Oral Lipid Based DDS

330 Current Drug Delivery, 2011, 8, 330-345
Oral Lipid Based Drug Delivery System (LBDDS): Formulation,

Characterization and Application: A Review
Md. Akhlaquer Rahman1,3,*, Ranjit Harwansh1, Mohd. Aamir Mirza2, Sarfaraj Hussain3 and
Arshad Hussain3
1
SLT institute of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur- 495009, (C.G), India;
2
Department of Pharmaceutics, Faculty of pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062, India;
3
Faculty of Pharmacy, Integral University, Lucknow-226026, India
Abstract: The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor
aqueous solubility. This may lead to high inter- and intra subject variability, lack of dose proportionality and therapeutic
failure. The improvement of bioavailability of drugs with such properties presents one of the greatest challenges in drug
formulations. Oral lipid based formulations are attracting considerable attention due to their capacity to increase the solu-
bility, facilitating gastrointestinal absorption and reduce or eliminate the effect of food on the absorption of poorly water
soluble, lipophilic drug and thus increasing the bioavailability. The present review outlines the recent findings on self-
emulsifying drug delivery system (SEDDS), self-micro/nanoemulsifying drug delivery system (SMEDDS/SNEDDS) and
evaluation of these formulations published over the past decade. The application of lipid based formulations as a promis-
ing system for the oral delivery of many therapeutic agents including traditional medicine (TM) has also been examined in
the current review.
Keywords: Self-Micro/Nanoemulsifying drug delivery system (SMEDDS/SNEDDS), Solubility, Bioavailability, Oral absorp-
tion, Surfactant, Co-surfactant.
INTRODUCTION products are those in which the drug is dissolved in digesti-

ble oil, usually a vegetable oil or a medium chain triglyc-
The fact that a large majority of the newly discovered
eride. The inclusion of surfactants may improve the solvent
chemical entities and many existing drug molecules are
capacity of the formulations and promote their emulsification
poorly water soluble (belonging to BCS class II and IV) pre-
into water to produce emulsion or microemulsion. One of the
sents a serious challenge to the successful formulation and
promising technologies is lipid based micro/nanoemulsion
marketing of new drugs in the pharmaceutical industry. The
drug delivery system, which is being used to enhance
oral delivery of such compounds presents a major challenge bioavailability. The microemulsion concept was introduced
because of the low aqueous solubility. For those compounds,
as early as the 1940s by Hoar and Schulman, 1943 [1] who
the absorption rate from the gastrointestinal (GI) lumen is
generated a clear single-phase solution by titrating a milky
controlled by dissolution and it becomes a rate limiting step.
emulsion with hexanol. Subsequently, Schulman et al., 1959
Formulation design can be a useful approach to improve the
[2] introduced the term microemulsion as the droplet sizes
absorption and thus the oral bioavailability of such drug can-
(100-600 nm), which has been defined and redefined on
didates. In recent years, there has been a growing interest in many occasions. Microemulsion are best defined as a system
the potential of lipid based formulations for oral administra-
of water, oil and an amphiphile, which is a single optically
tion. Nevertheless, a preference for solid dosage forms pre-
isotropic, and thermodynamically stable liquid solution [3].
vailed until the case of Cyclosporin A emerged, when it be-
Nanoemulsion are almost similar in properties with microe-
came clear that its formulation with lipids or surfactants had
mulsion, the only difference is in the droplet size (10-100
been crucial to the success of the oral capsule product. Re-
nm) [4].
ports on the mechanisms of action, optimization and per-
formance of lipid formulations for oral administration are In practice, the key difference between emulsions and
relatively sparse. In practice, lipid formulations are a diverse micro/nanoemulsions are that the former, while they may
group of formulations, which have a wide range of proper- exhibit excellent kinetic stability, are fundamentally thermo-
ties. These result from the blending of up to five classes of dynamically unstable and will eventually phase separate [5,
excipients, ranging from pure triglyceride oils, through 6]. Another difference concerns their appearance; emulsions
mixed glycerides, lipophilic surfactants, hydrophilic surfac- are cloudy while microemulsions are clear or translucent.
tants and water soluble co-solvents. The simplest lipid Additionally, there are distinct differences in their method of
preparation. Emulsions require a large input of energy while
microemulsions do not. The difference in energy require-
*Address correspondence to this author at the Faculty of Pharmacy, Integral ments has obvious implications when considering the rela-
University, Lucknow-226026, India; Tel: +91-9565402042; tive cost of commercial production of the two types of for-
Fax: 0522-2890809; E-mail: [email protected] mulations.
1567-2018/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Oral Lipid Based Drug Delivery System (LBDDS) Current Drug Delivery, 2011, Vol. 8, No. 4 331
Potential Advantages of these Systems Include stitute a route for the migration of solubilized hydrophobic
drug. Liquid crystalline phases are eventually broken down
1) Enhanced oral bioavailability enabling reduction in
in the presence of (unsaturated) bile salt micelles, leading to
dose,
the formation of lipid-rich, swollen, mixed micelles. Thus, a
2) More consistent temporal profiles of drug absorption, direct pathway exists for the flow of solubilized drug from
digesting oil droplets to the final product phase, mixed mi-
3) Selective targeting of drug(s) toward specific absorption
celles, which provide a strong solubilizing environment for
window in GIT,
hydrophobic drugs. This provides the reservoir of drug from
4) Protection of drug(s) from the hostile environment in which partitioning will occur, allowing absorption of free
gut, drug from the lumen of the gut. It is reasonable to expect that
5) Control of delivery profiles, the rate at which a hydrophobic drug diffuses from the dis-
persed oil phase into aqueous intestinal fluids is governed by
6) Reduced variability including food effects, its solubility in mixed micelles and the rate at which these
7) Protective of sensitive drug substances, structures are formed by lipolysis. Since the latter is an inter-
facial process, the rate of lipolysis is itself dependent on the
8) High drug payloads. size of the emulsion particles.
MECHANISM OF DRUG ABSORPTION FROM LIPID Therefore, if it is necessary to maximize the rate of drug
BASED FORMULATIONS partitioning into aqueous intestinal fluids, and hence the ab-
sorption rate, the formulation should be highly dispersible.
• Digestion of lipids and lipid-based formulations is the One mechanism by which this can be achieved is by formu-
result of three sequential processes [7] that involve: lation of a self-emulsifying drug delivery system (SEDDS)
• Dispersion of fat globules into a coarse emulsion of high and self-micro/nanoemulsifying drug delivery system
surface area. (SMEDDS/SNEDDS) using surfactants and other excipient.
• Enzymatic hydrolysis of fatty acid glyceryl esters (pri- SELF-EMULSIFYING, SELF-MICRO/NANOEMUL-
marily triglyceride lipid) at the oil/water interface. SIFYING DRUG DELIVERY SYSTEM (SEDDS, SME-
• Dispersion of the products of lipid digestion into an ab- DDS/SNEDDS)
sorbable form. Extensive research has been done in the area of self-
emulsifying drug delivery systems (SEDDS) and self-
Lingual and gastric lipases secreted by the salivary gland
and the gastric mucosa, respectively, are responsible for ini- micro/nanoemulsifying drug delivery system (SMEDDS/
SNEDDS). The principal characteristic of this type of system
tiating triglyceride (TG) hydrolysis to the corresponding
is its ability to form fine oil-in water emulsions upon subse-
diglyceride (DG) and fatty acid (FA) within the stomach.
quent dilution in gastric fluids, with gastric motility supply-
The liberation of these amphiphilic lipid digestion products
ing the necessary agitation. Therefore they are considered to
facilitates formation of a crude emulsion that empties into
be good candidates for the oral delivery of hydrophobic
the duodenum. The optimal pH range for lingual and gastric
lipase is 3-6. Medium chain triglycerides are hydrolyzed at a drugs, provided they possess adequate solubility in oil or oil–
surfactant blends. However, the development of a drug de-
faster rate than long chain triglycerides [8, 9]. Following
livery system is a time-consuming process, requiring the
passage into the small intestine, the formulation will become
matching of the appropriate delivery system components,
exposed to local secretions of lipase and bile salts from the
and their relative levels, to the drug substance to obtain the
pancreas and gall bladder, respectively. These secretions will
desired absorption characteristics. SMEDDS are distin-
together facilitate lipolysis, wherein dietary fat is ultimately
broken down to fatty acids and monoglycerides. Biliary salts guished from SEDDS by the much smaller emulsion droplets
produced on dilution, resulting in a transparent or translucent
adsorbed to the surface of the DG and TG entering from the
solution. SMEDDS generally contain relatively high concen-
stomach stabilizes the system and reduces emulsion droplet
trations of surfactant (typically 40-60% w/w), and regularly
size [7]. Subsequently, TG hydrolysis occurs primarily under
contain hydrophilic co-solvents (e.g. propylene glycol, poly-
the action of pancreatic lipase. Pancreatic lipase is an inter-
ethylene glycols).
facial enzyme that preferentially acts at the surface of emul-
sified TG droplets to quantitatively produce the correspond- The key difference between the two preparations is the
ing Two-monoglyceride (MG) and two fatty acids (FA). The optical clarity and the finer droplet size achieved when
overall lipolytic process is essentially self-promoting as the SMEDDS are dispersed into the aqueous phase [13]. Classi-
FA and MG products of lipid digestion are effective emulsification of lipid based delivery system by Pouton in 2000 is
fying agents and the presence of liberated FA further pro- given in Table 1 [14]. Type I and type IV formulations are
motes binding of the lipase to the emulsion surface [10, 11]. not described in this article, to see the detail consult the lit-
During the process of lipolysis, however, multi-lamellar, erature [14]. A SMEDDS typically comprises a mixture of
liquid crystalline, intermediate phases build up on the surface surfactant, oil and drug (known as the concentrate) which
of degrading oil droplets. when introduced into the body is rapidly dispersed to form
droplets of approximately the same size range as those ob-
Microscopic studies [12] have provided evidence to sup-
served in microemulsion systems [15]. Once dispersed, such
port the existence of a hydrophobic continuum linking the
dispersed and degrading oil droplets to the interior of these systems would be expected to self-emulsify rapidly in the
aqueous contents of the stomach and to behave in vivo much
intermediate product phases. These channels effectively con-
the same way as oil-in-water (o/w) microemulsions.
332 Current Drug Delivery, 2011, Vol. 8, No. 4 Rahman et al.
Table 1. Classification of Lipid-based Delivery System by Pouton [14]
Type I Type II Type III Type IIIA Type IV
Triglycerides or mixed
100% 40-80% 40-80% 20% 0%
glycerides
20-60% 20-40% 20-50%

