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Microemulsions: A Novel Approach to Enhanced Drug Delivery

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238 Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257

Microemulsions: A Novel Approach to Enhanced Drug Delivery

Sushama Talegaonkar*, Adnan Azeem, Farhan J. Ahmad, Roop K. Khar, Shadab A. Pathan and
Zeenat I. Khan
Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India

Received: January 26, 2008; Accepted: May 15, 2008; Revised: June 1, 2008
Abstract: Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and
surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. They can
be classified as oil-in-water (o/w), water-in-oil (w/o) or bicontinuous systems depending on their structure and are
characterized by ultra low interfacial tension between oil and water phases. These versatile systems are currently of great
technological and scientific interest to the researchers because of their potential to incorporate a wide range of drug
molecules (hydrophilic and hydrophobic) due to the presence of both lipophilic and hydrophilic domains. These adaptable
delivery systems provide protection against oxidation, enzymatic hydrolysis and improve the solubilization of lipophilic
drugs and hence enhance their bioavailability. In addition to oral and intravenous delivery, they are amenable for
sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes. Microemulsions are
experiencing a very active development as reflected by the numerous publications and patents being granted on these
systems. They have been used to improve the oral bioavailability of various poorly soluble drugs including cyclosporine
and paclitaxel as professed by Hauer et al., US patent 7235248, and Gao et al., US patent 7115565, respectively.
Furthermore, they can be employed for challenging tasks such as carrying chemotherapeutic agents to neoplastic cells and
oral delivery of insulin as diligently described by Maranhao, US patent 5578583 and Burnside et al., US patent 5824638
respectively. The recent commercial success of Sandimmune Neoral® (Cyclosporine A), Fortovase® (Saquinavir), Norvir®
(Ritonavir), etc. also reflects the tremendous potential of these newer drug therapeutic systems. A critical evaluation of
recent patents claiming different approaches to improve the drug delivery is the focus of the current review.
Keywords: Microemulsion, self microemulsifying, microemulsion preconcentrate, thermodynamically stable, poorly soluble
drugs, bioavailability, sustained and targeted drug delivery.

1. INTRODUCTION build up of static charges, present handling difficulties and is

Recent progress in combinatorial chemistry has led to the
generation of a large number of new compounds. Today, a
large percent of these new chemical entities (NCEs) in addi-
tion to many existing drugs often show poor solubilization
behaviour which lead to poor oral bioavailability with wide
intra- and inter- subject variation and present formulators
with considerable technical challenges. The selection of an
appropriate dosage form is critical because a dosage form
with poor drug delivery can make a useful drug worthless.
Bioavailability has important clinical implications as both
pharmacologic and toxic effects are proportional to both
dose and bioavailability [1]. Many approaches have been
meticulously explored to improve the oral bioavailability of
such drugs including particle size reduction (micronization
or nanosizing), complexation with cyclodextrins, salt for-
mation, solubilization based on cosolvents, surfactants, etc.
Modification of the physicochemical properties, such as by
salt formation and particle size reduction of the drug may
improve the dissolution rate of the drug but these methods
are not always practical, for example, salt formation of
neutral compounds is not feasible. Moreover, the salts of
weak acid and weak base may convert back to their original
acid or base forms and lead to aggregation in the
gastrointestinal tract [2]. Particle size reduction may lead to
*Address correspondence to this author at the Department of Pharmaceutics,
Faculty of Pharmacy, Jamia Hamdard, New Delhi -110062, India;
Tel: +91-11- 32917377; Fax: +91-11-26059663;
E-mail: stalegaonkar@jamiahamdard.ac.in
not desirable where poor wettability are experienced for very
fine powders. To overcome these limitations, various other
formulation strategies have been attempted such as use of
cyclodextrins, nanoparticles, solid dispersions and per-
meation enhancers [1, 3]. Indeed, in some selected cases,
these approaches have been successful. Some of the
approaches have been highlighted in Fig. (1).
Of late lipid-based formulations have attracted great deal
of attention to improve the oral bioavailability of poorly
water soluble drugs. In fact, the most favoured approach is to
incorporate lipophilic drugs into inert lipid vehicles such as
oils, surfactant dispersions, microemulsions, self-emulsi-
fying formulations, self microemulsifying formulations, and
liposomes [4-14]. This could lead to increased solubilization
with concomitant modification of their pharmacokinetic
profiles, leading to increase in therapeutic efficacy.
Microemulsions have been widely studied to enhance the
bioavailability of the poorly soluble drugs. They offer a cost
effective approach in such cases. Microemulsions have very
low surface tension and small droplet size which results in
high absorption and permeation. Interest in these versatile
carriers is increasing and their applications have been
diversified to various administration routes in addition to the
conventional oral route. This can be attributed to their unique
solubilization properties and thermodynamic stability which
has drawn attention for their use as novel vehicles for drug
delivery. The results obtained have been indeed very
promising. In recent past, microemulsion formulation of a

1872-2113/08 $100.00+.00 © 2008 Bentham Science Publishers Ltd.

