self-emulsifying drug delivery systems (SEDDSs) is recently used method to increase solubility and bioavailability of poorly soluble drugs. SEDDSs are isotropic mixtures of oils , surfactants,and cosurfactants , and can be used in order to improve the oral absorption of highly lipophilic compounds. SEDDSs spontaneously form fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation...
In recent years, the formulation of poorly soluble compounds presented interesting challenges for formulation scientists in the pharmaceutical industry. Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which leads to poor oral bioavailability, high intra- and inter-subject variability, and lack of dose proportionality .
In the oral formulation of such compounds, a number of attempts-such as decreasing particle size, use of wetting agents, coprecipitation, and preparation of solid dispersions- have been made to modify the dissolution profile and thereby improve the absorption rate. Recently, much attention has focused on lipid-based formulations to improve the bioavailability of poorly water soluble drugs. Among many such delivery options, like incorporation of drugs in oils (2), surfactant dispersion (3), emulsions (4) and liposomes (5), one of the most popular approaches are the self-emulsifying drug delivery systems (SEDDSs).
SEDDSs are mixtures of oils and surfactants, ideally isotropic and sometimes containing cosolvents, which emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for selfemulsification. These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption (6). SEDDSs typically produce emulsions with a droplet size between 100-300 nm while self-microemulsifying drug delivery systems (SMEDDSs) form transparent microemulsions with a droplet size of less than 50 nm. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDSs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles (7).
Composition of SEDDSs
The self-emulsifying process is depends on: (7)
The nature of the oil-surfactant pair
The surfactant concentration
The temperature at which self-emulsification occurs.
Oils. Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract (9). Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDSs. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages (8). Novel semisynthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride (9).
Surfactant. Nonionic surfactants with high hydrophilic-lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). The usual surfactant strength ranges between 30-60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules (10).
Cosolvents. Cosolvents like diehylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.
Formulation of SEDDSs
With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble cosolvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures which disperse to give fine colloidal emulsions (11). The following should be considered in the formulation of a SEDDS:
The solubility of the drug in different oil, surfactants and cosolvents.
The selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram (12).
The preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant and cosolvent.
The addition of a drug to a SEDDS is critical because the drug interferes with the self-emulsification process to a certain extent, which leads to a change in the optimal oil-surfactant ratio. So, the design of an optimal SEDDS requires preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS, formulation is made by adding the polymer or gelling agent (13).
Mechanism of self-emulsification
According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation:
Where, DG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and s represents the interfacial energy. The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets, and hence reduces the interfacial energy, as well as providing a barrier to prevent coalescence (14).
Characterization of SEDDSs
The primary means of self-emulsification assessment is visual evaluation. The efficiency of self-emulsification could be estimated by determining the rate of emulsification, droplet-size distribution and turbidity measurements.
Visual assessment. This may provide important information about the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion (15, 16, 17).
Turbidity Measurement. This is to identify efficient self-emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time.
Droplet Size. This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as the stability of the emulsion (10, 18). Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are mainly used for the determination of the emulsion droplet size (10, 19, 20). The reduction of the droplet size to values below 50 μm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions (6).
Zeta potential measurement. This is used to identify the charge of the droplets. In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids (17).
Determination of emulsification time. Self-emulsification time, dispersibility, appearance and flowability was observed and scored according to techniques described in H. Shen et al. (21) used for the grading of formulations.
Application
SEDDS formulation is composed of lipids, surfactants, and cosolvents. The system has the ability to form an oil-in-water emulsion when dispersed by an aqueous phase under gentle agitation. SEDDSs present drugs in a small droplet size and well-proportioned distribution, and increase the dissolution and permeability. Furthermore, because drugs can be loaded in the inner phase and delivered by lymphatic bypass share, SEDDSs protect drugs against hydrolysis by enzymes in the GI tract and reduce the presystemic clearance in the GI mucosa and hepatic first-pass metabolism. Table I shows the SEDDSs prepared for oral delivery of lipophilic drugs in recent years.
Conclusion
Self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.