Surfactants - 30-100%
HLB<12 HLB>11 HLB>11
Hydrophilic Co-solvents - - 0-40% 20-50% 0-50%
Dispersion Particle size Course 100-250nm 100-250nm 50-100nm <50nm
Not crucial but

Digestibility Crucial Not crucial but likely Not important Not important
may occur
Therefore, it presents the drug in solution in small drop- instrumentation. On the other hand, Liao and Jarowski, 1984
lets of oil. Fine oil droplets should empty rapidly from the [9]; Yang et al., 1979 [22] and later on Spireas et al., 1992
stomach and promote wide distribution of the drug through- [23]; Spireas and Sadu, 1998 [24] worked on producing solid
out the gastrointestinal tract. An additional advantage of the solutions and "liquisolids" compacts. Historically, liquisolid
self-emulsified systems over simple oil solutions is that they compacts are descendants of powdered solutions, an older
provide large interfacial area for partitioning of the drug be- technique which was based on the conversion of a solution
tween oil and water. For drugs subject to dissolution rate of a drug in a nonvolatile solvent into a dry-looking, nonad-
limited absorption, self-emulsified systems may offer an herent powder by adsorbing the liquid onto silicas of large
improvement in both the rate and extent of absorption [13]. specific surfaces [25]. Such preparations, however, have
SEDDS and SMEDDS/SNEDDS can therefore be defined as been investigated for their dissolution profiles while being in
"isotropic solutions of oil, surfactant, co-surfactant, and drug a powder-dispersion form and not as compressed entities
which form o/w (micro) emulsions when introduced into because they could not be compressed into tablets [22]. In
aqueous phases under gentle agitation [16, 17]. The optimum later studies on powdered solutions, compression enhancers
concentrations, or concentration ranges of oil, surfactant and such as microcrystalline cellulose were added in such disper-
co-surfactant necessary to promote self-emulsification are sions in order to produce liquisolid compacts and to increase
determined by construction of a pseudoternary phase dia- the compressibility of the systems [26, 23].
gram, which should also assess the effect of drug loading on
The concept of "liquisolid" compacts is based on formu-
the efficiency of self-emulsification.
lating liquid medications such as oily liquid drugs and solu-
tions or suspensions of water-insoluble solid drugs carried in
SELF-EMULSIFYING, SELF-MICRO/NANOEMUL-
suitable nonvolatile solvent systems, termed the liquid vehi-
SIFYING DRUG DELIVERY SYSTEM IN SOLID
cles, into acceptably flowing and compressible powders.
DOSAGE FORM Simple blending of such liquid medications with selected
Lipid based self- (micro/nano) emulsified drug delivery powder excipients, referred to as the carrier and coating ma-
systems require incorporation into capsules directly, or trans- terials can yield dry-looking, nonadherent, free flowing, and
formed into granules, pellets, and powders for dry filled cap- readily compressible powders. Various grades of cellulose,
sules as well as tablet preparations. The latter are possible by starch, lactose, etc., may be used as the carriers, whereas
innovative adaptations of conventional equipment with rela- very fine particle size silica powders may be used as the
tive ease and process simplicity, using methods like melt coating materials. Utilizing a similar approach, Akzo Nobel
granulation, melt extrusion, adsorption on solid support, [27] and Cima Labs [19] introduced a solid dosage form
spray cooling, spray drying supercritical fluid based methods based on microemulsion adsorbed onto colloidal silicon di-
and high pressure homogenization (to produce Solid Lipid oxide and microcrystalline cellulose. In solid solutions and
Nanoparticles (SLN) or Nanostructured Lipid Carriers "liquisolid" compacts, however, large quantities of silicas
(NLC) [18]. Recently, pellets containing a self emulsifying often exceeding the limits stated by the Code of Federal
mixture were prepared by extrusion/spheronization [19]. Regulation (CFR) were used. Furthermore, when these
Details of formulation techniques are excluded from this preparations were compressed into tablets, they presented
review. Table 2 sorts out these techniques according to significant "liquid-squeezing out" phenomena and unac-
physical nature of the excipients used, lipid exposure capac- ceptably soft tablets, thereby hampering the industrial appli-
ity, and maximum drug loading reported in the literature. cation of such systems [23].
Solid-state microemulsion for the delivery of Cy- A different approach could be utilized to produce micro-
closporine was also prepared by coating the pre-microemul- emulsion adsorbed compacts. A "wax-like" paste could be
sion with an enteric coating material [20]. Similarly, solvent obtained by adsorbing the liquid vehicle onto properly se-
evaporation method was used to prepare tocopheryl nicoti- lected adsorbent. Grinding this paste with soluble excipients
nate tablets utilizing calcium silicates as the adsorbing agent such as maltodextrin and lactose produces granules with
[21]. Such methods often require elaborate processing and good flow properties. Subsequent reinforcement with cellu-
Table 2. Considerations in Selection of Formulation Techniques for Bioavailability Enhancement with Lipid-based Excipients
Physical Property of the Lipid Excipients Applied Formulation Advantages and Limits
Formulation Techniques
for Solid Formulation Maximum Lipid Exposure‡ Maximum Drug Loading‡
Liquid Semi-solid to Solid
(% w/w) (% w/w)
Capsule filling X X 99 50
Spray-cooling X 99 30
Spray-drying X X 60 50
Adsorption on solid carrier X 80 10
Melt granulation X 50 80
Melt extrusion X 50 60
Supercritical fluid based