Microemulsions in Drug Delivery
Fig. (1). Some of the formulation approaches to improve the oral bioavailability of poorly water soluble drugs.
poorly soluble immunosuppressant was marketed as a soft
capsule which contains a mixture of drug dissolved in oil and
surfactant [15-17]. It converts into an oil-in-water (o/w)
microemulsion in situ in an aqueous environment in the
stomach and the small intestine. Microemulsion formulation
made the bioavailability and plasma concentration profiles of
the drug more reproducible which is clinically important in
the case of drugs showing serious adverse effects. This is a
significant step forward in the delivery of poorly soluble
drugs. Microemulsion systems are also now being increa-
singly investigated for transdermal [18-22], ocular [23],
nasal [24, 25], pulmonary [26], vaginal [27, 28], rectal [29,
30] and intravenous drug delivery [31].
This review focuses on recent developments in the field
of microemulsion technology with respect to drug delivery.
The article summarizes the recently introduced patents on
microemulsion systems and explores their potential in the
delivery of poorly soluble drug compounds in particular in
addition to their novel applications.
2. MICROEMULSIONS
In 1959, Schulman et al. visualized the existence of small
emulsion-like structures by electron microscopy and subse-
quently coined the term “microemulsions” [32]. Micro-
emulsions are isotropic, thermodynamically stable trans-
parent (or translucent) systems of oil, water and surfactant,
frequently in combination with a cosurfactant with a droplet
size usually in the range of 20-200 nm. These homogeneous
systems, which can be prepared over a wide range of
surfactant concentration and oil to water ratio, are all fluids
of low viscosity.
Microemulsions as drug delivery tool show favourable
properties like thermodynamic stability (long shelf-life),
easy formation (zero interfacial tension and almost sponta-
neous formation), optical isotropy, ability to be sterilized by
filtration, high surface area (high solubilization capacity) and
very small droplet size. The small droplets also provide
better adherence to membranes and transport drug molecules
in a controlled fashion. Microemulsions are easy to
administer to children and to people who have difficulty
swallowing solid oral dosage forms. The key differences
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 239
between ordinary emulsions (macro emulsions) and micro-
emulsions are shown in Table 1.
A self microemulsifying drug delivery system
(SMEDDS) is an anhydrous system of microemulsions. It
has also been referred to as microemulsion preconcentrate by
some researchers. It is composed of oil, surfactant and
cosurfactant and has the ability to form o/w microemulsion
when dispersed in aqueous phase under gentle agitation. The
agitation required for the self-emulsification comes from
stomach and intestinal motility [33-35].The nanosized drop-
lets have very high surface to volume ratios which are able
to efficiently solubilize the drug. The drug is released in a
more reproducible manner which will become less dependent
on the GI physiology and the fed/fasted state of the patient.
Since the drug delivery system should be mild and
biocompatible, the choice of excipients is, however, limited.
Also a large amount of surfactant is required for micro-
emulsion formation which is undesirable. Therefore, proper
selection of the components and their use concentration is
imperative for a wider acceptability. The field of existence of
microemulsion is generally narrow and their temperature
stability, particularly of nonionic surfactant containing
microemulsions, can be limited.
2.1. Structure
Microemulsions are dynamic systems in which the
interface is continuously and spontaneously fluctuating [36].
Structurally, they are divided into oil-in-water (o/w), water-
in-oil (w/o) and bicontinuous microemulsions. In w/o micro-
emulsion, water droplets are dispersed in the continuous oil
phase while o/w microemulsion is formed when oil droplets
are dispersed in the continuous aqueous phase. In systems
where the amounts of water and oil are similar, a
bicontinuous microemulsion may result. In all three types of
microemulsions, the interface is stabilized by an appropriate
combination of surfactants and/or co-surfactants. The
mixture of oil, water and surfactants is able to form a wide
variety of structures and phases depending upon the
proportions of the components. The flexibility of the
surfactant film is an important factor in this regard. A
flexible surfactant film will enable the existence of several
different structures like droplet like shapes, aggregates and
240 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
Table 1. Comparison of Microemulsion with Conventional Emulsion
S. No Property Microemulsion
1 Appearance Transparent (or translucent)
2 Optical Isotropy Isotropic
3 Interfacial tension Ultra low
4 Microstructure Dynamic (interface is continuously and spontaneously fluctuating)
5 Droplet size 20-200 nm
6 Stability Thermodynamically stable, long shelf-life
7. Phases Monophasic
8 Preparation Facile preparation, relatively lower cost for commercial production
9 Viscosity Low viscosity with Newtonian behaviour
bicontinuous structures, and therefore broaden the range of
microemulsion existence. A very rigid surfactant film will
not enable existence of bicontinuous structures which will
impede the range of existence. Besides microemulsions,
structural examinations can reveal the existence of regular
emulsions, anisotropic crystalline hexagonal or cubic phases,
and lamellar structures depending on the ratio of the
components.
The internal structure of a microemulsion vehicle is very
important for the diffusivity of the phases, and thereby also
for the diffusion of a drug in the respective phases.
Researchers have been trying zealously to understand the
complicated phase behaviour and the various microstructures
encountered in the microemulsion systems [37].
2.2. Components of Microemulsion Formulations
A large number of oils and surfactants are available
which can be used as components of microemulsion systems
but their toxicity, irritation potential and unclear mechanism
of action limit their use. One must choose materials that are
biocompatible, non-toxic, clinically acceptable, and use
emulsifiers in an appropriate concentration range that will
result in mild and non-aggressive microemulsions. The
emphasis is, therefore, on the use of generally regarded as
safe (GRAS) excipients.
Oil Phase
The oil component influences curvature by its ability to
penetrate and hence swell the tail group region of the
surfactant monolayer. Short chain oils penetrate the tail
group region to a greater extent than long chain alkanes, and
hence swell this region to a greater extent, resulting in
increased negative curvature (and reduced effective HLB)
[38]. Saturated (for example, lauric, myristic and capric acid)
and unsaturated fatty acids (for example, oleic acid, linoleic
acid and linolenic acid) have penetration enhancing property
of their own and they have been studied since a long time.
Fatty acid esters such as ethyl or methyl esters of lauric,
myristic and oleic acid have also been employed as the oil
phase.
Talegaonkar et al.
Emulsion
Cloudy
Anisotropic
High
Static
> 500 nm
Thermodynamically unstable (kinetically stable),
will eventually phase separate
Biphasic
Require a large input of energy, higher cost
Higher viscosity
Lipophilic drugs are preferably solubilized in o/w
microemulsions. The main criterion for selecting the oil
phase is that the drug should have high solubility in it. This
will minimize the volume of the formulation to deliver the
therapeutic dose of the drug in an encapsulated form.
Surfactants
The surfactant chosen must be able to lower the
interfacial tension to a very small value which facilitates
dispersion process during the preparation of the micro-
emulsion and provide a flexible film that can readily deform
around the droplets and be of the appropriate lipophilic
character to provide the correct curvature at the interfacial
region. It is generally accepted that low HLB surfactants are
favoured for the formulation of w/o microemulsion, whereas
surfactants with high HLB (>12) are preferred for the
formation of o/w microemulsion. Surfactants having HLB
greater than 20 often require the presence of cosurfactants to
reduce their effective HLB to a value within the range
required for microemulsion formation.
Cosurfactants
In most cases, single-chain surfactants alone are unable
to reduce the o/w interfacial tension sufficiently to enable a
microemulsion to form [39-42]. The presence of cosur-
factants allows the interfacial film sufficient flexibility to
take up different curvatures required to form microemulsion
over a wide range of composition [38, 43-45]. If a single
surfactant film is desired, the lipophilic chains of the
surfactant should be sufficiently short, or contain fluidising
groups (e.g. unsaturated bonds). Short to medium chain
length alcohols (C3-C8) are commonly added as cosur-
factants which further reduce the interfacial tension and
increase the fluidity of the interface.
2.3. Method of Preparation
2.3.1. Phase Titration Method
Microemulsions are prepared by the spontaneous
emulsification method (phase titration method) and can be
depicted with the help of phase diagrams. Construction of
Microemulsions in Drug Delivery
phase diagram is a useful approach to study the complex
series of interactions that can occur when different com-
ponents are mixed. Microemulsions are formed along with
various association structures (including emulsion, micelles,
lamellar, hexagonal, cubic, and various gels and oily disper-
sion) depending on the chemical composition and con-
centration of each component. The understanding of their
phase equilibria and demarcation of the phase boundaries are
essential aspects of the study.
As quaternary phase diagram (four component system) is
time consuming and difficult to interpret, pseudo ternary-
phase diagram is often constructed to find the different zones
including microemulsion zone, in which each corner of the
diagram represents 100% of the particular component Fig.
(2). The region can be separated into w/o or o/w micro-
emulsion by simply considering the composition that is
whether it is oil rich or water rich. Observations should be
made carefully so that the metastable systems are not inclu-
ded. The methodology has been comprehensively discussed
by Shafiq-un-Nabi et al. [46].
Fig. (2). Pseudoternary phase diagram of oil, water and surfactant
showing microemulsion region.
2.3.2. Phase Inversion Method
Phase inversion of microemulsions occurs upon addition
of excess of the dispersed phase or in response to tempe-
rature. During phase inversion drastic physical changes
occur including changes in particle size that can affect drug
release both in vivo and in vitro. These methods make use of
changing the spontaneous curvature of the surfactant. For
non-ionic surfactants, this can be achieved by changing the
temperature of the system, forcing a transition from an o/w
microemulsion at low temperatures to a w/o microemulsion
at higher temperatures (transitional phase inversion). During
cooling, the system crosses a point of zero spontaneous
curvature and minimal surface tension, promoting the
formation of finely dispersed oil droplets. This method is
referred to as phase inversion temperature (PIT) method.
Instead of the temperature, other parameters such as salt
concentration or pH value may be considered as well instead
