactant concentration was
efflux mediated by P-gp resulting in an increased oral lowered and a cellulose polymer, hydroxypropyl meth-
absorption of cytotoxic drugs109,110. ylcellulose (HPMC) was used as a viscosity enhancer
Paclitaxel is one of the most potent chemotherapeu- in an attempt to reduce/prevent drug precipitation
tic agents currently employed for the treatment of solid upon GI fluid dilution. The resultant formulations were
tumors. However, it is a very lyophobic compound; stable and contained paclitaxel at a temporarily super-
insoluble in most pharmaceutically acceptable sol- saturated state. Oral administration of a 10 mg/kg dose
vents. Therefore, it is formulated in a 1:1 combination of paclitaxel as S-SEDDS containing 5% HPMC yielded
of polyoxyethylated castor oil (Cremophor® EL) and almost five-fold higher AUC0-∞ values compared to the
dehydrated ethanol for i.v use and is currently mar- market formulation Taxol® i.v injection (formulation
keted as Taxol®. In addition, paclitaxel is a substrate for containing Cremophor® EL and dehydrated ethanol in

 Drug Development and Industrial Pharmacy

 Self-emulsifying drug delivery systems 15
1:1 ratio). These findings demonstrated that the pres- ability to dissolve large amounts of lipophilic drugs.
ence of HPMC in the paclitaxel SEDDS prevented mac- Emulsifiers of natural origin are preferred since they
roscopic precipitation of the drug from the formulation are considered to be safer than the synthetic surfac-
and thus provided a supersaturable formulation with tants. However, these excipients have a limited self-
improved oral bioavailability146. emulsification capacity.
However, it should be emphasized that the plasma Grinding is regularly used in the pharmaceutical
concentration of paclitaxel did not reach the therapeutic industry to reduce particle size but it generates heat,
level when the drug was administered alone in SMEDDS sound and vibration energy. It must be performed at a
at different doses despite the presence of well known temperature below the melting temperature. Cryogenic
moderate P-gp inhibitors, D-alpha-tocopheryl polyethyl- grinding is chosen because it is a process carried out
ene glycol 1000 succinate (TPGS) and Cremophor in the at low temperature with frozen samples, used for dif-
formulation146. The low plasma concentration and poor ferent biological materials (plants, animal tissues) and
oral bioavailability of paclitaxel were due not only to the unstable compounds (vitamins, volatile substances,
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Guelph on 09/06/12

over expression of P-gp by the intestinal cells but also to etc). However, grinding induces mechanical activa-
the significant first pass extraction by cytochrome P450- tion and generation of energy can lead to physical and
dependent process. It can be deduced from the overall chemical changes in crystalline solid which can affect
data presented that SMEDDS alone cannot overcome, its efficacy150.
for the time being, the efflux effect of the P-gp in the case
of paclitaxel. Thus, when different doses of paclitaxel
Conclusion
SMEDDS were co-administered with 40 mg CsA/kg,
there was a substantial increase in the Cmax and AUC val- The full potential of oral lipid-based drug delivery sys-
ues compared to those obtained with paclitaxel SMEDDS tems has yet to be achieved. These formulations must
alone in rats145. be designed to work in harmony with the physiological
Furthermore, when co-administered with CsA, there environment, the incorporation of bioactive excipients
was a significant improvement in the relative bioavail- should be explored, and known biochemical processes
ability (by 168%) of the drug in SMEDDS as compared to in the GIT should be exploited.
those of Taxol®. SMEDDS might have a delayed positive A lot of innovations are expected to come in the
For personal use only.

