Self-Emulsifying Drug Delivery Systems and Their Marketed Products: A Review
Self-Emulsifying Drug Delivery Systems and Their Marketed Products: A Review
Self-Emulsifying Drug Delivery Systems and Their Marketed Products: A Review
College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, USA - 91766
Abstract
Self-emulsifying drug delivery systems (SEDDS) are one of the proven methods to increase solubility and
bioavailability of poorly soluble drugs. SEDDS are isotropic mixtures, consisting of oils, surfactants, and
sometimes cosolvents. Designed formulations are used to improve the oral absorption of highly lipophilic
compounds. Multiple lipid-based drug delivery systems are widely reported in literature and they include simple
oil solutions, coarse, multiple and dry emulsions, and more complex self-emulsifying, microemulsifying or
nanoemulsifying drug delivery systems. The process of self-emulsification is dependent on diverse factors such
as the nature of oil, surfactant, cosurfactant, oil/surfactant ratio, and the polarity of the emulsion. Considering the
ease of large-scale production and the robustness of SEDDS, several formulations are commercially available
which utilize this technology. This article attempts to present an overview of SEDDS along with their applications,
compiled literature data, commercially available products, and their descriptions.
Key words: Commercial products, Lipid formulations, Lipophilic drugs, Oral bioavailability, Oral delivery, Self-
microemulsifying drug delivery systems
S
elf-emulsifying system (SES) is one of SEDDS are easy to manufacture and physically stable
the most prevalent and commercially formulations and may enhance the rate and the extent of
feasible oil based approaches for the absorption for lipophilic drug compounds where dissolution
delivery of drugs that show dissolution rate is the deciding factor. SEDDS approach can be used for
speed limited absorption. SES is an isotropic all categories of the biopharmaceutics classification system
mixture of oils, surfactants, cosurfactants, (BCS). Although multiple reviews have been published on
and at times cosolvents, which emulsify SEDDS/SMEDDS, a review with a focus on commercial
extemporaneously to produce oil-in-water or aspects is not available which calls for an updated review.
water-in-oil emulsion when introduced into
the gastrointestinal tract (GIT).[1] Based on The process of self-emulsification depends on multiple factors
the droplet size after emulsification, they are such as the nature of oil, surfactant, and cosurfactant and on
classified into two broad classes, namely self- oil to surfactant ratio or oil to surfactant and cosurfactant
emulsifying drug delivery systems (SEDDS) ratio, the self-emulsification temperature, the polarity of the
with a droplet size range of 100–300 nm emulsion, and droplet size and charge. From multiple studies,
and self-microemulsifying drug delivery it was evident that only a specific combination of drug and
systems (SMEDDS) with a droplet size range excipients lead to efficient SES.[4]
<50 nm.[2] As a result of the lower globule size,
the micro/nanoemulsified drug can be taken
Address for correspondence:
up efficiently through lymphatic pathways,
Guru V Betageri, College of Pharmacy,
where it bypasses the hepatic first-pass
Western University of Health Sciences, Pomona,
effect.[3] Larger lipid droplet which represents
California, USA - 91766. E-mail: [email protected]
SMEDDS or microemulsions is converted into
smaller micelles on coming in contact with bile
Received: 02-03-2019
salts and lipases. These micelles, on absorption
Revised: 24-03-2019
through intestinal villi and microvilli help
Accepted: 29-03-2019
enhance the absorption of the drug which is
Advantages of SEDDS over the conventional of surfactants for oil-in-water emulsion, a high hydrophilic-
emulsion lipophilic balance (HLB) is preferred as it ensures efficient
self-dispersibility and stability of the formed emulsion. For
As compared to conventional emulsions which require high a stable SEDDS, an optimum concentration of surfactant in
shear to form a dispersion, SEDDS preparation involves the range of 30%–60% (w/w) is required.[4] Examples include
a simple process of dissolving the drug in oil followed by Span 80, Tween 80, Tween 20, and Cremophor RH40.