Introduction
In drug discovery, about 40% of new drug candidates display lowsolubility in water, which leads
to poor bioavailability, highintrasubject/intersubject variability and lack of dose proportionality.
Furthermore, oral delivery of numerous drugs is hinderedowing to their high hydrophobicity [1,2]. Therefore, producingsuitable formulations is very important to improve the solubility
and bioavailability of such drugs.One of the most popular and commercially viable formulation
approaches for solving these problems is self-emulsifying drugdelivery systems (SEDDS). SEDDS have been shown to be reasonablysuccessful in improving the oral bioavailability of poorlywater-soluble and lipophilic drugs [3]. Traditional preparationof SEDDS involves dissolution of drugs in oils and their blendingwith suitable solubilizing agents. However, SE formulations arenormally prepared as liquids that produce some disadvantages, forexample, high production costs, low stability and portability, lowdrug loading and few choices of dosage forms. [4]. More importantly,the large quantity (30-60%) of surfactants in the formulationscan induce gastrointestinal (GI) irritation.To address these problems, S-SEDDS have been investigated, as
alternative approaches. Such systems require the solidification ofliquid self-emulsifying (SE) ingredients into powders/nanoparticlesto create various solid dosage forms (SE tablets [5,6] and SEpellets [7,8], and so on). Thus, S-SEDDS combine the advantages of
SEDDS (i.e. enhanced solubility and bioavailability) with those ofsolid dosage forms (e.g. low production cost, convenience ofprocess control, high stability and reproducibility, better patient
compliance.).To date, there have been some studies that mainly focus on the
preparation and characterization of a solid SE dosage
Self-emulsifying drug delivery systemsSEDDS belong to lipid-based formulations. Lipid formulations canbe oils, surfactant dispersions, emulsions, SEDDS, solid lipid nanoparticles
and liposomes.SEDDS are isotropic mixtures of drug, oil/lipid, surfactant, and/or cosurfactant, which form fine emulsion/lipid droplets, rangingin size from approximately 100 nm (SEDDS) to less than 50 nm forself-microemulsifying drug delivery systems (SMEDDS), on dilutionwith physiological fluid. The drug, therefore, remains insolution in the gut, avoiding the dissolution step that frequentlylimits the absorption rate of hydrophobic drugs from the crystallinestate [9].
Excipient selectionThe oily/lipid component is generally a fatty acid ester or a
medium/long chain saturated, partially unsaturated or unsaturatedhydrocarbon, in liquid, semisolid or solid form at roomtemperature. Examples include mineral oil, vegetable oil, silicon
oil, lanolin, refined animal oil, fatty acids, fatty alcohols, andmono-/di-/tri-glycerides [10].
The most widely recommended surfactants are non-ionic surfactantswith a relatively high hydrophilic-lipophilic balance(HLB) value. The surfactant concentration ranges between 30%
and 60% (w/w) in order to form stable SEDDS [3]. More detaileddescriptions are given elsewhere [3,11], which can serve as a usefulguide for excipient selection.
Biopharmaceutical issues
It is important to note that lipids (e.g. triglycerides) affect the oral
bioavailability of drugs by changing biopharmaceutical properties,
such as increasing dissolution rate and solubility in the intestinal
fluid, protecting the drug from chemical as well as enzymatic
degradation in the oil droplets and the formation of lipoproteins
promoting lymphatic transport of highly lipophilic drugs [12]. The
absorption profile and the blood/lymph distribution of the drug
depend on the chain length of the triglyceride, saturation degree,
and volume of the lipid administered. Drugs processed by the
intestinal lymph are generally transported to the systemic circulation
in association with the lipid core of lipoproteins. In addition
to the stimulation of lymphatic transport, administration of lipophilic
drugs with lipids may enhance drug absorption into the
portal blood compared with non-lipid formulations [13].
Specificity
Self-emulsification depends on the nature of the oil/surfactant
pair, surfactant concentration and oil/surfactant ratio, and the
temperature at which self-emulsification occurs. Only very specific
pharmaceutical excipient combinations lead to efficient self-emulsifying
systems (SES). The efficiency of drug incorporation into a
SEDDS is dependant upon the particular physicochemical compatibility
of the drug/system [3,11]. So, pre-formulation solubility and
phase diagram studies are required in order to obtain an optimal
formulation design.