effect on the P-gp inhibitory effect of CsA either through field of microemulsion technology. The role of SEDDS
increasing its oral absorption or enhancing the inter- and SMEDDS is of paramount importance in provid-
action of CsA with cytochrome P 450 at the level of the ing novel solutions to overcome the problems of poor
mature villus tip enterocytes of the small intestine143,147, aqueous solubility of highly lipophilic drug compounds
leading to further improvement in paclitaxel oral bio- and provide high, more consistent and reproducible
availability. These findings were recently confirmed in bioavailability.
the S-SEDDS study since the co-administration of CsA SEDDS present drugs in a small droplet size and well-
was again needed to increase markedly the bioavailabil- proportioned distribution and increase the dissolution
ity of paclitaxel146,148. and permeability. Furthermore, because drugs can be
loaded in the inner phase and delivered by lymphatic
bypass share, SEDDS protect drugs against hydrolysis
Potential limitations by enzymes in the GI tract and reduce the presystemic
One of the advantages of SEDDS in relation to scale-up clearance in the GI mucosa and hepatic first-pass
and manufacturing is that they form spontaneously metabolism.
upon mixing with GI fluid under mild agitation and The efficiency of the formulation is case specific in
they are thermodynamically stable. Besides that, the most instances; thus, composition of the formulation
major drawback of the system is chemical instabilities should be determined very carefully. Since a relatively
of drugs and toxicity as well as irritation of GIT due to high concentration of surfactants is generally employed
high surfactant concentration. Non-ionic surfactants in the SEDDS formulation, toxicity of the surfactant
are less toxic than ionic surfactants but they may lead being used should be taken into account. In fact, a
to reversible changes in the permeability of the intesti- compromise must be reached between the toxicity and
nal lumen. self-emulsification ability of the surfactant that is con-
Consequently, the safety aspect of the surfactant vehi- sidered for use.
cle had to be considered. Moreover, volatile co-solvents Successful lipid based delivery system hence
in the conventional self-emulsifying formulations are requires a holistic approach to formulation. A system-
known to migrate into the shells of soft or hard gelatin atic elucidation of the rationale may be achieved by i)
capsules, resulting in the precipitation of the lipophilic pre-selecting excipients for their fatty acid make up,
drugs149. melt characteristics, HLB or emulsification properties,
Edible oils which could represent the logical and potential effect on enterocytes-based drug transport
preferred lipid excipient choice for the development and disposition and overall digestibility; ii) conduct-
of SEDDS are not frequently selected due to their poor ing binary screening with the pre-selected excipients

© 2012 Informa Healthcare USA, Inc.

 16 M.A. Rahman et al.
for drug solubility, compatibility, stability, and dis- 10. Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ,
solution/dispersion properties (in biorelevant media) Pouton CW. (1992). Self-emulsifying drug delivery systems:
formulation and biopharmaceutic evaluation of an investigational
to identify one or more suitable systems for further lipophilic compound. Pharm Res, 9:87–93.
studies; iii) identifying the formulation technique(s) 11. Shah NH, Carvajal MT, Patel CI, Infeld MH, Malick AW. (1994). Self-
suitable for the dosage form intended; iv) confirming emulsifying drug delivery systems (SEDDS) with polyglycolized
the in vivo performance of the chosen formulation glycerides for improving in vitro dissolution and oral absorption of
system(s) in appropriate animal models; v) optimizing lipophilic drugs. Int J Pharm, 106:15–23.
12. Craig DQM, Lievens HSR, Pitt KG, Storey DE. (1993). An investigation
the formulation for drug loading or dissolution profile into the physicochemical properties of self-emulsifying systems
and if necessary, gain control of the oxidative and poly- using low frequency dielectric spectroscopy, surface tension
morphic changes. measurements and particle size analysis. Int J Pharm, 96:147–155.
Certain excipients are not “inert” but are “functional 13. Toguchi H, Ogawa Y, Iga K, Yashiki T, Shimamoto T. (1990).
excipients” such as Cremophor®, Tween® 80 and Gastro-intestinal absorption of ethyl 2-chloro-3-[4-(2-methyl-2-
phenylpropyloxy)phenyl]propionate from different dosage forms
Labrasol® called bioenhancers act as p-glycoprotein
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and/or CYP450 enzymes inhibitors decreasing intestinal 14. Palin KJ, Phillips AJ, Ning A. (1986). The oral absorption of cefoxitin
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Acknowledgements 17. Kararli TT, Needham TE, Griffin M, Schoenhard G, Ferro LJ, Alcorn
L. (1992). Oral delivery of a renin inhibitor compound using
One of the authors, Md. A. Rahman is highly grateful to emulsion formulations. Pharm Res, 9:888–893.
the University Grant Commission (UGC), Government 18. Schwendener RA, Schott H. (1996). Lipophilic 1-beta-D-
of India for providing financial assistance in the form of arabinofuranosyl cytosine derivatives in liposomal formulations
Maulana Azad National Fellowship (MANF). for oral and parenteral antileukemic therapy in the murine L1210
leukemia model. J Cancer Res Clin Oncol, 122:723–726.
For personal use only.

19. Constantinides PP. (1995). Lipid microemulsions for improving drug

Declaration of interest dissolution and oral absorption: physical and biopharmaceutical
aspects. Pharm Res, 12:1561–1572.
There is no declaration of interest. 20. Craig DQM. (1993). The use of self-emulsifying systems as a means
of improving drug delivery. B T Gattefosse, 86:21–31.
21. Pouton CW. (2000). Lipid formulations for oral administration
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