X 99 20
methods
Solid lipid Nanoparticles X X 99 50

‡
Percentage calculated after evaporation of solvent whenever applicable.
lose derivatives such as microcrystalline cellulose (MCC) efficient self-emulsification region. The use of lipid excipi-
produces a powder mix that exhibits excellent compression ents for formulations is inevitably complicated, and thus has
properties. Extragranular MCC was shown to increase disso- presented challenges to both pharmaceutical and regulatory
lution rates, compressibility, and hardness of tablets made by scientists. Lipid excipients are able to solubilize hydrophobic
high shear granulation. Several properties of the powder to drugs within the dosage form matrix. However, as with die-
be compressed affect the strength of the compacts. These tary lipids, these excipients can also be digested and dis-
include particle shape, surface texture, and size [28, 29]. The persed in the GI tract. Therefore, one of the questions for a
initial size of the particles constituting a powder is an impor- lipid-based oral formulation is whether the drug remains in
tant factor in determining its compaction behavior. For most solubilised form in the presence of changing phases of the
powdered materials, compaction of the smaller particles re- formulation after it is administered. This is a difficult ques-
sult in stronger tablets because of their larger surface area tion, which can be illustrated by a simplified phase diagram
available for bonding [30-32]. for an oily formulation dispersed in water and a surfactant.
The mechanism of consolidation and the effect of oil As shown in Fig. (1), various possible lipid assemblies can
arise from the interplay of the three major components (i.e.,
adsorption and the initial particle size of the excipients used
oil, water and surfactant) present in the system [37]. These
to prepare emulsion adsorbed compacts on the strength of the
assemblies may include emulsion, micelle, water-in-oil mi-
tablets can be evaluated by several methods. Some of the
croemulsion, oil-in-water microemulsion, and bicontinuous
methods reported for the determination of compaction
microemulsion. The phase of the lipid formulation may be
mechanisms, both qualitatively and quantitatively, include
scanning election microscopy [29], work measurements from changing as it reaches the GI tract and is subject to the diges-
tion, dispersion and transport process in the body.
work-displacement curves [33], the use of ratios from axial
and radial tensile strengths measurements [28, 29], meas-
urement of surface area changes by permeametry and gas
adsorption techniques [34], and measurement of porosity
changes during compression [31, 32, 35, 36]. The later tech-
nique, where changes in porosity against compression pres-
sure load are recorded and expressed by mathematical func-
tions, has been extensively used.
FORMULATION CONSIDERATION
Preliminary studies are performed for selection of oil,
which is an important and critical requisite for formulation of
SEDDS and SMEDDS/SNEDDS. Solubility of drug is de-
termined in various oils and surfactants. Prepare a series
such type of delivery system containing drug in various oil
and surfactant. Then, in vitro self-emulsification properties
and droplet size analysis of these formulations upon their
Fig. (1). A simplified phase diagram for an oily formulation dis-
addition to water under mild agitation conditions is studied.
persed in water and a surfactant [37].
Pseudo-ternary phase diagram is constructed, identifying the
Oils w/o microemulsions whereas surfactants with high HLBs (8-

18) are preferred for the formation of o/w microemulsion
Oils represents one of the most important excipients in
systems [38]. Ionic surfactants such as sodium dodecyl sul-
the micro/nanoemulsion formulation not only because they
phate which have HLBs greater than 20, often require the
can solubilize large amounts of the lipophilic drug but also
presence of a co-surfactant to reduce their effective HLB to a
because it can increase the fraction of lipophilic drug trans- value within the range required for micro/nanoemulsion for-
ported via skin, thereby increasing absorption from the skin
mation. The formulation of w/o microemulsions for use as
depending on the molecular nature of the triglyceride. Both
SEDDS or SMEDDS has been investigated using blends of
long and medium chain triglyceride oils with different de-
low and high HLB surfactants, which were commercially
grees of saturation have been used for the design of mi-
available and pharmaceutically acceptable. Typical example
cro/nanoemulsion formulations. Hydrolyzed vegetable oils
of different oils (Lipid ingredients), surfactant and co-
have been widely used since these excipients form good surfactant that has been used by many researchers are given
emulsification systems with a large number of surfactants
in Table 3.
approved for topical and oral administration and exhibit bet-
ter drug solubility properties [38]. Novel semisynthetic me- Usually the surfactant concentration ranges between 30
dium chain derivatives, which can be defined as amphiphilic and 60% v/v in order to form stable microemulsion. There is
compounds with surfactant properties, are progressively and a relationship between the droplet size and the concentration
effectively replacing the regular medium chain triglyceride of the surfactant being used. In some cases, increasing the
oils [38]. Solvent capacity for less hydrophobic drugs can be surfactant concentration can lead to droplets with smaller
improved by blending triglycerides with other oily excipi- mean droplet size such as in the case of a mixture of satu-
ents, which include mixed monoglycerides and diglycerides. rated C8-C10 polyglycolized glycerides (Labrafac CM-10).
Most of the drugs are not soluble in hydrocarbon oils. The On the other hand, in some cases the mean droplet size may
polarity of the majority of the poorly water soluble drugs increase with increasing surfactant concentrations [40, 41].
favour their solubilization in small/medium molecular vol-
ume oils such as tributyrin, medium chain triglycerides or Co-Surfactant
mono or diglycerides [39].
Almost always in the case of micro/nanoemulsions, self-
micro/nanoemulsified drug delivery systems will contain co-
Surfactant
surfactants. In most cases, single-chain surfactants alone are
The surfactant chosen must be able to lower interfacial unable to reduce the oil/water interfacial tension sufficiently
tension to a very small value to aid dispersion process during to enable a microemulsion to form [42-47]. The co-surfactant
the preparation of the micro/nanoemulsion. They should also is an amphiphile with an affinity for both the oil and aqueous
provide a flexible film that can readily deform around drop- phases and partitions to an appreciable extent into the surfac-
lets and be of the appropriate lipophillic character to provide tant interfacial monolayer present at the oil-water interface.
the correct curvature at the interfacial region for the desired The co-surfactant need not necessarily be capable of forming
micro/nanoemulsion type. Conventional surfactant molecules association structures by itself. A wide variety of molecules
comprise a polar head group region and a hydrophobic tail can function as co-surfactants including non-ionic surfac-
region, the latter having the larger molecular volume particu- tants [48, 49], alcohols [50, 51], alkanoic acids, alkanediols
larly in the case of ionic surfactants. On dispersal in water, and alkyl amines [51]. Medium chain length alcohols are
surfactants self-associate into a variety of equilibrium commonly added as co-surfactants. They have the effect of
phases, the nature of which stems directly from the interplay further reducing the interfacial tension, while increasing the
of the various intra and intermolecular forces as well as en- fluidity of the interface thereby increasing the entropy of the
tropy considerations. Surfactants also self associate in non- system [44, 47, 51]. Medium chain length alcohols also in-
aqueous solvents, particularly a polar liquid such as alkanes. crease the mobility of the hydrocabon tail and allow greater
In this case the orientation of the surfactant molecules is re- penetration of the oil into this region. Furthermore, any alco-
versed compared to those adopted in aqueous solution. This hol present may also influence the solubility properties of the
reorientation serves to optimize the solvation requirements of aqueous and oily phases due to its partitioning between these
the surfactant and minimizes the free energy of the system phases.
overall. When surfactants are incorporated into immiscible It has also been suggested that some oils, for example the
mixtures of oil and water, the surfactant molecules can locate ethyl esters of fatty acids, act as co-surfactants by penetrat-
at the oil/water interface, which is thermodynamically favor- ing the hydrophobic chain region of the surfactant monolayer
able. A number of phases can result which may be structured [52]. A number of double chain surfactants are able to form
on the microscopic or macroscopic scale, one example of a microemulsions without the aid of co-surfactants [53-58].
phase structured on the microscopic scale is an optically iso- These surfactants are characterized by having small head
tropic microemulsion phase. groups in comparison to their hydrocarbon tails. Phosphati-
Attempts have been made to rationalize surfactant behav- dylcholine or lecithin is an example of a twin-tailed surfac-
ior in terms of the hydrophile-lipophile balance (HLB). Even tant. However, in the case of lecithins it is generally neces-
though this approach is fairly empirical, it can be a useful sary to include a co-surfactant in order to disrupt the lamellar
guide to surfactant selection. The HLB takes into account the structures that characterize its biological behavior. Medium
relative contribution of hydrophilic and hydrophobic frag- chain alcohols have been successfully used as co-surfactants
ments of the surfactant molecule. It is generally accepted that for the formation of lecithin-based microemulsions [50, 59].
low HLB (3-8) surfactants are favored for the formation of Water in oil (w/o) microemulsions have been prepared using
Table 3. Example of Surfactant, Co-Surfactant, and Oils (Lipid Ingredients) Used in Commercial Formulations
Excipient Name (Commercial Name) Examples of Commercial Products in which it has been Used
Oils (Lipid ingredients)