of the temperature alone.
Additionally, a transition in the spontaneous radius of
curvature can be obtained by changing the water volume
fraction. By successively adding water into oil, initially
water droplets are formed in a continuous oil phase. Increa-
sing the water volume fraction changes the spontaneous
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 241
curvature of the surfactant from initially stabilizing a w/o
microemulsion to an o/w microemulsion at the inversion
locus. Short-chain surfactants form flexible monolayers at
the o/w interface resulting in a bicontinuous microemulsion
at the inversion point.
2.4. Characterisation
The characterization of these systems is highly chal-
lenging due to their small droplet size with fluctuating
boundaries and complex structure. Basic components in a
physicochemical characterization of microemulsion systems
are:
1. Phase stability and phase behavior,
2. Microstructure, dimension (size and size distribution),
shape and surface features (specific area, charge, and
distribution),
3. Local molecular arrangements, interactions and
dynamics.
Among these properties, particle size, interactions, and
dynamics are of fundamental importance since they control
many of the general properties of microemulsions. In
particular, the size distributions of microemulsions give
essential information for a reasonable understanding of the
mechanism governing both the stability and penetration into
the membrane [47, 48]. Many technologies like dynamic
light scattering (DLS) [4, 49], small angle neutron scattering
(SANS) [50-52] and small angle X-ray scattering (SAXS)
[53-58] as well as cryo transmission electron microscopy
[59-62] and pulsed field gradient spin echo (self-diffusion)
NMR [63-67] have been in growing use in particle size
characterization. Other methods, e.g. electrokinetic chroma-
tography, conductance, viscosity, electrical birefringence,
infrared spectroscopy and calorimetry are also employed for
investigating the internal physicochemical states of
microemulsions [40, 56, 68-71].
Viscosity measurement can indicate the presence of rod-
like or worm-like reverse micelles while conductivity
measurement provides a means of determining whether a
microemulsion is oil-continuous or water-continuous as well
provide a means of monitoring phase inversion phenomena
[43]. Dielectric measurements are a powerful means of pro-
bing both the structural and dynamic features of micro-
emulsion systems. Pulsed field gradient NMR is also used
extensively to measure self-diffusion coefficients of the
various components and yields information on the mobility
and microenvironment.
3. MICROEMULSIONS IN DRUG DELIVERY
During the last two decades, microemulsions have been
extensively researched because of their tremendous potential
in many applications. The role of microemulsions in drug
delivery and the patents granted shall be discussed
comprehensively herein.
3.1. Oral Delivery
The development of the effective oral delivery systems
has always been the main goal because drug efficacy can be
severely limited by instability or poor solubility in the
gastrointestinal fluid. Biopharmaceutical Classification
242 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
System (BCS) is a useful guidance by US FDA and it takes
into account contributions of three major factors, dissolution,
solubility, and intestinal permeability, which affect oral drug
absorption. According to the BCS, drug substances are
classified as follows:
Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
Knowledge of BCS help the formulation scientists to
develop a dosage form based on mechanistic, rather than
empirical approaches. Drug substances are considered highly
soluble when the largest dose of a compound is soluble in
<250 mL of water over a range of pH from 1.0 to 7.5 and
highly permeable when they show >90 percent absorption of
the administered dose [1, 72]. In contrast, compounds with
solubility below 0.1mg/mL provide significant dissolution
related problems, and often, even compounds with solubility
below 10mg/mL present difficulties related to solubilization
during formulation. A major technological hurdle for routine
clinical use of many drugs is their very poor solubility in
water.
Microemulsions have the potential to enhance the
solubilization of the poorly soluble drugs and overcome the
dissolution related bioavailability problems. This is parti-
cularly important for the BCS class II or class IV drugs. The
successful formulation of such drugs is highly dependent on
the performance of the formulated product. Microemulsions
act as super solvent of these drugs and can be optimized to
ensure consistent bioavailability. In addition, they can be
used for the delivery of hydrophilic drugs including
macromolecules such as proteins and peptides. This is due to
the existence of polar, nonpolar and interfacial domains
which allow encapsulation of drugs with varying solubility.
Moreover, these systems have been reported to protect the
incorporated drugs against oxidation, enzymatic degradation
[73] and enhance the membrane permeability [74]. Presently,
Sandimmune Neoral® (Cyclosporine A), Fortovase®
(Saquinavir), Norvir® (Ritonavir), etc. are the commercially
available SMEDDS formulations.
A detailed illustration of their role in oral drug delivery is
discussed in this section.
3.1.1. Bioavailability Enhancement of Poorly Water
Soluble Drugs
Paclitaxel, an anticancer drug, has poor aqueous solu-
bility and therefore, formulation of paclitaxel has proven to
be difficult. Gao et al. disclosed self emulsifying compo-
sitions that generated a supersaturated paclitaxel micro-
emulsion upon contact with water in vivo that permitted its
rapid and efficient absorption resulting in improved oral
bioavailability [75]. The composition comprised of a solvent,
a surfactant, a substituted cellulosic polymer (e.g. hydroxy-
propyl methyl cellulose, hydroxypropyl cellulose, hydroxy-
ethyl cellulose, methyl cellulose, etc.), and optionally a P-
glycoprotein inhibitor. Paclitaxel and surfactant were present
in a ratio of from about 1:3 to about 1:20 by weight; and the
substituted cellulosic polymer and paclitaxel were present in
a ratio of from about 50:1 to about 0.1:1 by weight. The oral
Talegaonkar et al.
administration of a commercial product, Taxol® (Bristol
Myers Squibb) showed approximately 10-fold lower Cmax
than that obtained with their composition in rats.
Farah et al. in US Patent 6054136 provided a SMEDDS
capable of forming a microemulsion in situ with the
physiological fluid of the stomach and intestine for the
enhancement of drug bioavailability [76]. The SMEDDS
consisted of an active constituent, a lipophilic phase, a
surfactant and a cosurfactant. The lipophilic phase consisted
of a mixture of C8-C18 polyglycolized glycerides having a
HLB of less than 16. Surfactant was chosen from the group
comprising saturated C8-C10 polyglycolized glycerides and
oleic esters of polyglycerol also having an HLB of less than
16 (e.g. Labrasol®, Labrafac CM 10®) and cosurfactant was
chosen from the group comprising lauric esters of propylene
glycol (Lauroglycol®), oleic esters of polyglycerol and ethyl
diglycol (Transcutol®). The surfactant/cosurfactant ratio was
between 0.5 and 6. The composition being free from aqueous
phase would facilitate packaging in hard gelatin capsules.
The US Patent 6312704 granted to the same inventors was
the extension of their earlier patent [77]. In that there was an
additional claim in which it was said that lipophilic phase
was obtained by esterification of polyethylene glycol and
glycerol with fatty acids, or by mixing of glycerol esters and
condensates of ethylene oxide with fatty acids. The
surfactant was selected from the group consisting of oleic
esters of polyglycerol or a product obtained by esterification
of glycerol and polyethylene glycol with caprylic acid and
capric acid, or by mixing of glycerol esters and condensates
of ethylene oxide with caprylic acid and capric acid.
The use of rapamycin (macrolide antibiotic) and its
structurally similar analogs are limited by their very low
solubility, low and variable bioavailability and their high
toxicity. They have potent immunosuppressive activity and
also antitumor and antifungal activity. Fricker et al. taught a
microemulsion preconcentrate carrier medium for their
effective oral delivery [78]. The carrier medium comprised a
reaction product of a castor oil and ethylene oxide; a
transesterification product of a vegetable oil and glycerol
comprising predominantly linoleic acid or oleic acid, mono-,
di-, and triglycerides or a polyoxyalkylated vegetable oil; 1,2
-propylene glycol; and ethanol. When administered orally
high and consistent absorption was obtained. Therefore, the
macrolide might be administered in lower doses, which
might alleviate toxicity problems. Earlier they had described
a microemulsion preconcentrate for their delivery com-
prising hydrophilic component (Transcutol®, Glycofurol,
1,2-propylene glycol, or their mixtures), a lipophilic
component selected from the group consisting of fatty acid
triglycerides (Miglyol®, Captex®, Capmul®, etc.), mixed
mono-, di-,and tri-glycerides and transesterified ethoxylated
vegetable oils (e.g. Maisine®), and a surfactant which was
selected from the group consisting of polyethyleneglycol,
natural or hydrogenated castor oils (Cremophor EL®, Cre-
mophor RH40®), polyethylene-sorbitan fatty acid esters
(Tweens), polyoxyethylene fatty acid esters (Myrj),
polyoxyethylene-polyoxypropylene co-polymers, and block
co-polymers (Pluronic, Polaxamers) [79]. The composition
on dilution with water gave a microemulsion having an
average particle size of <150 nm.
Microemulsions in Drug Delivery
Liang et al. disclosed self-emulsifying formulations of
fenofibrate or fenofibrate derivatives having an improved
oral bioavailability and/or reduced food effect when
compared to commercial available formulations such as
Lipanthyl® (Groupe Fournier) or TriCor®. (Abbott Labo-
ratories) [80].The particle size of the active agent was not
critical to the bioavailability of the product. Fenofibrate or
fenofibrate derivative was dissolved in a solubilizer that
allowed the complete dissolution of the fenofibrate or a
fenofibrate derivative and prevented or minimized the
crystallization of fibrate in the formulation. With the
complete dissolution of the fibrate, the fibrate solution
allowed for an increase in absorption of the fibrate by the
patient. Some of the earlier strategies for increasing the
bioavailabilty included the use of micronized fenofibrate
[81-84], use of diethylene glycol monoethyl ether as
solubilizer [85], etc.
Bioavailability for orally administered conventional
crystalline or amorphous forms of cholesterol ester transfer
protein (CETP) inhibitors is quite low, often having absolute
bioavailabilities of less than 1%. Gumkowski et al. provided
self-emulsifying or self-microemulsifying compositions for
the improved solubility and bioavailability of CETP inhi-
bitors [86]. The formulation had a CETP inhibitor, a cosol-
vent, a surfactant having an HLB of 1 to 8, a surfactant
having an HLB of over 8 to 20, and optionally a digestible
oil.
Lambert et al. provided a composition which could be a
emulsion or a microemulsion having oil and a water phase
for improving the solubility of poorly soluble drugs [87].
Chemotherapeutic agent could be a taxoid, a taxane, or a
taxine, preferably paclitaxel. Alpha-tocopherol or a toco-
pherol polyethylene glycol succinate was also incorporated
in the oil phase. The resulting formulation was inexpensive,