Characterization
The very essence of SEDDS is self-emulsification, which is primarily
assessed visually. The efficiency of self-emulsification can be estimated
by determining the rate of emulsification and droplet size
distribution. The charge on the oil droplets of SEDDS is another
property that needs to be assessed [3]. Melting properties and
polymorphism of lipid or drug in SES may be established by Xray
diffraction and differential scanning calorimetry.
Solid self-emulsifying drug delivery system
SEDDS can exist in either liquid or solid states. SEDDS are usually,
however, limited to liquid dosage forms, because many excipients
used in SEDDS are not solids at room temperature. Given the
advantages of solid dosage forms, S-SEDDS have been extensively
exploited in recent years, as they frequently represent more effective
alternatives to conventional liquid SEDDS.
From the perspective of dosage forms, S-SEDDS mean solid
dosage forms with self-emulsification properties. S-SEDDS focus
on the incorporation of liquid/semisolid SE ingredients into powders/
nanoarticles by different solidification techniques (e.g.
adsorptions to solid carriers, spray drying, melt extrusion, nanoparticle
technology, and so on). Such powders/nanoparticles,
which refer to SE nanoparticles [14]/dry emulsions/solid dispersions,
are usually further processed into other solid SE dosage
forms, or, alternatively, filled into capsules (i.e. SE capsules). SE
capsules also include those capsules into which liquid/semisolid
SEDDS are directly filled without any solidifying excipient.
To some extent, S-SEDDS are combinations of SEDDS and solid
dosage forms, so many properties of S-SEDDS (e.g. excipients
selection, specificity, and characterization) are the sum of the
corresponding properties of both SEDDS and solid dosage forms.
For instance, the characterizations of SE pellets contain not only
the assessment of self-emulsification, but also friability, surface
roughness, and so on.
In the 1990s, S-SEDDS were usually in the form of SE capsules, SE
solid dispersions and dry emulsions, but other solid SE dosage
forms have emerged in recent years, such as SE pellets/tablets, SE
microspheres/nanoparticles and SE suppositories/implants.
Solidification techniques for transforming liquid/
semisolid SEDDS to S-SEDDS
Capsule filling with liquid and semisolid self-emulsifying
formulations
Capsule filling is the simplest and the most common technology
for the encapsulation of liquid or semisolid SE formulations for the
oral route.
For semisolid formulations, it is a four-step process: (i) heating
of the semisolid excipient to at least 20 8C above its melting point;
(ii) incorporation of the active substances (with stirring); (iii)
capsule filling with the molten mixture and (iv) cooling to room
temperature. For liquid formulations, it involves a two-step process:
filling of the formulation into the capsules followed by
sealing of the body and cap of the capsule, either by banding or
by microspray sealing [15].
In parallel with the advances in capsule technology proceeding,
liquid-Oros technology (Alza Corporation) has been designed for
controlled delivery of insoluble drug substances or peptides. This
system is based on osmotic principles and is a liquid SE formulation
system. It consists of an osmotic layer, which expands after
coming into contact with water and pumps the drug formulation
through an orifice in the hard or soft capsule [16,17].
A primary consideration in capsule filling is the compatibility of
the excipients with the capsule shell. The liquid/semisolid lipophilic
vehicles compatible with hard capsules were listed by Cole
et al. [18]. The advantages of capsule filling are simplicity of
manufacturing; suitability for low-dose highly potent drugs and
high drug loading (up to 50% (w/w)) potential.
Spray drying
Essentially, this technique involves the preparation of a formulation
by mixing lipids, surfactants, drug, solid carriers, and solubilization
of the mixture before spray drying. The solubilized
liquid formulation is then atomized into a spray of droplets. The
droplets are introduced into a drying chamber, where the volatile
phase (e.g. the water contained in an emulsion) evaporates, forming
dry particles under controlled temperature and airflow conditions.
Such particles can be further prepared into tablets or
capsules.