Corn oil mono,di,,tri-glycerides Nerol soft gelatin Capsule, Nerol Oral Solution
DL-alpha-Tocopherol Nerol Oral Solution, Fortavase soft gelatin capsule
Fractionated triglyceride of coconut oil Rocaltrol soft gelatin capsule, Hectrol soft gelatin capsule
(medium-chain triglyceride)
Fractionated triglyceride of palm seed oil Rocatrol oral solution
(medium-chain triglyceride)
Mixture of mono-and di-glycerides of caprylic/capric acid Avodat soft gelatin capsule
Medium chain mono-and di-glycerides Fortavase soft gelatin capsule
Corn oil Sandimmune soft gelatin capsule, Depakene capsule
Olive oil Sandimmune oral solution
Oleic acid Ritonavir soft gelatin capsule, Norvir soft gelatin capsule
Sesame oil Marinol soft gelatin capsule
Hydrogenated soyabean oil/ vegetable oils Accutane soft gelatin capsule,Vesanoid soft gelatin capsule
Soyabean oil Accutane soft gelatin capsule
Peanut oil Prometrium soft gelatin capsule
Beeswax Vesanoid soft gelatin capsule
Surfactant
Polysorbate 20 (Tween 20) Targretin soft gelatin capsule
Polysorbate 80 (Tween 80) Gengraf hard gelatin capsule
Sorbitan monooleate (Span 80) Gengraf hard gelatin capsule
Polyoxy-35-castor oil(Cremophor EL) Gengraf hard gelatin capsule, Ritonavir soft gelatin capsule
Polyoxy-40- hydrogenated castor oil (Cremophor RH40) Nerol soft gelatin capsule, Ritonavir oral solution
Polyoxyethylated glycerides (Labrafil M 2125 Cs) Sandimmune soft gelatin capsules
Polyoxyethlated oleic glycerides (Labrafil M1944 Cs) Sandimmune oral solution
D-alpha Tocopheryl polyethylene glycol 1000 succinate (TPGS) Agenerage Soft gelatin capsule, Agenarage oral solution
Co- Surfactant
Ethanol Nerol soft gelatin Capsule, Nerol Oral Solution, Gengraf hard gelatin Capsule,
Sandimmune soft gelatin Capsule, Sandimmune oral solution
Glycerin Nerol soft gelatin Capsule, Sandimmune soft gelatin Capsules. Nerol soft gelatin
Polypylene glycol Capsule, Nerol Oral solution, Lamprene soft gelatin capsule, Agenerage Oral solu-
tion , Gengraf hard gelatin capsule
Polyethylene glycol Targretin soft gelatin capsule, Gengraf hard gelatin, capsule, Agenerase soft cap-
sule, Agenerase oral solution
short diacyl chain lecithins and small molecular volume oils mulsion region) from 1:2.5 for polysorbate 80 to 1:2 for
where it is possible that the small molecular volume oils polysorbate 60 to 1:1.5 for polysorbate 40. Such effects have
penetrate the hydrophobic chain region thereby facilitating been attributed to differences in the packing of surfactants
microemulsion formation [60]. and co-surfactants at the oil water interface.
Surfactant Co-Surfactant Ratio IN VITRO CHARACTERIZATION

The surfactant and co-surfactant ratio is a key factor in- Self-emulsifying formulations have been evaluated using
fluencing the phase properties. Attwood et al. showed how a wide range of different techniques over the years. How-
size and location of microemulsion is changed on changing ever, these methods should be complementary to each other
the mass ratio of polysorbate 40/sorbitol from 1:1 to 1:3.5 in order to fully characterize these systems at the micro-
[50]. Similar studies using polysorbate 80 [61] and polysor- scopic and macroscopic level. Some of the most common
bate 60 [62] have shown a change in the optimum polysor- techniques used are:
bate/sorbitol mass ratio (i.e., that produce the largest nanoe-
Spontaneity of Self-Emulsification coalescence of the finer droplets or the presence of large