sterilizable by either heat or filtration, stable for at least a
year and accommodated a wide variety of water insoluble
and poorly soluble drugs and was ethanol-free. Non-aqueous
solvents and solubilizers such as alcohol used in pharma-
ceutical formulations may extract toxic substances, for
example plasticizers, from their containers. This may cause
adverse reactions such as respiratory distress. This problem
could be circumvented by their invention. The US Patent
6660286 described a similar composition which in addition
claimed a composition consisting of paclitaxel, one or more
tocopherols or their derivatives, a tocopherol polyethylene
glycol derivative, polyethylene glycol, a polyoxypropylene-
polyoxyethylene glycol nonionic block polymer, and an
aqueous phase [88].
Benameur et al. have found that the incorporation of an
active agent, particularly statins, into a self-micro-
emulsifying system made it possible to reduce the first
intestinal passage effect, and thus improve the systemic
bioavailability of the active molecule [89]. Earlier SMEDDS
had been reported to improve the solubility of the water-
insoluble active principles but there was no knowledge on
the action of SMEDDS on intestinal metabolism. The
inventors had found surprisingly that the incorporation of an
active principle (statins) with a strong first intestinal passage
effect into a self-microemulsifying system made it possible
to reduce the first intestinal passage effect, and thus
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 243
improved the systemic bioavailability of the active molecule.
The self micro-emulsfying carrier included a lipophilic
phase, which was a mixture of glycerol mono-, di- and
triesters and of PEG mono- and diesters with at least one
fatty acid chosen from the group comprising C8 - C18 fatty
acids (LabrafilM1944CS®), a surfactant phase which is a
mixture of glycerol mono-, di- and triesters and of PEG
mono- and diesters with caprylic acid (C8) and capric acid
(C10) (Capryol 90®), a co-surfactant phase which was an
ester of a polyvalent alcohol with at least one fatty acid
chosen from the group comprising caprylic esters of
propylene glycol, lauric esters of propylene glycol and oleic
esters of polyglycerol. The ratio of surfactant/cosurfactant
varied between 0.2 and 6.
The object of the invention of von Corswant was to
provide a vehicle which increased the solubility of
compounds having a low solubility in water and at the same
time being non-toxic [90]. In that direction he presented a
non-toxic o/w or bicontinous microemulsion which was
comprised of a polar phase comprising water and a
component for adjusting the polarity of the polar phase, a
surfactant film modifier which is a monohydric alcohol with
2-3 carbon atoms (e.g. ethanol), a non-polar phase comp-
rising oil, and a mixture of a hydrophilic surfactant and a
hydrophobic surfactant which was selected from the group
consisting of lecithin, sphingolipids and galacto lipids. The
inventors had found that by using at least two types of
modifiers for adjusting the polarity it was possible to
minimize the amount of the surfactant and thus, also the
toxicity was minimized.
Chen et al. described a microemulsion of pyranone
protease inhibitor compounds that was free of alcohol and
propylene glycol comprising a pyranone protease inhibitor,
surfactant, and a polyethylene glycol solvent having a mean
molecular weight of greater than 300 but lower than 600, and
a lipophilic component comprising medium chain mono- and
di-glycerides, and optionally a basic amine [91]. The
formulations of this invention provided for improved
solubilization, stability and/or bioavailability of the pyranone
drug and permit less arduous manufacturing processes to be
undertaken in the fill process and allow the capsules to be
stored at room temperature.
Gao et al. provided pharmaceutical compositions in a
self-emulsifying formulation which permitted a high loading
of lipophilic compounds (up to about 400 mg/g) in addition
to good oral bioavailability [92]. The novel composition
comprised a lipophilic drug , a mixture of diglyceride and
monoglyceride in a ratio of from about 9:1 to about 6:4 by
weight wherein the diglyceride and monoglyceride are
mono- or di- unsaturated fatty acid esters of glycerol having
sixteen to twenty-two carbon chain length, solvent and
surfactant. The composition might be in the form of liquid
for soft elastic capsules or hard gelatin capsules for oral
application and might also be in the form of a liquid solution
for oral, parenteral, rectal or topical application. In their
earlier patent they had mentioned the use of pyranone
compound as the active agent [93]. They also provided a
formulation for pyranone compounds which was based on
the use of a particular amount (0.1% to about 10% by
244 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
weight) of the basic amine along with solvents, surfactants
and oil [94].
The invention of Bauer et al. included o/w micro-
emulsion containing one polyglycerol ester as the emulsifier
and lipophilic substance as the internal phase [95]. The
emulsifier contained a triglycerol monofatty acid ester (e.g.
triglycerol monolaurate, triglycerol monocaprylate) and the
lipophilic substance was selected from the group consisting
of carotenoids, vitamins A, D, E and K and their derivatives
and polyunsaturated fatty acids. The emulsifiers used were
non-toxic and such microemulsions could also be used in
foodstuffs in addition to the pharmaceutical field.
Mishra et al. described self-emulsifying microemulsion
or emulsion preconcentrate formulations containing omega-3
fatty acid oil and a hydrophobic drug [96]. The drug was
soluble in the omega-3 fatty acid oil and the preconcentrates
were free of or contain only minor amounts of a hydrophilic
solvent system. US Patent 4678808 described the use of
these oils to treat disorders associated with arachidonic acid
metabolites, including autoimmune syndromes, acute and
chronic inflammatory diseases, atherosclerosis, etc. [97]. The
omega-3 fatty acid oil and drug can exert an additive or
synergistic therapeutic effect or the omega-3 fatty acid oil
counteracts the negative side effects of the therapeutic agent.
For example, cyclosporines are soluble in omega-3 fatty acid
oil and capable of exerting an additive or synergistic
therapeutic effect in various autoimmune and inflammatory
diseases. In addition, the omega-3 fatty acid oil mediated the
adverse side effects, such as nephrotoxicity, of a cyclos-
porine such as cyclosporine A by reduction of its dose. The
composition could be administered in soft or hard gelatin
capsule.
Crison et al. taught a self-microemulsifying formulation
for increasing the bioavailability of a drug which included
oil/ lipid material, a surfactant, and a hydrophilic co-surfac-
tant [98]. HLB of hydrophilic co-surfactant was greater than
8. The self-microemulsifying formulation could also include
the addition of an aqueous solvent such as triacetin. They
had found that a more hydrophilic co-surfactant not only
increased the dissolution of poorly water-soluble drugs but,
that it also increased their in vivo bioavailability.
Orally administered acyclovir (in tablet, capsule or
suspension form) is slowly and erratically absorbed with 15-
30% bioavailability. For improved patient compliance an
acyclovir preparation is required which would permit lower
dosing and less frequent administration. In one embodiment
of their invention Burnside et al. provided a pharmaceutical
preparation comprising a w/o emulsion, preferably a
microemulsion, containing an oil phase (such as a long chain
carboxylic acid or ester or alcohol thereof), a surfactant
(such as poloxamer) and an aqueous phase containing the
drug acyclovir [99]. It was found that microemulsions were
ideal for oral acyclovir delivery since they contain
homogeneous and uniform droplet size of approximately 20-
40 nm and had the ability to dissolve relatively large
amounts of polar solutes in an overall oily environment. The
outer oily phase of the microemulsion was able to
incorporate into the intestinal cell matrix, thus creating
channels (either paracellularly or transcellularly) through
which the acyclovir could pass. Thus, malabsorption in the
Talegaonkar et al.
intestine could be circumvented. Further, the work of Rudnic
et al. described a pharmaceutical preparation comprising a
stable, surface-active emulsion or dispersion of a
pharmaceutical agent incorporated into an emulsion having a
hydrophobic discontinuous phase of a long chain carboxylic
acid (e.g. lauric acid, capric acid, myristic acid, behenic acid,
etc.) or ester (glyceryl monostearate, glyceryl monopal-
mitate, etc.) or alcohol thereof dispersed in an aqueous phase
or having a hydrophilic discontinuous phase dispersed in a
hydrophobic phase of a long chain carboxylic acid or alcohol
thereof [100]. The materials when combined in accordance
with the invention to form a w/o microemulsion gave
enhanced absorption capabilities.
Melatonin is a hormone synthesized in the epiphysis, in
the retina and, presumably in the chromaffinic cells of the
intestinal tract. It has immunostimulant and immuno-
modulatory effects. An attempt had been made by Graziella
et al. to improve the oral bioavailability of melatonin [101].
They described a microemulsion containing melatonin, L-
alpha-phosphatidylcholine (emulsifier) and a solvent mixture
consisting of ethanol, propylene glycol and water in which
the weight ratio of L-alpha-phosphatidylcholine to melatonin
was about 1:1.
Eugster et al. taught in their invention a spontaneously
dispersible concentrate which formed an ultramicroemulsion
when diluted with water or a glucose solution [102]. The
concentrate contained sterolester and/or sterolphosphor
compounds, surfactant, vitamin or provitamin, free fatty acid
and a carrier or diluent. They had found that the newly syn-
thetised sterolesters and sterolphosphatides had a pronoun-
ced antitumour activity, particularly if these compounds
were being incorporated into spontaneously dispersible
concentrates.
Ecanow proposed drug delivery systems which included
one or more monomeric or polymerized surface active agents
(e.g. polymerized lecithin) which allowed for rapid
dissolution and smooth liberation of the incorporated drug
[103]. Stable microemulsions could be produced by encasing
the microemulsions in a coacervate phase matrix and/or film.
Table 2 shows the utilization of the microemulsion
technology to improve the solubility and bioavailability of
some of the poorly water soluble drugs.
3.1.2. Controlled and Sustained Release of Drugs
US Patent 7147867 disclosed a sustained-release dosage
form for the delivery of a progestogenic steroid comprising
of a capsule, a self-emulsifying drug formulation contained
within a first portion of the capsule, an expandable layer
contained within a second portion of the capsule [104]. The
expandable layer was so positioned that the self-emulsifying
drug formulation could be expelled from the capsule upon
expansion of the expandable layer and a semipermeable
membrane is formed over at least a portion of an outer
surface of the capsule Fig. (3). The semipermeable mem-
brane comprised of a thermoplastic polymer composition
having a softening point of 40- 180oC. The aqueous fluid
dissolved the gelatin capsule and the imbibed fluid caused
the push-displacement layer to expand and push the
emulsified formulation through an orifice at a controlled
rate. The dosage form comprising the liquid formulation
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 245