The atomizer, the temperature, the most suitable airflow pattern
and the drying chamber design are selected according to the
drying characteristics of the product and powder specification.
Adsorption to solid carriers
Free flowing powders may be obtained from liquid SE formulations
by adsorption to solid carriers. The adsorption process is simple
and just involves addition of the liquid formulation onto carriers
by mixing in a blender. The resulting powder may then be filled
directly into capsules or, alternatively, mixed with suitable excipients
before compression into tablets. A significant benefit of the
adsorption technique is good content uniformity. SEDDS can be
adsorbed at high levels (up to 70% (w/w)) onto suitable carriers
[19].
Solid carriers can be microporous inorganic substances, highsurface-
area colloidal inorganic adsorbent substances, cross-linked
polymers or nanoparticle adsorbents, for example, silica, silicates,
magnesium trisilicate, magnesium hydroxide, talcum, crospovidone,
cross-linked sodium carboxymethyl cellulose and crosslinked
polymethyl methacrylate [20]. Cross-linked polymers create
a favorable environment to sustain drug dissolution and also
assist in slowing down drug reprecipitation [21]. Nanoparticle
adsorbents comprise porous silicon dioxide (Sylysia 550), carbon
nanotubes, carbon nanohorns, fullerene, charcoal and bamboo
charcoal [22].
Melt granulation
Melt granulation is a process in which powder agglomeration is
obtained through the addition of a binder that melts or softens at
relatively low temperatures. As a 'one-step' operation, melt granulation
offers several advantages compared with conventional wet
granulation, since the liquid addition and the subsequent drying
phase are omitted. Moreover, it is also a good alternative to the use
of solvent.
The main parameters that control the granulation process are
impeller speed, mixing time, binder particle size, and the viscosity
of the binder.
A wide range of solid and semisolid lipids can be applied as
meltable binders. Thereinto, Gelucire1, a family of vehicles
derived from the mixtures of mono-/di-/tri-glycerides and polyethylene
glycols (PEG) esters of fatty acids, is able to further
increase the dissolution rate compared with PEG usually used
before, probably owing to its SE property [23]. Other lipid-based
excipients evaluated for melt granulation to create solid SES
include lecithin, partial glycerides, or polysorbates. The melt
granulation process was usually used for adsorbing SES (lipids,
surfactants, and drugs) onto solid neutral carriers (mainly silica
and magnesium aluminometa silicate) [24,25].
Melt extrusion/extrusion spheronization
Melt extrusion is a solvent-free process that allows high drug
loading (60%) [15], as well as content uniformity. Extrusion is a
procedure of converting a raw material with plastic properties into
a product of uniform shape and density, by forcing it through a die
under controlled temperature, product flow, and pressure conditions
[26]. The size of the extruder aperture will determine the
approximate size of the resulting spheroids.
The extrusion-spheronization process is commonly used in the
pharmaceutical industry to make uniformly sized spheroids (pellets).
The extrusion-spheronization process requires the following
steps: dry mixing of the active ingredients and excipients to
achieve a momogenious powder; wet massing with binder; extrusion
into a spaghetti-like extrudate; spheronization from the
extrudate to spheroids of uniform size; drying; sifting to achieve
the desired size distribution and coating (optional).
In the wet masses comprising SES (polysorbate 80 and mono-/
di-glycerides), lactose, water and MCC, the relative quantities of
SES and water had a significant effect on the extrusion force, size
spread, disintegration time, and surface roughness of pellets.
Studies suggested that the maximum quantity of this SES that
can be solidified by extrusion spheronization occupies 42% of
the dry pellet weight [27]. Generally, the higher the water level,
the longer the disintegration time [28]. The rheological properties
of wet masses may be measured by an extrusion capillary. It
has been shown that SES containing wet mass with a wide range
of rheological characteristics can be processed, but a single
rheological parameter cannot be used to provide complete characterization
of how well it can be processed by extrusion-spheronization
[29].
Applying extrusion-spheronization, SE pellets of diazepam and
progesterone and bi-layered cohesive SE pellets have been prepared
[7,30,31].