particles in the solution [68]. Laser diffraction, on the other
The mechanism by which self-emulsification takes place
hand, measures the angular distribution of the light scattered
is not fully understood. The thermodynamic treatment of
by the sample. This method is effective in detecting droplets
conventional emulsion formation has been described by Re-
within a diameter range from 0.5 nm to 200 m, which
iss, 1975 [63], where the free energy of emulsion formation makes it ideal for studying the accumulation of larger secon-
is a direct function of the energy required to create a new
dary flocculation. The main problem with this technique is
surface between the formed phases. This can be given as:
that it provides only the shape of the particle size distribu-
G = i (Ni4ri2) tion, and does not give an absolute count of the number of
particles and it requires the operator to add the sample until
Where G is the free energy associated with the process,
N is the number of droplets of radius r, and is the interfa- the desired scattering intensity is reached. Nevertheless, laser
diffraction is very useful for the study of emulsion size dis-
cial energy. Formed phases will tend to separate over time in
tributions [69]. A Coulter counter measures the change in the
order to reduce the interfacial energy, and hence reduce the
electrical resistance induced by the droplets of the sample
free energy of the system. Conventional emulsifying agents
flowing through a pinhole. A 30 m pinhole is suitable for
such as surfactants reduce the interfacial energy by forming a
measuring the diameter of droplets within the size range of
layer around the emulsion particles, which in turn provides a
barrier to coalescence. In this case, however, the separation 1.5 m to 10 m. The advantage of this technique is that it
provides an absolute droplet count within a specified size
of the phases is merely being delayed as these emulsions are
range, which is in contrast to the relative count provided by
still thermodynamically unstable. In the case of self-emulsi-
laser diffraction [69].
fying systems, the free energy required to form the emulsion
is either very low or negative when the formation is thermo-
Rheological Characterization/Viscosity Determination
dynamically spontaneous. It was reported by Groves and
Galindez, 1976b [64] and Wakeriy et al., 1986 [40] that a The SEDDS system is generally administered in soft
liquid crystalline phase formed between the oil/ surfactant gelatin or hard gelatin capsules. So, it can be easily pourable
and water phases effectively swells, thereby allowing spon- into capsules and such system should not be too thick to cre-
taneous formation of an interface between the oil droplets ate a problem. Study of the rheological properties of micro-
and water. emulsions and self-emulsifying formulations involves meas-
Spontaneity or the rate of self-emulsification can be as- urement of continuous shear or apparent viscosity of various
sessed by visual observation or by monitoring the turbidity formulations with increasing water content. These can be
change of the dispersion by appropriate instrumental method. carried out using Ferranti- Shirley Cone-and-Plate viscome-
In the method reported by Craig et al., 1995 [41] and Groves ter. The rheological properties of the micro emulsion are also
and Galindez, 1976b [64] the self-emulsifying formulation evaluated by Brookfield viscometer. These viscosities de-
was added to a known volume of water at room temperature termination conform whether the system is w/o or o/w. If
under gentle agitation. The ease of emulsion formation is system has low viscosity then it is o/w type of the system
observed and termed as "good," when the emulsion forma- and if a high viscosity then it is w/o type of the system [70,
tion is spontaneous and the formulation spreads into a uni- 71]. Viscosity measurements are especially important at the
form fine emulsion, or "bad," when poor or no emulsion is initial stages of the self-emulsification process when differ-
formed and an immediate coalescence of the droplets is ob- ent mesomorphic phases, such as lamellar, hexagonal, or
served. The spontaneity of emulsion formation was also ob- cubic liquid crystalline phases, can be formed at the oil-
served by injecting the formulation into a flowing stream of water interface. Water penetration into the oil phase may be
water and measuring the change in turbidity with time [65]. compromised by the ordered liquid crystalline phases formed
No assessment of particle size, however, was possible by this at the interface. It was observed that hexagonal and cubic
method. Pouton, 1985 [66] used the Nephlometer to continu- liquid crystalline phases have very limited swelling capacity
ously monitor the dispersion formation of a self-emulsifying upon addition of water. Lamellar phases, on the other hand,
formulation comprising Miglyol and Tween 85. were found to swell to very high water content. Lamellar
liquid crystalline phase at the oil-water interface demonstrate
Droplet Size Analysis/ Particle Size Measurement rheopectic behavior showing shear thickening, whereas hex-
agonal liquid crystals show thixotropy [72]. Viscosity meas-
Droplet size analysis is often used to assess the quality of urements can also indicate the presence of rod-like or worm-
the lipid-based formulations and has key importance for the like reverse micelles [73, 74]. The interaction of cylindrical
dissolution rate of low water solubility drugs [67]. Common or worm-like micelles in microemulsion formulations tends
techniques used to determine the droplet size distributions of to raise high viscosity systems. Lecithin in particular is
the resultant emulsions include photon correlation spectros- known to form such systems in microemulsions at low water
copy, laser diffraction and coulter counter. Photon correla- content [75]. In some instances the viscosity of the microe-
tion spectroscopy is a light scattering technique that uses mulsion may be tailored for a given application through for-
fluctuations in scattered light intensity to measure the veloc- mulation changes, or in some instances through the incorpo-
ity of the Brownian diffusion, and in turn the size, of the ration of specific gelling agents such as Carbopol [76, 77].
dispersed droplets [68]. Photon correlation spectroscopy is
sensitive to particles within a diameter range from 3 nm to 3 Phase Behavior Studies
m. This technique, however, is not suitable for measuring
larger secondary droplets, which result from considerable Not every combination of components produce microe-
mulsions or self-emulsifying systems over the whole range
of possible compositions, in some instances the extent of 84]. In low frequency dielectric spectroscopy, the application
microemulsion formation may be very limited. This relation- of an electric field to a sample results in the polarization of
ship between the phase behavior of a mixture and its compo- that material. When an alternating field is applied, the
sition can be captured with the aid of a phase diagram. Com- changes within the system will attempt to compensate for the
positional variables can also be studied as a function of tem- changes in field of direction by a number of mechanisms,
perature and pressure [78, 79]. The phase behavior of simple including reorientation and charge hopping. The overall ef-
microemulsion systems comprising oil, water and surfactant fect will be the movement of charge within the sample, thus
can be studied with the aid of ternary phase diagram in generating a polarization current (P). At any frequency, the
which each corner of the diagram represents 100% of that relationship between the polarization and the applied field
particular component. In the case where four or more com- will be given by:
ponents are investigated, pseudo-ternary phase diagrams are P()=x() E()
used where a corner will typically represent a binary mixture
of two components such as surfactant/co-surfactant, water/ Where the subscript () denotes that the equation de-
drug or oil/drug. The number of different phases present for scribing the relationship at frequency . The term x refers to
a particular mixture can be visually assessed. Microstructural the susceptibility of the sample, which is a measure of the
features can also be investigated and mapped on the phase responsiveness of that material to an electric field [17]. In
diagrams with the aid of a wide variety of techniques. this method, two stainless steel electrodes are inserted into
the liquid and a voltage of 0.1 V r.m.s. is generated by a fre-
Polarizing microscopy is often used to identify the liquid
quency response analyzer (FRA) and passed through the
crystalline phases that exist in a system comprising surfac-
sample via an interface. The returning signal is analyzed by
tants at low levels of the aqueous phase. This is feasible, as
the FRA and displayed in terms of capacitance and dielectric
liquid crystals are birefringent. In birefringence, the light
loss. The capacitance and loss are usually plotted against
passing through a material is divided into two components frequency on logarithmic scales and the slope of the resultant
with different velocities and hence different refractive indi-
graph is measured as an indication of the conductance. Un-
ces [13, 40, 66]. Transitions between the various phases
like most other methods used for the examination of emul-
mapped out in these phase diagrams can be driven by the
sions, the dielectric technique is applied to the material to be
further addition of one of the components, addition of a new
investigated while it is in its normal, as-prepared state.
component such as drug or electrolyte, or by changing the
Changes in the dielectric response can be observed as the
temperature. Microemulsions stabilized by non-ionic surfac- material is exposed to air. This makes the technique particu-
tants, especially those based on polyoxyethylene, are very
larly useful for the observation and monitoring of processes
susceptible to temperature because a decrease in surfactant
that can lead to deterioration such as globule size coarsening
solubility occurs with increasing temperature. As a result,
and/or phase separation [85].
systems stabilized by non-ionic surfactants often have char-
acteristic phase inversion temperatures (PITs), with the PIT Craig et al., 1995 [41] applied this technique to charac-
of the microemulsion varying with a range of experimental terize the self-emulsification properties of a system compris-
factors including the amount and nature of the oil present ing Imwitor-742 and Tween 80. It was observed that an in-
and the nature of the surfactant(s) present. crease in oil content from 20% to 30% w/w resulted in a de-
crease in conductivity from 4.922x10-4 to 1.575x10-5 and the
Constructing phase diagrams, however, is time consum-
capacitance slope from -0.461 to -0.636. It was concluded
ing particularly when the aim is to accurately determine a
that the change in the slope reflects an increase in the leaki-
phase boundary, as the time taken for the system to equili- ness and a decrease in the mobility of the charges within the
brate can be greatly increased as the phase boundary is ap-
system, suggesting the formation of liquid crystalline phases.
proached. Heat and sonication are often used, particularly
with systems containing nonionic surfactants, to accelerate
Interfacial Tension Measurement
the process. The procedure most often employed is to pre-
pare a series of (pseudo) binary compositions and titrate with The formation and properties of micro/nanoemulsions
the third component, evaluating the mixture after each addi- can be studied by measuring the interfacial tension. Spin-
tion. Care must be taken to ensure not only that the tempera- ning-drop apparatus can be used to measure the ultra low
ture is precisely and accurately controlled, but also those interfacial tension.
observations are not made on metastable systems. Clearly,
time constraints impose a physical limit on the length of time Refractive Index and Percent Transmittance
systems can be left to equilibrate. Moreover, the elimination
Refractive index and percent transmittance proved the
of metastable states can be difficult to ensure in practice
[80]. transparency of formulation. The refractive index of the sys-
tem is measured by refractometer by placing drop of solution
on slide and it compare with water (1.333). The percent
Dielectric Spectroscopy
transmittance of the system is measured at particular wave-
Dielectric spectroscopy has been recently introduced as a length using UV-spectrophotometer keeping distilled water
powerful method of probing both the structural and dynamic as blank. If refractive index of system is similar to the refrac-
features of microemulsion systems [54, 81, 82]. The use of tive index of water (1.333) and formulation have percent
dielectric spectroscopy in the low frequency range below 104 transmittance > 99 percent, then formulation have transpar-
Hz for the examination of the physical structure of emulsion ent nature.
systems by a noninvasive manner has been established [83,
Electro Conductivity Study droplet sizes and phase changes must be followed. To over-
come the problem of metastable formation which are not
The SEDD system contains ionic or non-ionic surfactant,
thermodynamically stable and takes long time to separate,
oil, and water. So, this test is used to measure the electocon-
thermodynamic stability tests are recommended. The formu-
ductive nature of system. The electro conductivity of resul-
lations are subjected to different stresses such as heating
tant system is measured by electoconductometer. cooling cycle, centrifugation and freeze thaw cycle tests. If
the micro/nanoemulsions are stable over these conditions
Drug Content
they do not require frequent testing during storage, unless of
Drug from pre-weighed SEDDS is extracted by dissolv- course chemical reactions occur (e.g., oxidation, pH varia-
ing in suitable solvent. Drug content in the solvent extract tions) which changes the nature of the components and hence
was analyzed by suitable analytical method against the stan- of the micro/nanoemulsion [86].
dard solvent solution of drug.
ASSESSMENT OF LIPID-BASED FORMULATIONS
Turbidimetric Evaluation USING IN VITRO LIPOLYSIS
Nepheloturbidimetric evaluation is done to monitor the The design of self-emulsifying lipid-based formulations
growth of emulsification. Fixed quantity of Self emulsifying has focussed on optimizing the solubility of the drug in the
system is added to fixed quantity of suitable medium (0.1N formulation and on the in vitro emulsification efficiency and
hydrochloric acid) under continuous stirring (50 rpm) on particle size of the dispersion obtained on dilution in aqueous
magnetic plate at ambient temperature, and the increase in media [14, 38]. In recent years, however, in vitro dispersion
turbidity is measured using a turbidimeter. However, since tests and in vitro lipid digestion models that are more reflec-
the time required for complete emulsification is too short, it tive of the gastrointestinal environment have been developed