Table 2. Bioavailability Enhancement of Some Drugs Using Microemulsion Technology

S. No Drug Category System Ref.

1 Paclitaxel Anticancer SMEDDS [75]

Microemulsion [87]

2 Fenofibrate SMEDDS [80]

3 Cholesterol ester transfer protein (CETP) inhibitors Antihyperlipidimic SMEDDS [86]

4 Atorvastatin, Fluvastatin SMEDDS [89]

5 Rapamycin Immunosuppressive SMEDDS [78]

6 Cyclosporine SMEDDS [97]

7 Felodipine Antihypertensive Microemulsion [90]

8 Nifedipine SMEDDS [100]

9 Indomethacin SMEDDS [76]

10 Ibuprofen Analgesic SMEDDS [95]

11 Naproxen SMEDDS [109]

12 Tipranavir Anti HIV Microemulsion [91]

13 Progesterone, Testosterone Hormones SMEDDS [92]

14 Vitamins (A,D, E, K) Nutrition supplement Microemulsion [96]

15 Acyclovir Antiviral Microemulsion [99]

16 Melatonin Immunomodulatory Microemulsion [102]

provided various advantages such as improved solubility,
improved bioavailability, sustained release and inhibition of
crystal growth during storage thereby providing improved
stability.
Gattefosse had been assigned a patent for a composition
with sustained release of active agent which was capable of
forming a microemulsion with an external hydrophilic phase,
for example physiological fluid or water [105]. The
composition comprised of an inert polymeric matrix which
couldn’t be ionised at physiological pH, dispersed in the
microemulsion forming system. After ingestion, polymeric
matrix on contacting the physiological fluid formed a gelled
polymeric matrix. The gelled barrier controlled the pene-
tration of water from the outside inwards, making possible
the gradual release of the microemulsified active principle by
diffusion, in a continuous and prolonged manner. Figure (4).
shows the functioning of the polymer matrix dispersed in a
SMEDDS formulation, the composition obtained being in
the form of gel capsule.
ALZA Corporation had been assigned a patent for a
sustained release self emulsifying formulation to enhance the
solubility, the dissolution, and the bioavailability of the drug
[106]. The formulation process involved the following steps:
(a) blending an osmotic hydrogel and an osmotically
effective solute, (b) blending a hydroxyalkylcellulose and
water to provide a granulation solution, (c) spraying the
granulation solution of step (b) onto the composition
provided in step (a) to provide granules, (d) forming a
blended, liquid mixture consisting essentially of a drug, a
surfactant, and a member selected from the group consisting
of a mono- and di-glyceride to provide a liquid self-emul-
sifying drug formulation, (e) adding the drug formulation
formed in step (d) to a capsule, (f) adding the sprayed
composition of step (c) to the capsule, (g) coating the
capsule with a semipermeable composition to provide a
membrane permeable to an aqueous fluid and providing an
exit in the membrane for delivering the drug formulation at a
sustained-release and controlled rate over an extended period
of time.
3.1.3. Manufacturing Improvements
SMEDDS based formulations require filling into soft or
hard gelatin capsules. Some of the problems encountered in
the processing of liquid SMEDDS include leaching and
leakage of the formulation, interaction with capsule shell
components and handling difficulties for the manufacturers.
It is therefore of interest to incorporate the self micro-
emulsifying vehicles into a powder to produce solid dosage
forms which may provide an attractive alternative to filled-
capsule preparations. The proper excipients selection,
however, is crucial when formulating dry adsorbed solid
formulations. A comprehensive review on these systems
focusing on formulation considerations, selection and func-
tion of solidifying excipients and techniques of preparation
has been published recently [107].
246 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
Fig. (3). Dosage form comprising a capsule made of two parts
consisting of a body portion and a cap portion in which capsule
contains a drug microemulsion formulation and an expandable
composition.
Fig. (4). Functioning of the polymer matrix dispersed in a
SMEDDS formulation.
Talegaonkar et al.
Pather et al. provided a method for converting drug-
containing microemulsion or self-microemulsifying drug
delivery system into a free-flowing, compressible powder by
admixing drug-containing microemulsion or self-micro-
emulsifying drug delivery system with a solid particle
adsorbent such as silicon dioxide, clays, magnesium
trisilicate, talc, etc. [108]. The composition could be further
formulated into solid dosage forms. Advantages of this
invention were numerous and helped in eliminating or
reducing the problems encountered with the earlier formu-
lations. For example, w/o microemulsion can absorb water
from gelatin shells. This may change the proportions of the
different phases and may cause the gelatin shell to become
dry and susceptible to cracking. The gelatin may absorb
water from w/o microemulsion and becomes soft.
Surfactants and co-surfactants within the microemulsions
can also react with the capsule shell. On the other hand, o/w
microemulsions cannot be incorporated in such capsules
because the water in the external phase would react with the
capsule shell. Capsules containing liquids also present
handling problems to the manufacturers. Capsules leakage is
a common problem. Presentation of microemulsions in a
solid dosage form provided a more robust, stable dosage that
was convenient and easy to handle.
The invention of Mulye was concerned with self-
emulsifying compositions for poorly soluble drugs [109].
Their composition included a lipophilic drug in association
with a carrier which was comprised of a lipophilic drug
solubilizing effective amount of a propylene glycol mono-
ester of C6-C18 fatty acid having at least 60% by weight
monoester based on the total weight of the propylene glycol
ester (e.g. propylene glycol monocaprylate) and a non-ionic
surfactant. Due to the greater solubility of lipophilic drugs in
the carrier, the capsule size was reduced, providing greater
patient acceptance and compliance. Moreover, there was an
excellent compatibility of the propylene glycol ester with a
hard or soft shell gelatin capsule or with a non-gelatin
capsule, thereby preventing brittleness and leakage of the
formulation during storage. Another advantage was that the
composition formed a microemulsion upon exposure to
aqueous fluid in the gastrointestinal tract which would
provide enhanced bioavailability.
3.1.4. Protein and Peptide Drug Delivery
Numerous peptide and proteins have been identified for
use as novel therapeutic agents. With increase in the
understanding of their structure and mechanism, recent
research has shifted to biotechnological products [110].
Changing scenario and increased market competitiveness is
pressurizing companies to address significant protein
delivery issues already at late discovery and early develop-
ment stages. However, in spite of tremendous advances in
peptide and protein development, their delivery is limited to
systemic route. This is due to their low oral bioavailability
which can be ascribed to their inactivation by gastrointestinal
enzymes and poor permeability of the intestinal mucosa. To
circumvent this, microemulsions have been developed as
smart systems and patented for the oral delivery of protein
and peptide drugs.
One preferred embodiment of the invention of Burnside
et al. comprised of a microemulsion containing an oil phase
Microemulsions in Drug Delivery
(such as a long chain carboxylic acid or ester or alcohol
thereof), a surface active agent (such as a poloxamer) and an
aqueous phase containing the insulin [111]. They had
attempted to increase the intestinal absorption of the
hormone which had met with only limited success earlier.
The hydrophobic material formed the continuous phase and
the hydrophilic material formed the discontinuous phase in
which the hydrophilic material was emulsified (w/o). A large
amount of polar solutes could be dissolved in an overall oily
environment by using w/o microemulsion thereby creating
an oral delivery system for oral delivery of insulin.
Cho et al. taught in US Patent 5656289 that oral pro-
teinaceous compositions comprising w/o microemulsions
could form chylomicra or provide chylomicra to sites of
absorption in the gastrointestinal tract [29]. It is believed that
when a biologically active material is administered in asso-
ciation with chylomicra or the constituents of chylomicra, it
is targeted to the villae and microvillae of the intestinal wall,
from where it is secreted into the lacteals and intestinal
lymph and then drained into the thoracic duct and, ulti-
mately, the circulating bloodstream. Therefore, proteina-
ceous active agents administrable only parenterally can be
given by the more preferred oral or rectal route. Formu-