mixing it with surfactants and cosurfactants.[5] Conventional
emulsions display multiple instabilities such as creaming, Cosurfactants play an important role in decreasing the surfactant
coalescence, breaking, and phase inversion. On the other hand, related gastrointestinal distress and lowering the interfacial
SEDDS formulations are physically stable as they are clear, tension to a small or negative value. They also improve the
isotropic mixtures immune to small changes in temperature. penetrability of the dispersion media and decrease the shear
In addition, the final dosage forms of SEDDS formulations required to disperse globules. Widely used cosurfactants
are presented as patient compliant soft or hard gelatin include glycerin, propylene glycol, and ethanol.[8]
capsules, which are compatible with strip or blister packing
and assure dose uniformity. Large containers required for
conventional formulations are cumbersome to carry, and dose FACTORS AFFECTING SEDDS
nonuniformity of the droplets and dispersion media can lead
to decreased efficacy (Khedekar and Mittal, 2013). Another Critical factors affecting SEDDS include drug dose, the drug
advantage of SEDDS is the amenability to be manufactured solubility in the oil phase, and the drug log P value. It is crucial
by the basic equipment whereas emulsion and suspension to consider these factors as high dose drugs are not suitable
need specialized high-cost equipment to monitor the critical for SEDDS due to the restricted amount of lipid phase being
processes such as intensity, rate, and duration of mixing. used and drugs with log P < 2 are more challenging to deliver
by SEDDS. If surfactant or cosurfactant is contributing to
a higher amount for drug solubilization, then there may be
EXCIPIENT SELECTION a higher chance of precipitation on dilution.[9] However, in
some cases, ion pairing agents have been utilized to enhance
Drug solubility plays a pivotal role in the selection of excipients the oil solubility of peptides with very low log P values
in SEDDS formulation.[6] The lipids used generally consist of such as desmopressin (log P =−6.13) and enhance the
a fatty acid ester or a medium/long chain saturated, partially oral bioavailability by prevention against glutathione and
unsaturated or unsaturated hydrocarbon chain. Examples α-chymotrypsin mediated presystemic inactivation.[10]
include mineral oil, vegetable oil, silicon oil, lanolin, refined
animal oil, fatty acids, corn oil, peanut oil, soybean oil,
fatty alcohols, and mono-/di-/tri-glycerides.[7] The oil plays LIPID FORMULATION CLASSIFICATION
a key role in the drug bioavailability and its lymphatic SYSTEM
transportation. The solubility and the bioavailability of the
drug are enhanced as the presence of lipidic system in the GIT Lipid classification is introduced in 2000,[11] which is used
enhances secretion of lipases and cholic acids, which form a to interpret in vivo studies and to enable the identification
colloidal micelle resulting in lymphatic absorption. In the case of thermostable formulations for specific drugs in relation to
their physicochemical properties.[12] It is classified into four hydrophobic but not lipophilic. However, it is necessary to
different classes depending on the concentration of the lipids note that the high concentration of surfactants used may lead
and the surfactant types used. to gastric distress on chronic usage.
the clear solution under agitation is observed after dropwise Thermodynamic stability
formulation addition to the basket containing water.
Diluted SEDDS are centrifuged either at 3500rpm for 30min
or 15,000rpm for 15 min. Subsequently, these formulations
Cloud point determination
are subjected to freeze-thaw cycles (−20°C and 40°C
temperature, respectively) and observed visually. If there
Cloud point is the temperature above which the homogenous
solution loses its transparency. The surfactant usually loses its is no change in the visual description (creaming or phase
micelle forming capacity above the cloud point. It is determined separation), then the formulation is considered to be stable.[21]
by gradually increasing the temperature of the formulation
and measuring the turbidity spectrophotometrically. The In vitro dissolution profile
temperature at which percentage transmittance is decreased is
considered as the cloud point of the surfactant. Formulations Drug release from formulation can be evaluated after filling
should exhibit a cloud point greater than 37.5°C to retain its the formulation in a hard gelatin capsule or as other dosage
self-emulsification property.[18] forms using USP XXIII apparatus I (100rpm) or USP XXIII
apparatus II (50rpm) or with dialysis method at 37°C. Samples
Viscosity measurements at regular intervals are withdrawn from the medium and drug
content is estimated and compared with the control.[22]
The viscosity of diluted SMEDDS formulation that is
microemulsion is generally determined by rheometer such Stability assessment
as Brookfield cone and plate rheometer fitted with cone
spindle[19] or rotating spindle Brookfield Viscometer.[20] These studies are performed according to the international
conference on harmonization guidelines. Samples are
Impact of dilution-induced stress tested for appearance, color, drug content, pH of the diluted
formulation, and dissolution profile. If these properties
Dilution studies help to understand the effect of dilution- match the initial formulations, it can be concluded as a stable
induced stress on the physicochemical properties of the pre- formulation.[23,24]
diluted emulsions. These studies are performed by diluting
the microemulsion to various dilution ratios with distilled
water, simulated gastric fluid, or simulated intestinal fluid. If RELEASE MECHANISM OF THE DRUG
the emulsion shows no turbidity, which indicates the absence FROM SEDDS
of drug precipitation, the formulation is considered as a stable
formulation. The release from the microemulsion depends on the lipid
phase polarity, which is affected by factors such as HLB,
Refractive index fatty acid length and number of double bonds, hydrophilic
portion molecular weight, and the emulsifier concentration.