is not possible to monitor the rate of change of turbidity (rate in order to better predict the in vivo dissolution profile of
of emulsification) [70]. poorly water soluble drug [87].
Considerable advances have been made in the design of
Dispersibility Test biorelevant dissolution media in order to better predict the in
The efficiency of self-emulsification of oral micro or vivo performance of poorly water soluble drugs from more
nanoemulsion is assessed using a standard USP XXII disso- traditional solid dosage forms and these approaches have
lution apparatus 2. One milliliter of each formulation was been well reviewed recently [88]. In contrast the application
added to 500 mL of water at 37 ± 0.5 0°C. A standard stain- of these concepts to the in vitro assessment of lipid-based
less steel dissolution paddle rotating at 50 rpm provide gentle delivery systems has been less widely embraced and is less
agitation. The in vitro performance of the formulations is readily understood. In large part this reflects the fact that for
visually assessed using the following grading system: lipid-based formulations (where this terminology is used in
its broadest sense to reflect solubilising formulations that
Grade A contain varying proportions of lipids, surfactants and co-
solvents) drug solubilisation is not simply a function of the
Rapidly forming (within 1 min) nanoemulsion, having a
properties of the formulation, or the dissolution media.
clear or bluish appearance.
Rather, the solubilisation capacity of the intestine or in vitro
Grade B test media reflects the colloidal species that are formed by
dispersion and digestion of the formulation together with the
Rapidly forming, slightly less clear emulsion, having a species produced by incorporation of lipid digestion products
bluish white appearance. into endogenous solubilising species including bile salts
(BS), phosphatidylcholine (PL) and cholesterol (Ch) mixed
Grade C micelles. Furthermore, true ‘dissolution’ (i.e. formation of a
Fine milky emulsion that formed within 2 min. homogenous molecular solution) does not occur, since the
endpoint of most in vitro tests is drug solubilised in a range
Grade D of colloidal species which exist in equilibrium with a very
small fraction of the total quantity of solubilised drug that is
Dull, grayish white emulsion having slightly oily appear- in true solution in the intermicellar phase (and from where
ance that is slow to emulsify (longer than 2 min). absorption presumably occurs).
Grade E In contrast to traditional dissolution testing, therefore,
where the dissolution of drug from the solid state into both
Formulation, exhibiting either poor or minimal emulsifi- simple and biorelevant dissolution media is measured, as-
cation with large oil globules present on the surface.
sessment of the utility of lipid-based formulations is more
Grade A and Grade B formulation will remain as nanoe- appropriately based on evaluation of the rate and extent of
mulsion when dispersed in GIT. While formulation falling in drug precipitation with respect to time (rather than solubili-
Grade C could be recommend for SEDDS formulation [86]. sation), since drug is usually already dissolved in the formu-
lation. In this case, in vitro ‘dispersion’ testing appears to be
Thermodynamic Stability Studies a more accurate description of the process of monitoring the
ability of a formulation to maintain the drug in a solubilised
Stability tests are much simpler and are needed less fre-
state during dispersion in the stomach and subsequent proc-
quently as compared to that for coarse dispersions, where
essing of the formulation in the presence of pancreatic and administered triglyceride lipid. The extent of mesenteric
biliary fluids. In laboratories in vitro evaluation is typically lymphatic transport of Hf (expressed as a percentage of the
conducted as a two step process. Initially, the dispersion dose) increased from 2.2 to 5.5 to 15.8% following oral ad-
properties of the formulation are assessed under simulated ministration in short (C4), medium (C8-C10) and long (C18)
gastric conditions (0.1 N HCl) using traditional dissolution chain triglyceride vehicles, respectively. The influence of the
equipment. The ease of dispersion can be assessed kineti- degree of fatty acid unsaturation (oleic [C18:1], linoleic
cally and via particle size measurements, but more impor- [C18:2], or linolenic acid [C18:3]) on intestinal lymphatic
tantly the likelihood of drug precipitation as the formulation transport of Hf free base has also been compared [92]. Re-
is dispersed may also be assessed. This is achieved simply by sults indicate that linoleic acid was significantly superior to
sampling the dispersion media with respect to time, centri- linolenic acid, but not statistically better than oleic acid.
fuging and assaying both pellet and supernatant for drug. In
practice the likelihood of drug precipitation on dispersion is APPLICATION
low/ negligible for lipid solution formulations and emulsions Increase in Solubility and Bioavailability
and self-emulsifying formulations (Types I and II) where
quantities of relatively lipophilic (and non-water miscible) Microemulsions have generated considerable interest
components are high. However, for Type III and IV formula- over the years as potential drug delivery systems [42-45].
tions which contain large quantities of water miscible surfac- Advantages associated with micro/nanoemulsions include
tants and co-solvents, the likelihood of drug precipitation on their thermodynamic stability, optical clarity and ease of
dispersion increases and care should be taken to minimize preparation. The attraction of o/w microemulsion systems
the quantity of formulation components such as co-solvents lies in their ability to incorporate hydrophobic drugs into the
that have limited ‘on going’ solubilisation capacity after di- apolar oil phase thereby enhancing their solubility [46, 47,
lution into GI fluids. 93, 104]. Additionally, the existence of microdomains of
different polarity within the same single-phase solution en-
Subsequently, possible changes to solubilisation capacity ables both water-soluble and oil-soluble materials to be solu-
that occur as a result of digestion of formulation components bilized. Furthermore it is also possible to incorporate am-
and interaction with endogenous biliary solubilising agents phiphilic drugs into the microemulsion, sometimes even
(BS, PL) are assessed using an in vitro model of lipid diges- leading to an increase in the extent of existence of the micro-
tion [87]. To this point most of the studies in the literature emulsion region. Drug particles partition between the micro-
have examined formulation digestion under simulated intes- emulsion droplet and the continuous phase. While there may
tinal conditions, since the majority of lipid digestion is be a preferred site of solubilization within the microemulsion
thought to occur in the intestine. However, lipolysis is initi- droplet, drug particles may be localized at one of a number
ated in the stomach via acid-stable gastric lipase, and after of sites. For example the likely preferred sites of incorporat-
oral administration of the relatively small quantities of lipid ing a lipophilic, water-insoluble drug into an o/w microemul-
commonly contained in lipid-based formulations, gastric sion are the dispersed oil phase and/or hydrophobic tail re-
lipolysis may be significant. gion of the surfactant molecule. However, most drugs are not
especially soluble in hydrocarbon oils, rather the polarity of
DIGESTIBILITY OF LIPID BASE FORMULATION the majority of poorly water-soluble drugs favour their solu-
One of the earliest reports of intestinal lymphatic trans- bilization in small/medium molecular volume oils such as
port was a study by Palin et al., 1982 [89] using DDT in a tributyrin or Miglyol 812. Water-soluble drugs, on the other
range of lipid vehicles including: arachis oil, Miglyol 812 hand, are most likely to be incorporated into the dispersed
(fractionated coconut oil) and liquid paraffin. Arachis oil aqueous phase of a water-in-oil droplet. It is noteworthy that
significantly increased lymphatic transport of DDT relative the use of o/w microemulsions in drug delivery is more
to the other vehicles. This study illustrated the importance of straightforward than is the case with w/o microemulsions.
digestibility of the vehicle (liquid paraffin is non digestible) This is because the droplet structure of o/w microemulsions
on the extent of lymphatic transport. Also important was the is often retained on dilution by a biological aqueous phase,
nature of the fatty acid in the triglyceride vehicle, long chain thereby permitting oral as well as parenteral administration.
unsaturated fatty acids, such as those in arachis oil, and were However, the process of dilution will result in the gradual
more successful due to the increased ability to stimulate chy- desorption of surfactant located at the droplet interface.
lomicron production. This work was confirmed and devel- Microemulsions have not only been used directly as drug
oped by Charman et al., 1986 [90], who showed that the rate delivery vehicles, but have also been used indirectly as a
and extent of lymphatic transport of DDT, following in- means of producing solid drug-loaded nanoparticles. In this
traduodenal administration, from an oleic acid vehicle was case, solid lipid nanoparticles were synthesized by spraying
faster and higher relative to the triglyceride, peanut oil. In an o/w microemulsion into cold water at a temperature below
the case of the triglyceride, digestion was a prerequisite to the melting point of the oil. The microemulsion itself is typi-
producing the fatty acids necessary to drive chylomicron cally stabilized by lecithin and uses a mixture of capric and
production. In addition, this study confirmed that chylomi- palmitic acid as the oil phase. The microemulsion in addition
cron flux was directly related to the extent of lymphatic may contain taurodeoxycholate and alkyl phosphates as co-
transport of DDT. surfactants. The resulting drug loaded particles could be iso-
More recently, Caliph et al., 2000 [91] have shown that lated, washed and freeze dried [5, 95-97]. The properties of
the lymphatic transport of halofantrine (Hf) in a conscious w/o microemulsions were similarly exploited by utilizing
rat model is highly dependent on the chain length of the co- droplets as supermolecular templates for the synthesis of
drug-loaded polybutylcyanoacrylate nanoparticles [98, 99].
SEDDS and SMEDDS represent an efficient vehicle for ies, reduce myocardial oxygen consumption and improve
the in vivo administration of lipophilic drugs. The determin- microcirculation in both animals and humans suffering from
ing factors for the in vivo performance of the self- (micro) cardiovascular disease [109].
emulsifying formulations are their ability to form fine emul-
sion and the polarity of the formed oil droplets, which affects
their ability to promote rapid drug release into the aqueous
phase. Smaller oil droplets provide large interfacial area for
pancreatic lipases to hydrolyze the glycerides and the fatty
constituents of the emulsion and the subsequent drug con-
tainment into mixed micelles formed from biliary extracts
[16].
The most notable example of a SMEDDS relates to the
oral delivery of Cyclosporin A, currently marketed as
Neoral® formulation. The original Sandimmune® formula-
tion was based on a solution of Cyclosporin A in vegetable
oil. Although the co-administration of triglyceride with Cy-
closporin A improved its bioavailability, there was consider-
able pharmacodynamic inter- and intra-patient variability.
Bioavailability of Cyclosporin A showed wide variation
ranging from 1-95% [100].
Fig. (2). Silybin plasma concentration-time curves of either micro-
The Neoral® formulation uses an isotropic concentrated
emulsion of Carduus marianus extract, Legaron capsule or Legaron
blend of surfactant based on medium chain length partial
tablet after oral administration of a single dose of 60 mg silybin/ kg
glycerides, a medium chain length triglyceride oil and drug.
to rats [108].
Exposure of this concentrate to water results in formation of
initially a w/o microemulsion, which on further mixing with
water undergoes phase inversion to yield a transparent o/w Yufengningxin tablets are a formulation of total isofla-
microemulsion with a droplet size less than 100 nm [101]. vones obtained from Pueraria lobata, and are available
Neoral® was shown to offer more predictable and more ex- commercially in China. The dissolution rate of Yufengnin-
tensive drug absorption than the standard Sandimmune® gxin tablets is very low and, therefore, a SMEDDS formula-
formulation [102]. tion of Pueraria lobata isoflavone was developed to improve
the oral bioavailability. An optimized formulation consisted
Levy and Grant,1994 [103] have reported a 2.0-fold in-
ethyl oleate, Tween 80 and transcutol P as co-surfactant. The
crease in Cmax and a 74%-139% increase in the bioavailabil-
ity of Cyclosporin A following oral administration of dissolution of SMEDDS after 10 min was more than 90%,
and the dissolution of Yufengningxin tablets at 60 min was
Neoral®. The delivery of Cyclosporin A via microemulsion
less than 30% Fig. (3). The absorption of puerarin from the
formulations and the superiority of the Neoral® microemul-
SMEDDS of Pueraria lobata isoflavone resulted in a 2.2-
sion preconcentrate over the original Sandimmune® formula-
fold increase in bioavailability compared with Yufengnin-
tion has been demonstrated on several occasions [104-107].
gxin tablets Fig. (4) [110].
Application of LBDDS to improve bioavailability was
also found to have remarkable effect in case of traditional
medicine. Silybin, the principal component of a Carduus
marianus extract, is reported to be very effective in protect-
ing liver cells from harmful effects caused by smoking,
drinking, overworking, environmental contaminants and
stress. However, the oral bioavailability of silybin is very
low due to its poor aqueous solubility. Woo et al. formulated
oral microemulsion consisting of extract containing a major
amount of silybin, or a silybin derivative. The composition
of the formulation consists of Miglyol 812 and ethyl lino-
leate as oils, HCO 50 and Tween 20 as surfactant, dimethyl
isosorbide as co-surfactant and D--tocopherol as an anti-
oxidant. The in vivo bioavailability of silybin, was found to
be increased by atleast 4-fold higher than that achievable by
conventional formulations Fig. (2) [108].
Pueraria lobata is a traditional Chinese medicinal herb. Fig. (3). Dissolution profiles of puerarin from SMEDDS and
Its extract has been used for the treatment of hypertension, Yufengningxin tablet formulation in water at 37°C [109].
senile ischemic cerebrovascular disease and angina pectoris.
Studies of its pharmacology and clinical applications have
Ginkgo biloba L., belong to family Ginkgoaceae men-
shown that the active constituents in the extract are isofla-
tioned in the Chinese Materia Medica. A standardized
vones, mainly puerarin. It is known to dilate coronary arter-
Ginkgo biloba extract (GBE) contains 5-7% terpene lactones
Protection Against Biodegradation