lations of the invention were suitable for the oral
administration of insulin in the treatment of diabetes. w/o
formulation for proteinaceous compounds comprised of a
hydrophilic phase dispersed in a lipophilic phase to form an
emulsion/microemulsion wherein hydrophilic phase
comprises water, a biologically active substance and lecithin
or a lecithin precursor comprising a phospholipid, and lipo-
philic phase comprises oil, a phospholipid and a lipophilic
surfactant [30]. Lecithin can integrate into chylomicra,
particularly into their membranes and ultimately carries the
protein with it into general circulation.
The invention of Cho et al. provided pro-micelle
compositions (microemulsion or liposome) comprising a
pharmaceutically active agent encapsulated with a membrane
of esterified C12 -C18 fatty acids wherein the concentration of
fatty acid is less than 15 weight % [112]. In the intestine,
exposure to C12 -C18 fatty acids resulted in conversion of the
pro-micelle to a stable micelle that effectively delivered the
pharmaceutically active agent to the systemic circulation.
The membrane could be further encapsulated with a film
coating or an enteric coating to provide a minicapsule. They
could be used to deliver acid labile molecules such as insulin
and other peptides by oral route and drugs showing
inadequate oral absorption.
Owen et al. provided a highly stable w/o microemulsion
which readily converted to an o/w emulsion by the addition
of aqueous fluid [113]. Proteins and peptides could be stored
for long periods of time at room temperature and above by
using the w/o microemulsion. When required for use
aqueous fluid was added which converted the microemulsion
to an o/w emulsion and released the protein. US Patent
5688761 described the extension of the above mentioned
work in which the same assignee (LDS Technologies, Inc)
had included high purity short chain monoglyceride
surfactant as the preferred low HLB surfactant after finding
that the use of C9-13 monoglycerides as the low HLB surfac-
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 247
tant enhanced the uptake of the active material upon
administration [114].
Desai described a microemulsion formulation for oral
administration, in which a liquid polyol solvent (propylene
glycol or polyethylene glycol) and lipid cosolvent containing
a proteinaceous medicament, e.g., insulin formed a micro-
emulsion in the gastrointestinal tract at sites of absorption
i.e. villi of the intestinal tract [115]. A vital ingredient in the
formulation was the protease inhibitor which inhibited or
prevented the degradation of the proteinaceous material.
Earlier preparations contained ethanol which might cause
protein denaturation.
Poli et al. presented compositions in the form of
microemulsions or liposomic dispersions for the transmu-
cosal administration of therapeutic proteins or peptidic
substances [116]. They contained in addition a thermosetting
agent (Pluronic F127®) which differentiated them from the
known liposomic or microemulsified compositions. The
composition had a low viscosity at room temperature which
helped in the distribution of finely absorbed divided product
on a larger surface and the viscosity increased on reaching
the mucous as a result of structural change took place as a
function of the body temperature.
Ekwuribe et al. prepared hydrophilic and lipophilic
balanced microemulsion formulations of free-form and/or
conjugation-stabilized therapeutic agents such as insulin
[117]. Microemulsion described was w/o type and had a
HLB value between 3 and 7. In one particular aspect, the
composition comprised insulin covalently coupled with a
polymer, a linear polyalkylene glycol moiety and a lipophilic
moiety, wherein the insulin, the linear polyalkylene glycol
moiety and the lipophilic moiety are conformationally
arranged in relation to one another such that the insulin in
the composition had an enhanced in vivo resistance to
enzymatic degradation, relative to insulin alone. HLB value
of less than 7 provided a stable formulation for incorporating
free form insulin and/or insulin conjugates suitable for oral
administration. The microemulsion compositions could also
be employed for non-therapeutic purposes, e.g., diagnostic.
3.1.4.1. Cyclosporine Delivery
Cyclosporine delivery has remained a challenge for the
formulation scientists. It is an immunosuppressive agent and
is widely used in recipients of organ transplants and in
various autoimmune diseases. It exerts potent immuno-
suppressive activity by inhibiting the growth and
differentiation of T cells. The inherent insolubility of the
cyclosporine provides the major hurdle for the low and
variable bioavailability and there is variability in inter- and
intra-patient dose response and low formulation stability
during storage. It is, therefore, necessary to monitor
blood/blood-serum levels of patients receiving cyclosporine
therapy at regular and frequent intervals which is time
consuming and inconvenient and adds to the overall cost of
therapy. Due to poor bioavailability, higher doses may be
needed which may result in undesirable adverse side effects
such as nephrotoxicity and renal side effects which can be
troublesome and may lead to an ineffective therapy. On
reviewing general and patent literature it was found that a lot
of researchers have endeavoured to make effective delivery
248 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
systems for cyclosporine which can provide a suitable
uniform dosage and appropriate bioavailability.
Initially, cyclosporine was commercially available as a
cyclosporine drink solution which provided an average
absolute bioavailability of 30% only, with marked variation.
The commercial product that had been sold under the name
Sandimmune® (Sandoz Ltd.) was made according to US
Patent 4388307 [118]. The Sandimmune formulation con-
tained cyclosporine in olive oil with the surfactant Labrafil
and ethanol. However, the resulting liquid formulation was
administered as an aqueous dilution (solution or emulsion)
which was not convenient for the subject and might provide
a non-uniform dosage for oral administration. In Sandi-
mmun® soft capsule a large amount of ethanol was used as a
cosurfactant in order to solubilize the cyclosporine. How-
ever, since ethanol permeates the gelatin shell of the capsule
and is volatile, its content may greatly vary during storage
and may in turn result in crystallization of the cyclosporine
which may lead to variation in the bioavailability. Sandoz
Ltd. introduced an improved formulation later under the
trademark Neoral® according to the composition disclosed in
US Patent 5342625 [119]. The Neoral formulation was a
microemulsion pre-concentrate which contained cyclos-
porine in an anhydrous oily vehicle, medium chain trigly-
cerides, surfactants, glycerol and alcohol which exhibited
better and more consistent bioavailability. The preparation
showed that cyclosporin bioavailability was almost not
affected by food, bile secretion, etc. Therefore, frequent
monitoring of the plasma level of patient was not needed,
and hence was a remarkable improvement.
A recent patent assigned to Novartis AG was concerned
with the delivery of cyclosporines (excluding cyclosporine
A) [120]. It included microemulsions and microemulsion
pre-concentrate composition comprising of a hydrophilic
component, lipophilic component containing cyclosporine
and hydrophilic surfactant. The hydrophilic phase comprised
of C1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low
molecular weight mono- or poly-oxy-alkanediol (e.g.
Transcutol® , Glycofurol®); or 1,2-propyleneglycol. The
composition upon dilution with adequate water sponta-
neously produced an o/w microemulsion having an average
particle size of less than about 0.15 microns. The compo-
sitions permitted the preparation of solid, semi-solid and
liquid preparations containing a cyclosporine in sufficiently
high concentration which allowed convenient oral
administration while at the same time achieving improved
efficacy., e.g. in terms of bioavailability characteristics and
there was reduced intra and inter individual variability. The
compositions were non-alkanol based, e.g. which may be
free or substantially free of ethanol. Earlier ethanol based
formulations presented a number of problems. Evaporation
of the ethanol, e.g. from capsules or from other forms, e.g.
when opened, resulted in the development of a cyclosporine
precipitate. Encapsulation of cyclosporine in soft gelatin
encapsulated form necessitated packaging in an air-tight
compartment, for example an air-tight blister or aluminium-
foil blister-package. This in turn rendered the product both
bulky and more expensive to produce. Their compositions
eliminated or reduced the packaging difficulties which were
encountered with alkanolic compositions. In their earlier