Dosage form development of S-SEDDS
Dry emulsions
Dry emulsions are powders from which emulsion spontaneously
occurs in vivo or when exposed to an aqueous solution. Dry
emulsions can be useful for further preparation of tablets and
capsules.
Dry emulsion formulations are typically prepared from oil/
water (O/W) emulsions containing a solid carrier (lactose, maltodextrin,
and so on) in the aqueous phase by rotary evaporation
[32], freeze-drying [33] or spray drying [34-36]. Myers and Shively
obtained solid state glass emulsions in the form of dry 'foam' by
rotary evaporation, with heavy mineral oil and sucrose. Such
emulsifiable glasses have the advantage of not requiring surfactant
[32]. In freeze-drying, a slow cooling rate and the addition of
amorphous cryoprotectants have the best stabilizing effects, while
heat treatment before thawing decreases the stabilizing effects
[33]. The technique of spray drying is more frequently used in
preparation of dry emulsions. The O/W emulsion was formulated
and then spray-dried to remove the aqueous phase.
The most exciting finding in this field ought to be the newly
developed enteric-coated dry emulsion formulation, which is
potentially applicable for the oral delivery of peptide and protein
drugs. This formulation consisted of a surfactant, a vegetable oil,
and a pH-responsive polymer, with lyophilization used [37].
Recently, Cui et al. prepared dry emulsions by spreading liquid
O/W emulsions on a flat glass, then dried and triturated to powders
Self-emulsifying capsules
After administration of capsules containing conventional liquid
SE formulations, microemulsion droplets form and subsequently
disperse in the GI tract to reach sites of absorption. However, if
irreversible phase separation of the microemulsion occurs, an
improvement of drug absorption cannot be expected. For handling
this problem, sodium dodecyl sulfate was added into the SE
formulation [39]. With the similar purpose, the supersaturatable
SEDDS was designed, using a small quantity of HPMC (or other
polymers) in the formulation to prevent precipitation of the drug
by generating and maintaining a supersaturated state in vivo. This
system contains a reduced amount of a surfactant, thereby minimizing
GI side effects [40,41].
Besides liquid filling, liquid SE ingredients also can be filled into
capsules in a solid or semisolid state obtained by adding solid
carriers (adsorbents, polymers, and so on). As an example, a solid
PEG matrix can be chosen. The presence of solid PEG neither
interfered with the solubility of the drug, nor did it interfere with
the process of self-microemulsification upon mixing with water
[42,43].
Oral administration of SE capsules has been found to enhance
patient compliance compared with the previously used parenteral
route. For instance, low molecular weight heparin (LMWH) used
for the treatment of venous thrombo-embolism was clinically
available only via the parenteral route. So, oral LMWH therapy
was investigated by formulating it in hard capsules. LMWH was
dispersed in SMEDDS and thereafter the mixture was solidified to
powders using three kinds of adsorbents: microporous calcium
silicate (FloriteTM RE); magnesium aluminum silicate (NeusilinTM
US2) and silicon dioxide (SylysiaTM 320). Eventually these solids
were filled into hard capsules [44]. In another study, such adsorbents
were also applied to prepare SE tablets of gentamicin that, in
clinical use, was limited to administration as injectable or topical
dosage forms [19].
Self-emulsifying sustained/controlled-release tablets
Combinations of lipids and surfactants have presented great
potential of preparing SE tablets that have been widely researched.
Nazzal and Khan evaluated the effect of some processing parameters
(colloidal silicates-X1, magnesium stearate mixing time-
X2, and compression force-X3) on hardness and coenzymum Q10
(CoQ10) dissolution from tablets of eutectic-based SMEDDS. The
optimized conditions (X1 = 1.06%, X2 = 2 min, X3 = 1670 kg) were
achieved by a face-centered cubic design [45].
In order to reduce significantly the amount of solidifying excipients
required for transformation of SEDDS into solid dosage
forms, a gelled SEDDS has been developed by Patil et al. In their
study, colloidal silicon dioxide (Aerosil 200) was selected as a
gelling agent for the oil-based systems, which served the dual
purpose of reducing the amount of required solidifying excipients
and aiding in slowing down of the drug release [46].