Refractive index (RI) can be used as an important tool to The drug polarity is an indicator for its affinity toward oil
investigate the microemulsion structure. It is evaluated by and/or water and provides an idea of the forces involved.
recording the RI of samples stored at 4°C and 25°C at multiple Although higher polarity will enhance the drug release rate
time intervals till 6h. Insignificant changes in the RI at these in the aqueous media, it may have an adverse effect on the
time points indicate constant microemulsion structure. The drug solubility.
constant RI also indicates the thermodynamic stability of the
formulation.[20]
FORMULATION OPTIMIZATION OF SEDDS
Percentage transmittance The quality by design (QbD) is a systematic pharmaceutical
approach toward formulation development that is initiated
Percentage transmittance is determined following the dilution with preset objectives and lays stress on product and process
of the formulation and recording the transmittance with water understanding and process control through robust science and
as a blank. A percentage transmittance value closer to 100% quality risk management. QbD helps in building excellent
indicates a clear and transparent microemulsion formation.[8]
products and to recognize critical process parameters affecting
the drug products fabrication. It also helps in designing
Transmission electron microscopy (TEM) approaches to retain quality throughout its life cycle. QbD
is majorly applied through design of experiment which uses
TEM is mainly used to investigate the structure and morphology multiple designs such as plackett-Burman, Box–Behnken
of microemulsions that are formed by dilution of SES.[21] design, fractional factorial design, central composite design,
and mixture design for either screening or optimization of the PERFORMANCE OF SEDDS IN
variables.[25] A detailed discussion of these designs and their BIOLOGICAL SYSTEMS
applications is beyond the scope of this review. The readers
are directed to a few successful formulations using factorial Lipid-based formulations help in increasing solubilization
design.[26] capacity and prevent drug precipitation post intestinal
dilution. Although this issue is not extensively investigated, it
is reported that the absorption of the drugs through SMEDDS/
MECHANISM OF SEDDS SEDDS is dependent on the globule size of the formulation.
A formulation with a lower globule size (~200 nm) displays
A brief review of literature reveals multiple mechanisms for enhanced bioavailability as compared to formulation with
microemulsion formation. It is considered that the surfactant- relatively higher globule size (~800 nm).[28] However, there
mediated intricate film formation at the oil-water interface have been some contrary reports which downplay the effect of
leads to the microemulsion droplets formation [Figure 2]. As globule size on the bioavailability of the SEDDS/SMEDDS.
per the thermodynamic theory of microemulsion formation, SEDDS and SMEDDS of halofantrine having significantly
the emulsification ensues as soon as the change in entropy different globule size did not affect the halofantrine
favoring dispersion is higher than the energy necessary for absorption from the gut.[29] The influence of globule size on
the dispersion surface area amplification and the free energy the absorption and bioavailability needs to be studied while
maintaining the concentrations of the lipids and surfactants
(ΔG) is negative.[27] The free energy in the microemulsion
at the same level.
formation is related to the energy required to create a new
surface between the two phases as given in the below
As mentioned earlier, SMEDDS have been utilized for
equation:
augmenting the stability and improving the bioavailability
of peptides and drugs by decreasing the presystemic
ΔG=Σ Nr2 σ metabolism and enhancing bioavailability. Drugs entrapped
in the globules of emulsions formed from SMEDDS/
Where ΔG is the free energy associated with the process SEDDS are protected against the proteases such as trypsin
(where free energy of the mixing was ignored), “N” is number and chymotrypsin and the gastric acids, which are capable
of droplets, “r” is radius, and “σ” is the interfacial energy, of degrading it. Entrapment of the peptides in the globules
respectively. The two emulsion phases are likely to separate also offers protection against the biological thiols, which
to reduce the interfacial area, which subsequently, decreases can degrade the intramolecular disulfide bonds and disrupt
the free energy of the system. The emulsion resulting post the 3-D structure of peptides. In addition, the globules also
aqueous dilution is stabilized by surfactants, by forming a enhance the drug and peptide bioavailability by increasing
single layer surrounding the emulsion droplets, which results membrane fluidity, the opening of tight junctions, inhibition
in the reduction of the interfacial energy, and provides a of P-gp and CYP450.[30] As mentioned previously, the
barrier against coalescence.[16] SEDDS/SMEDDS lead to the formation of chylomicrons,[31]
Figure 2: Mechanism of emulsion formation after interaction with aqueous media. Initial agitation dislodges the oil from the solid
support to form a system, which has low free energy, due to low interfacial tension. After further agitation, the entropy change
favoring dispersion is greater than the energy required to increase the surface area of the dispersion and the free energy (ΔG) is
negative. The surfactants decrease the interfacial tension, thus reducing the free energy while maintaining the reduced droplet
size. In absence of surfactants, the oil droplets coalesce thus reducing the free energy of the system
Table 1: (Continued)
Product name/ Use BCS Strength (mg) Dosage Inactive ingredients Manufactured
drug class form by/for
Vesanoid® Retinoid that induces II 10 Soft gelatin Beeswax, butylated Roche
(Tretinoin) maturation of acute capsule hydroxyanisole, Laboratories Inc.