The ability of self emulsifying drug delivery system to
reduce degradation as well as to improve absorption may be
especially useful for drugs, for which both low solubility and
degradation in the GI tract contribute to low oral bioavail-
ability. Many drugs are degraded at acidic pH in stomach,
undergo enzymatic degradation or hydrolytic degradation
etc. Such drugs when administered in the form of SEDDS
can be well protected against these degradation processes as
liquid crystalline phase in SEDDS might be act as barrier
between degradating environment and the drug. Acetylsali-
cylic acid degrades in the GI tract because it readily hydro-
lyzed to salicylic acid in an acidic environment.
When the drug was formulated in a Galacticles™ Oral
Lipid Matrix System and compared with a commercial for-
mulation, it showed the good plasma profile as compared to
Fig. (4). Puerarin serum concentration-time profiles after oral ad-
reference formulation. The oral bioavailability of acetylsali-
ministration of either SMEDDS (66 mg) or Yufengningxin tablets
cylic acid is improved by 73% by the Galacticles™ Oral
(65 mg) to dogs [110].
Lipid Matrix System formulation compared to the reference
formulation. This suggests that the SEDDS formulation has
(ginkgolides and bilobalide) and 22-27% ginkgo flavonol capacity to protect the drug from degradation in the GI tract
glycosides [111]. Many pharmacological and clinical studies [115]. Supersaturable SEDDS contain a reduced amount of
have demonstrated that the extracts of Ginkgo biloba possess surfactant and water-soluble cellulosic polymer to prevent
antioxidant, anti-ischemic, neuro-protective, cardiovascular precipitation of the drug by generating and maintaining a
and cerebrovascular activities, and have beneficial effects on supersaturated state in vivo.
cognitive deficits, including Alzheimer’s-type and multiin-
The S-SEDDS formulations can result in enhanced oral
farct dementia, as well as peripheral vascular disease [112].
absorption as compared with the related self-emulsifying
The dissolution and bioavailability of the active components drug delivery systems (SEDDS) formulation and the reduced
from the oral solid preparations of different Ginkgo biloba
surfactant levels may minimize gastrointestinal surfactant
brands were obviously different and irreproducible, due to
side effects. Oral drug delivery systems are designed address
the lower solubility of the active components [113]. The
the varied challenges in oral delivery of numerous promising
SEDDS formulation of GBE was accordingly developed to
compounds including poor aqueous solubility, poor absorp-
increase the dissolution rate and thus improve oral absorp-
tion and large molecular size. These are both liquid and
tion and acquire the reproducible blood-time profiles of the powder-in-capsule products comprising our self-emulsifying
active components of GBE. The prepared SEDDS was com-
liquid crystalline nano-particles (LCNP) technology (featur-
pared with the conventional GBE tablets following admini-
ing Cubosome®, Hexosome®, and Flexosome™). Liquid
stration to fasted dogs. The active components of GBE, ter-
crystalline nano-particles (LCNPs) are excellent solubilizers.
pene lactones, were determined using liquid chromatography
Compared with conventional lipid or nonlipid carriers,
with electrospray ionization mass spectrometric detection
LCNPs show high drug carrier capacity for a range of spar-
[114]. The relative bioavailability of SEDDS for ginkgolide ingly water-soluble drugs.
A was 154%, compared with the reference tablets Fig. (5).
For drugs susceptible to in vivo degradation, such as pep-
tides and proteins, LCNP vehicles protect the sensitive drug
from enzymatic degradation. The LCNP systems also ad-
dress permeability limitations by exploiting the lipid-
mediated absorption mechanism. For water-soluble peptides
typical bioavailability enhancement range from 20 to more
than 100 times. In an alternative application large proteins
have been encapsulated for local activity in the gastrointesti-
nal tract. LCNP carriers can be combined with controlled-
release and targeting functionalities. The particles are de-
signed to form in situ at a controlled rate, which enables an
effective in vivo distribution of the drug. LCNP carriers can
also be released at different absorption sites, for example in
the upper or lower intestine, which is important for drugs
that have narrow regional absorption windows. SMEDDS
composition of PNU156804 showed a good chemical stabil-
ity and a higher bioavailability with respect to a conventional
Fig. (5). Ginkgolide A plasma concentration-time profiles of GBE
formulation [116].
SEDDS and GBE tablet following oral administration of a single
dose of 800 mg GBE to dogs [114].
To date, micro/nanoemulsions and self-emulsifying vehi- ment and clean-up requirements during manufacture of
cles have been shown to be able to protect labile drug, con- highly-potent or cytotoxic drug products)
trol drug release, increase drug solubility and bioavailability
• Reduction or elimination of positive food effect
(Table 4). Furthermore, it has proven possible to formulate
preparations suitable for most routes of administration. There • Relative ease of manufacture using readily available
is still however a considerable amount of fundamental works equipment.
characterizing the physicochemical behavior of these formu- However, a considerable gap exists between the need for
lations that needs to be performed before they can attain their this technology, as justified by the preponderance of poorly
potential as multipurpose drug delivery vehicles. water soluble compounds filling drug discovery pipelines,
and its application, as evidenced by the low number of mar-
SUMMARY keted drug products relying on oral lipid-based formulations.
Among the benefits which oral lipid-based formulations A carefully planned study aimed at explaining this paradox
can provide are: has not yet been executed. However, a growing opinion in
the scientific community has suggested that lack of a clearly
• Improvement and reduction in the variability of GI ab- defined process for developing a lipid-based formulation
sorption of poorly water-soluble, lipophilic drugs. which, among other things, involves selecting excipients
• Possible reduction in, or elimination of, a number of from a list of hundreds of possibilities, has contributed sub-
development and processing steps (e.g., salt selection or stantially to the reluctance to use these formulations. Another
identification of a stable crystalline form of the drug, hurdle which arises with varying frequency is that of insuffi-
coating, taste masking, and reduced need for contain- cient drug solubility in the excipient matrix, which precludes
Table 4. Example of Bioavailability Enhancement of Pooly Soluble Drug after Administration of SEDDS and SMEDDS Formula-
tions
Compound Study Design Observation after Study References
Win 54954 Relative BA in dogs No difference in Bioavailability but improved reproducibility, increased Cmax [117]
Coenzyme Q10 Relative BA in dogs Bioavailability 2- fold higher from SEDDS [118]
Bioavailability 3- fold higher from SEDDS when compared with other for-
Ro-15-0778 Relative BA in dogs [119]
mulations
Indomethacin Relative BA in rats Bioavailability singnificantly increased from SEDDS [120]
Silymarin Relative BA in rabbits Bioavailability approximately 2-and 50- fold higher from SMEDDS [121]
Atorvastatin Relative BA in dogs Bioavailability significantly increased from all SMEDDS [122]
Itraconazole Relative BA in rats Increased Bioavailability and reduced food effect [123]
Atovaquone Relative BA in dogs Bioavailability 3-fold higher from SMEDDS [124]
Tocotrienols Relative BA in humans Bioavailability 2-3 fold higher from SEDDS [125]
Carvediol Relative BA in dogs Bioavailability 4- fold higher from SEDDS [126]
Solvent green 3 Relative BA in rats Bioavailability 1.7-fold higher from SMEDDS [127]
Simvastatin Relative BA in dogs Bioavailability 1.5 fold higher from SMEDDS [128]
Vitamin E Relative BA in humans Bioavailability 3- fold higher from SEDDS [129]
Cyclosporine Relative BA in humans Increased Bioavailability and Cmax and reduced T max from SMEDDS [130]
Ontazolast Absolute BA in rats Bioavailability increase at least 10- fold from all lipid based formulations [131]
Progesterone Relative BA in dogs Bioavailability 9- fold higher from SEDDS [132]
Biphenyl Dimethyl Di-