patent, the assignee had described a microemulsion pre-
Talegaonkar et al.
concentrate composition comprising a cyclosporine, 1,2-
propylene glycol, a mixed mono-, di-, tri-glyceride and a
hydrophilic surfactant [121]. They claimed a trans-
esterification product of corn oil and glycerol (Maisine® )
comprising a) a free glycerol content of less than 10%, b)
less than 1% of palmitic acid and stearic acid mono-, di- and
tri-glycerides; and c) 85% or more of linoleic acid and oleic
acid mono-, di- and tri-glycerides all parts by weight which
they didn’t claim in their previous patent [122]. Further
earlier the same assignee claimed an o/w microemulsion and
microemulsion concentrate for the delivery of Cyclosporine
A [123, 124]. The microemulsion had a particle size of less
than 2000Aº while the microemulsion concentrate upon
dilution with water spontaneously formed microemulsion
which also had a particle size of less than 2000 Aº.
Novartis AG in US Patent 5866159 described a micro-
emulsion pre-concentrate of cyclosporin A comprising a
hydrophilic component, triglyceride lipophilic component
and polyoxyethylene glycolated natural or hydrogenated
vegetable oil surfactant (Cremophor RH40®, Cremophor
RH60®, Cremophor EL®, etc.) [125].The composition upon
dilution to 5 parts by weight of water spontaneously formed
an o/w microemulsion having average particle size of less
than about 200 nm. Use of alkanols, e.g. ethanol, as hydro-
philic phase was less preferred. In an especially preferred
embodiment the hydrophilic phase of compositions would
consist of Transcutol, Glycofurol and/or 1,2-propylene
glycol. Effective cyclosporin dosaging with concomitant
enhancement of resorption/bioavailability levels, as well as
reduced variability in resorption/bioavailability levels could
be achieved both for individual patients receiving
cyclosporin therapy as well as between individuals.
Novartis AG in US Patent 7205279 described a micro-
emulsion pre-concentrate comprising a hydrophilic phase
which comprises dimethylisosorbide and/or a lower alkyl
alkanoic ester, a lipophilic phase, and a surfactant for the
delivery of cyclosporine and lactam macrolide [126]. The
composition could also be in the form of microemulsion. The
compositions provided good bioavailability and reduce
variability in inter- and intra-patient dose response.
Novartis AG had been granted a patent which described a
cyclosporine containing composition in the form of a capsule
comprising a polyoxyethylene sorbitan fatty acid ester, a
reaction product of a natural or hydrogenated castor oil and
ethylene oxide, a sorbitan fatty acid ester, and ethanol [127].
Mulye described an approach to deliver cyclosporine in a
carrier comprising a fatty acid solubilizer having 6-22 carbon
atoms and a non-ionic surfactant (HLB value greater than
10) which form an emulsion (emulsion or microemulsion) on
exposure to water [128]. The inventor had suprisingly found
that the use of a carrier system comprising a non-ionic
surfactant in conjunction with a cyclosporin solubilizing
agent consisting of C6-C22 fatty acids overcame the problems
of limited solubility and resulting bioavailability associated
with cyclosporin.
Bhalani and Patel described a polar lipid self-emulsifying
drug delivery system (PLSEDDS) of cyclosporine which
instantly forms a fine emulsion when brought into contact
with an aqueous medium [129]. The composition consisted
Microemulsions in Drug Delivery
of cyclosporine dissolved in a polar lipid, such as a medium
chain monoglyceride of C6-C12 fatty acids having a
monoglyceride content of at least 50% and a surfactant. They
had found that medium chain monoglyceride as a component
prevented crystallization of cyclosporine under storage
conditions and cyclosporine A exhibited superior self-
emulsification ability when dissolved in certain polar lipids
as mentioned above. The encapsulated dosage form of this
composition did not require a hydrophilic component (like
ethanol, propylene glycol, or polyethylene glycol) which
require specialized packaging, such as aluminum foil blister.
Formulation could be inexpensively packaged such as in
glass or OHD polyethylene bottles. The same inventors in
their next patent provided PLSEDDS of lipophilic drugs in
addition to cyclosporine dissolved in a polar lipid as men-
tioned earlier and containing surfactants and triglycerides
[130].
Naicker et al. provided microemulsion or microemulsion
preconcentrate of cyclosporine analogs that are structurally
similar to cyclosporine A consisting of Vitamin E TPGS
(Vitamin E-alpha-tocopheryl polyethylene glycol 1000
succinate), medium chain triglyceride oil, an emulsifier and
ethanol [131]. The formulations provided superior drug
bioavailability and reduced adverse effects.
Chakravorty et al. described a self emulsifiable formu-
lation consisting of cyclosporine, hydrophilic agent,
lipophilic agent, surfactants, antioxidant and preservative
[132]. Lipophilic system consisted of a medium chain
triglyceride of caprylic acid and capric acid. Labrasol served
as a surfactant, which was combined with other selected
surfactants, like cremophor RH 40 and/or polysorbate 80.
The formulation was filled in a soft-gelatin shell capable of
rupturing in less than 12 minutes to provide quick release of
the formulation in the upper part of the gastrointestinal tract.
Domb provided a dispersible concentrate for the adminis-
tration of a cyclosporine which included a hydrophilic
solvent comprising a lower alkyl ester of hydroxyalkanoic
acid or a lower alkyl ester of N-alkyl pyrrolidone and
surfactant [133]. Surfactant was preferably a combination of
a surfactant with high HLB of at least about 8 and a
surfactant with low HLB of less than about 5. The charac-
teristic feature of the concentrate was that it formed, upon
contact with an aqueous solution, particles of a size of less
than about 100 nm. Other ingredients were optional, such as
a fatty acid ester such as tricaprin, a phospholipid, and an
ethoxylated fat such as cremophor. The ethoxylated fat could
be optionally substituted for the surfactant. Their formu-
lations did not require stabilizers, such as anti-oxidants, for
good stability. They hypothesized that the excellent stability
compared to some of the earlier formulations was due to the
use of hydrophilic solvents such as ethyl lactate. Ethyl
lactate is miscible in both organic and inorganic solvents,
since it is more hydrophobic than ethanol and has higher
storage stability than ethanol owing to latter’s high volatility.
Egbaria et al. taught a pharmaceutical composition
comprising a spontaneous emulsion of cyclosporine, ethanol,
polyoxyethylene glycerol trioleate, and an oil component
[134]. A method for their preparation involved dissolving
cyclosporine in ethanol. Then polyoxyethylene glycerol
trioleate and an oil component were added, mixed and
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 249
diluted in an aqueous media to form a spontaneous emulsion.
Polyoxyethylene glycerol trioleate was used as a surfactant
which is non-toxic and well tolerated physiologically. The
formulation provided a self-emulsifying delivery system in
which the droplets are preferably from 50 to 150 nm and
higher bioavailability was achieved.
Meinzer et al. provided oil-free pharmaceutical
compositions containing cyclosporinA [135]. A hard gelatin
capsule dosage form containing cyclosporin A in a mixture
with a surfactant of HLB value of at least 10 and hydrophilic
phase being a polyethylene glycol and/or a lower alkanol
provided that any lower alkanol, if present, is less than 12%
of the total weight of the composition excluding the hard
gelatin capsule weight. Their earlier patent was similar
except in that they had specifically claimed a poly-
ethyloxylated castor oil having an HLB value of at least 10
instead of a surfactant of HLB value of at least 10 [136].
They found that the compositions were compatible with
tenside materials, e.g. bile salts, present in the gastro-
intestinal tract and were fully dispersible in aqueous systems
comprising such natural tensides and are capable of
providing microemulsion systems in situ which were stable
and do not exhibit precipitation.
Stuchlik et al. described cyclosporine compositions in
which the concentration of cyclosporine was higher than
10% and provided high bioavailability [137]. Polar solvents
had been omitted in the compositions which might cause
compatibility problems with the capsule shell. The carrier
was composed of partial esters of C16-22 fatty acids with a
glycerol derivative selected from diglycerol to decaglycerol
and partial esters of C8-16 fatty acids with pentaglycerol to
pentadecaglycerol in mutual weight ratios of 1:1.
Singh et al. taught in US Patent 6187747 substantially
alcohol free composition of cyclosporine which comprised a