SE tablets are of great utility in obviating adverse effect, as
disclosed by Schwarz in a patent. Inclusion of indomethacin (or
other hydrophobic NSAID), for example, into SE tablets may
increase its penetration efficacy through the GI mucosal membranes,
potentially reducing GI bleeding. In these studies, the SES
was composed of glycerol monolaurate and TyloxapolTM (a copolymer
of alkylphenol and formaldehyde). Polyethylene oxide
successfully illustrated its suitability for controlled-release
matrices. The resultant SE tablets consistently maintained a higher
active ingredient concentration in blood plasma over the same
time frame compared with a non-emulsifying tablet [47].
The newest advance in the research field of SE tablet is the SE
osmotic pump tablet, where the elementary osmotic pump system
was chosen as the carrier of SES. This system has outstanding
features such as stable plasma concentrations and controllable
drug release rate, allowing a bioavailability of 156.78% relative to
commercial carvedilol tablets [48].
Self-emulsifying sustained/controlled-release pellets
Pellets, as a multiple unit dosage form, possess many advantages
over conventional solid dosage forms, such as flexibility of manufacture,
reducing intrasubject and intersubject variability of
plasma profiles and minimizing GI irritation without lowering
drug bioavailability [49]. Thus, it is very appealing to combine the
advantages of pellets with those of SEDDS by SE pellets.
Serratoni et al. prepared SE controlled-release pellets by incorporating
drugs into SES that enhanced their rate of release, and
then by coating pellets with a water-insoluble polymer that
reduced the rate of drug release. Pellets were prepared by extrusion/
spheronization and contained two water-insoluble model
drugs (methyl and propyl parabens); SES contained mono-diglycerides
and Polysorbate 80. As shown in Figure 1, this research
demonstrated that combinations of coating and SES could control
in vitro drug release by providing a range of release rates; and the
presence of the SEDDS did not influence the ability of the polymer
film to control drug dissolution [50]. There is another report that
SE sustained-release matrix pellets could be successfully formulated
with glyceryl palmito-stearate (Gelucire 54/02) and glyceryl
behenate (Gelucire 70/02) [51].
Self-emulsifying solid dispersions
Although solid dispersions could increase the dissolution rate
and bioavailability of poorly water-soluble drugs, some manufacturing
difficulties and stability problems existed. Serajuddin
pointed out that these difficulties could be surmounted by the
use of SE excipients [52,53]. These excipients have the potential
to increase further the absorption of poorly water-soluble drugs
relative to previously used PEG solid dispersions and may also be
filled directly into hard gelatin capsules in the molten state, thus
obviating the former requirement for milling and blending
before filling [9,54]. SE excipients like Gelucire1 44/14, Gelucire1
50/02, Labrasol1, Transcutol1 and TPGS (tocopheryl polyethylene
glycol 1000 succinate) have been widely used in this
field [52-55].
For example, Gupta et al. prepared SE solid dispersion granules
using the hot-melt granulation method. Seven drugs, including
four carboxylic acid containing drugs, a hydroxyl-containing
drug, an amide-containing drug (phenacetin) and a drug with
no proton-donating groups (progesterone) were chosen. Gelucire1
50/13 was used as the dispersion carrier, whereas Neusilin
US2 was used as the surface adsorbent [25].
Self-emulsifying beads
In an attempt to transform SES into a solid form with minimum
amounts of solidifying excipients, Patil and Paradkar investigated
loading SES into the microchannels of porous polystyrene beads
(PPB) using the solvent evaporation method. PPB with complex
internal void structures are typically produced by copolymerizing
styrene and divinyl benzene. They are inert, stable over a wide pH
range and to extreme conditions of temperature and humidity.
This research concluded that PPB were potential carriers for solidification
of SES, with sufficiently high SES to PPB ratios required
to obtain solid form. Geometrical features, such as bead size and
pore architecture of PPB, were found to govern the loading efficiency
and in vitro drug release from SES-loaded PPB [56].