Relative BA in rats Bioavailability 5- fold higher from SEDDS [133]
carboxylate
Model Compounds in-

clunding disopyramide, Relative BA in rats and Improved Bioavailability relative to the suspension formulations for either or
[134]
ibuprofen, Ketoprofen, dogs both of the liquid microemulsion and SEDDS formulation in all cases
and Tolbutamide
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Received: December 20, 2010 Revised: February 28, 2011 Accepted: March 06, 2011

Oral Lipid Based DDS

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330 Current Drug Delivery, 2011, 8, 330-345

Oral Lipid Based Drug Delivery System (LBDDS): Formulation,

INTRODUCTION products are those in which the drug is dissolved in digesti-

1567-2018/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Table 1. Classification of Lipid-based Delivery System by Pouton [14]

Type I Type II Type III Type IIIA Type IV

20-60% 20-40% 20-50%

Hydrophilic Co-solvents - - 0-40% 20-50% 0-50%

Dispersion Particle size Course 100-250nm 100-250nm 50-100nm <50nm

Not crucial but

Adsorption on solid carrier X 80 10

Supercritical fluid based

Solid lipid Nanoparticles X X 99 50

Oils w/o microemulsions whereas surfactants with high HLBs (8-

Oils (Lipid ingredients)

Surfactant Co-Surfactant Ratio IN VITRO CHARACTERIZATION

Spontaneity of Self-Emulsification coalescence of the finer droplets or the presence of large

Protection Against Biodegradation

Compound Study Design Observation after Study References

Indomethacin Relative BA in rats Bioavailability singnificantly increased from SEDDS [120]

Atovaquone Relative BA in dogs Bioavailability 3-fold higher from SMEDDS [124]

Carvediol Relative BA in dogs Bioavailability 4- fold higher from SEDDS [126]

Vitamin E Relative BA in humans Bioavailability 3- fold higher from SEDDS [129]

Progesterone Relative BA in dogs Bioavailability 9- fold higher from SEDDS [132]

Biphenyl Dimethyl Di-

Model Compounds in-

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