promyelocytic edetate disodium,
leukemia (APL) hydrogenated
soybean oil flakes,
hydrogenated
vegetable oils, and
soybean oil
Accutane® Severe recalcitrant II 10/20/40 Soft gelatin Beeswax, butylated Roche
(Isotretinoin) nodular acne capsule hydroxyanisole, Laboratories Inc.
edetate disodium,
hydrogenated
soybean oil flakes,
hydrogenated
vegetable oil, and
soybean oil
Aptivus® Combination II 250 Soft gelatin Dehydrated alcohol Boehringer
(Tipranavir) antiretroviral capsule (7% w/w or 0.1 Ingelheim
treatment of HIV-1 g per capsule), Pharmaceuticals,
polyoxyl 35 castor Inc.
oil, propylene glycol,
mono/diglycerides of
caprylic/capric acid
BCS: Biopharmaceutics classification system, PEG: Polyethylene glycol
which are absorbed, through the lymphatic system. This absorption is not possible if irreversible phase separation of
lymphatic system mediated absorption is beneficial for microemulsion occurs in the GIT. The best-known example
drugs which display high first-pass effect.[32] Readers are of this type of formulation is Neoral. Sodium dodecyl sulfate
directed to some excellent reviews on this subject published can be added to the system to prevent irreversible phase
elsewhere.[33] separation.
Table 2: (Continued)
Drug/BCS class Oil, surfactant, and Result/outcome Reference
cosurfactant
Dutasteride/II Capryol 90, Cremophor EL, Improved physicochemical property and oral absorption [57]
Transcutol HP
Atorvastatin/II Oleic acid or Capryol 90, Increase in dissolution rate when compared to pure [58]
Tween 80, 1,2-propylene glycol drug
Simvastatin/II Capryol 90, Tween 80 SEDDS showed a remarkable reduction in plasma [59]
cholesterol level
Tacrolimus/II Labrasol, Lauroglycol, Enhanced oral bioavailability in rats due to faster [60]
Labrafac absorption and accelerated dissolution of the drug from
the solid SEDDS
Lornoxicam/II Labrafil M 1944 CS Kolliphor Improved solubility and bioavailability [61]
HS 15, Transcutol H
Lovastatin/II Capmul MCM, Nikkol HCO-50, Enhanced drug absorption and the pharmacodynamic [62]
Lutrol F127 potential in regulating serum lipid levels
Glipizide/II Phosphatidylcholine, Tween In vivo study demonstrated that blood glucose levels [63]
80, Transcutol P, Syloid 244 were effectively controlled with S-SEDDS compared
FP (adsorbent) with pure drug
Darunavir/II Capmul MCM C8, Tween 80, In vivo, pharmacokinetic studies in rats resulted [64]
Transcutol P Neusilin US2 in enhanced values of peak drug concentration
for L-SNEDDS and S-SNEDDS compared to pure
darunavir
Chlorthalidone/IV Capmul MCM, Tween 80, PEG In vitro dissolution study indicated a high dissolution [65]
400, Neusilin US2 rate of solid-SMEDDS over the pure drug and marketed
formulation
Etofibrate/II Oleic Acid, Tween 80 and Enhanced dissolution rate [66]
Isopropanol
Telmisartan/II Labrafil 1944, Kolliphor ELP: Dissolution rate was enhanced when compared to pure [67]
Span 80 (1:1) and PEG 400: drug
Ethanol (1:1)
Nateglinide/II Capyrol-90, Tween 80, Enhanced release of the drug from solid-SEDDS when [68]
Transcutol P, Aerosil-200 compared to plain drug
Bosentan/II Gelucire 44/14, Cremophor EL, Enhanced dissolution rate [69]
and PEG 400 (PEG 400)
BCS: Biopharmaceutics classification system, PEG: Polyethylene glycol, SMEDDS: Self-microemulsifying drug delivery systems, SEDDS:
Self-emulsifying drug delivery systems
COMMERCIALLY AVAILABLE strategy is a commercially viable system for drugs from BCS
PHARMACEUTICAL PRODUCTS Class II and IV.
by the rate of dissolution. The ease of manufacturing and (SEDDS) type O/W microemulsion II: Stable
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et al. Enhanced oral bioavailability of dexibuprofen by
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