Self-emulsifying sustained-release microspheres
Zedoary turmeric oil (ZTO; a traditional Chinese medicine) exhibits
potent pharmacological actions including tumor suppressive,
antibacterial, and antithrombotic activity. With ZTO as the oil
phase, You et al. prepared solid SE sustained-release microspheres
using the quasi-emulsion-solvent-diffusion method of the spherical
crystallization technique. ZTO release behavior could be
controlled by the ratio of hydroxypropyl methylcellulose acetate
succinate to Aerosil 200 in the formulation. The plasma concentration-
time profiles (Figure 2) were achieved after oral administration
of such microspheres to rabbits, with a bioavailability of
135.6% with respect to the conventional liquid SEDDS [57].
Self-emulsifying nanoparticles
Nanoparticle techniques have been useful in the production of SE
nanoparticles. Solvent injection is one of these techniques. In this
method, the lipid, surfactant, and drugs were melted together, and
injected drop wise into a stirred non-solvent. The resulting SE
nanoparticles were thereafter filtered out and dried. This approach
yielded nanoparticles (about 100 nm) with a high drug loading
efficiency of 74% [58]. A second technique is that of sonication
emulsion-diffusion-evaporation, by which co-loading 5-fluorouracil
(5-FU) and antisense EGFR (epidermal growth factor receptor)
plasmids in biodegradable PLGA/O-CMC nanoparticles was realized.
The mixture of PLGA (poly-lactide-co-glycolide) and O-CMC
(O-carboxmethyl-chitosan) had a SE effect, with no need to add
another surfactant stabilizer. Eventually the 5-FU and plasmid
encapsulation efficiencies were as high as 94.5% and 95.7%,
respectively, and the 5-FU release activity from such nanoparticles
could be sustained for as long as three weeks [59].
More recently, Trickler et al. developed a novel nanoparticle
drug delivery system consisting of chitosan and glyceryl monooleate
(GMO) for the delivery of paclitaxel (PTX). These chitosan/
GMO nanoparticles, with bioadhesive properties and increased
cellular association, were prepared by multiple emulsion (o/w/o)
solvent evaporation methods. The SE property of GMO enhanced
the solubility of PTX and provided a foundation for chitosan
aggregation, meanwhile causing near 100% loading and entrapment
efficiencies of PTX. These advantages allow the use of lower
doses of PTX to achieve an efficacious therapeutic window, thus
minimizing the adverse side effects associated with chemotherapeutics
like PTX [60].
Self-emulsifying suppositories
Some investigators proved that S-SEDDS could increase not only
GI adsorption but also rectal/vaginal adsorption [61].
Glycyrrhizin, which, by the oral route, barely achieves therapeutic
plasma concentrations, can obtain satisfactory therapeutic
levels for chronic hepatic diseases by either vaginal or rectal SE
suppositories. The formulation included glycyrrhizin and a mixture
of a C6-C18 fatty acid glycerol ester and a C6-C18 fatty acid
macrogol ester [62].
Self-emulsifying implants
Research into SE implants has greatly enhanced the utility and
application of S-SEDDS. As an example, 1,3-bis(2-chloroethyl)-1-
nitrosourea (carmustine, BCNU) is a chemotherapeutic agent
used to treat malignant brain tumors. However, its effectiveness
was hindered by its short half-life. In order to enhance its stability
compared with that released from poly (d,l-lactide-co-glycolide)
(PLGA) wafer implants, SES was formulated with tributyrin,
Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil) and
Labrafil 1944 (polyglycolyzed glyceride). Then the self-emulsified
BCNU was fabricated into wafers with flat and smooth surface by
compression molding. Ultimately, SES increased in vitro half-life
of BCNUup to 130 min contrastedwith 45 min of intact BCNU. In
vitro release of BCNU from SE PLGA wafers were prolonged up to 7
days. Such wafers had higher in vitro antitumor activity and were
less susceptible to hydrolysis than those wafers devoid of SES [63].
Loomis invented copolymers having a bioresorbable region, a
hydrophilic region and at least two cross-linkable functional
groups per polymer chain. Such copolymers show SE property
without the requirement of an emulsifying agent. These copolymers
can be used as good sealants for implantable prostheses [