cyclosporine in a hydrophilic carrier medium comprising
propylene glycol, esters of propylene glycol with C4 to C12
fatty acids and polyoxyethylene hydrogenated castor oils
[138]. On dilution with the gastrointestinal fluids the
hydrophilic end of the surfactant and the cosurfactant were
oriented towards hydrophilic environment of gastrointestinal
fluid and the drug molecules were entrapped in the
hydrophobic portions of the surfactant micelles. The drug
was released leading to improved absorption, thus providing
an increased and less variable bioavailibility. In their later
patent they have broadened the claim by extending the
percentage range of propylene glycol, esters of propylene
glycol and polyoxyethylene hydrogenated castor oils [139].
Hong et al. taught a solid-state microemulsion of cyclos-
porin prepared by dispersing of cyclosporin microemulsion
in enteric carrier [140]. The carrier prevented the release of
cyclosporin in the acidic condition, while allowing a rapid
release in the upper part of the small intestine thereby
forming the microemulsion. The composition could maintain
the plasma therapeutic level of cyclosporine for about 1 day
by only once daily dosing.
Hong et al. developed a cyclosporine containing micro-
emulsion preconcentrate, which comprised lipophilic
solvent, surfactant and oil [141]. Lipophilic solvent was
typically comprised of alkyl ester of polycarboxylic acid
250 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
(e.g. triethyl citrate, tributyl citrate) and/or carboxylic acid
ester of polyols (e.g. triacetin). They reported that using
lipophilic solvent was advantageous instead of hydrophilic
solvent which causes pharmaceutical instability and can
overcome the various problems of the prior formulations.
Lipophilic solvents used in the invention were odorless and
colorless oils in liquid state, and had high boiling point of
more than 250°C. They did not volatilize at the condition of
high temperature during the procedure for soft capsule
preparation as well as during storage at room temperature,
and therefore, could ensure the stability of preparation
comprising them. Moreover, they did not show such severe
hygroscopic property as glycols showed, did not dissolve the
gelatin shell, and did not induce the compositional change
due to non-volatility and non-permeability for gelatin shell.
Sherman described pharmaceutical compositions in the
form of an emulsion preconcentrate or microemulsion
preconcentrate comprising cyclosporine, acetylated mono-
glyceride (Myvacet®) as lipophilic solvent, a surfactant, and
optionally a hydrophilic solvent [142]. In comparison to
other ingredients used as lipophilic solvent in some of the
previous formulations, they found that acetylated mono-
glycerides offered various advantages such as low cost, good
solvent properties for cyclosporines, thus reducing the
amount of lipophilic solvent required and/or reducing the
need for a hydrophilic co-solvent to maintain the cyclo-
sporine in a stable solution and ready miscibility with
preferred hydrophilic co-solvents such as polycarbonate and
ready dispersibility into emulsions or microemulsions upon
inclusion of a suitable surfactant. In his earlier patent, the
inventor described a pharmaceutical composition in the form
of a microemulsion preconcentrate comprising a cyclo-spo-
rine dissolved in a solvent system comprising of a
hydrophobic component, a hydrophilic component, and a
surfactant, wherein either the hydrophobic component was
selected from tocol, tocopherols, tocotrienols, and deriva-
tives thereof, or the hydrophilic component was selected
from propylene carbonate or polyethylene glycol having an
average molecular weight of less than 1000 [143]. In a
subsequent patent, the same inventor taught pharmaceutical
compositions in the form of an emulsion preconcentrate or
microemulsion preconcentrate of cyclosporine comprising
propylene carbonate as hydrophilic solvent, glycerides as
lipophilic solvent, and a surfactant [144]. The disclosed
lipophilic solvents such as Vitamin E in his earlier patent
were relatively expensive. He found that when propylene
carbonate was used as hydrophilic solvent, excellent
emulsion preconcentrate and microemulsion preconcentrates
could be made using relatively inexpensive glycerides as
lipophilic solvent, and without the use of ethanol.
Kim et al. described pharmaceutical composition con-
taining cyclosporine, an oil component, a hydrophilic cosur-
factant consisting of propylene carbonate or a mixture of
propylene carbonate and polyoxyethylene-polyoxypropylene
block copolymer (pluronics, poloxamers), and a surfactant
[145]. The use of the above mentioned hydrophilic cosur-
factant provided a solubilizing effect sufficient for cyclos-
porine and also provided some advantages that it did not
cause the change in capsule appearance and the precipitation
of cyclosporine due to the change in solvent content, reduced
the manufacturing cost to provide an economical effect and
Talegaonkar et al.
does not have any toxicity problem of the solvent in
comparison to the soft capsule using ethanol, transcutol,
propylene glycol, glycofurol, dimethylisosorbide, etc., in the
prior compositions. The composition could be dissolved in
an external phase such as water, artificial gastric juice and
intestinal juice, etc. to form a self-emulsion with mild
stirring and therefore, by appropriately adjusting the
constitutional ratio of each component the diameter of
particles in the inner phase of the emulsion formed could be
controlled to 100 nm or less. The composition was suggested
to be formulated into the oral preparations such as soft
capsules, hard capsules sealed with gelatin bending at the
conjugated portion, oral liquid preparations, etc.
The invention of Woo was concerned with a micro-
emulsion concentrate containing cyclosporine as an active
ingredient, dimethylisosorbide as a cosurfactant, oil and a
surfactant where cyclosporine, dimethyl isosorbide, oil and
surfactant were present in the ratio of 1:1-5:1-5:2-10 by
weight [146]. The composition was suitable for the
formulation of a soft capsule for oral administration. Since
dimethylisosorbide has no membrane permeation property,
the soft capsule preparation was stable in comparison with
the soft capsules containing ethanol, propylene glycol,
transcutol, glycofurol, etc., as a cosurfactant in the prior dis-
closures. Furthermore, appearance and composition content
of the soft capsule according to the present invention were
not changed.
Earlier, the same inventor provided a cyclosporine soft
capsule composition comprising cyclosporine as an active
ingredient, dimethylisosorbide as a cosurfactant, components
of an esterified compound of fatty acid and primary alcohol,
medium chain fatty acid triglyceride and fatty acid
monoglyceride (e.g. Nikkol VF-E®, Miglyol 812®) as an oil
component, and a surfactant having an HLB value of 10 to
17 [147]. Another patent granted to the same inventor
described a cyclosporine containing soft capsule composition
which comprised cyclosporine as an active ingredient,
polyethylene glycol having a molecular weight of 200 to 600
as a cosurfactant, a mixture of an esterified compound of
fatty acid and primary alcohol, medium chain fatty acid
triglyceride and fatty acid monoglyceride as an oil com-
ponent, and a surfactant having HLB value of 10 to 17 [148].
Polyethylene glycol is non-volatile, does not permeate the
gelatin membrane of the soft capsule, and has a high
solubility for cyclosporine and is therefore advantageous for
administration of the composition in a soft capsule dosage
form.
3.2. Parenteral Delivery
The formulation of lipophilic and hydrophobic drugs into
parenteral dosage forms has proven to be difficult. O/w
microemulsions are beneficial in the parenteral delivery of
sparingly soluble drugs where the administration of suspen-
sion is not desirable. They provide a means of obtaining
relatively high concentration of these drugs which usually
requires frequent administration. Other advantages are that
they exhibit a higher physical stability in plasma than
liposomes or other vesicles [149] and the internal oil phase is
more resistant against drug leaching. Several sparingly
soluble drugs have been formulated into o/w microemulsion
for parenteral delivery [31, 149-156]. Microemulsions can
Microemulsions in Drug Delivery
also be used as intravenous delivery systems for the fat
soluble vitamins and lipids in parenteral nutrition [156].
Dennis et al. patented an intravenous microemulsion
delivery system for water insoluble or sparingly water
soluble drugs that comprised an oil phase comprising the
drug, a long polymer chain surfactant (e.g. lecithin, gelatin
casein, tweens, macrogol ethers, etc.) component and a short
fatty acid surfactant (e.g. stearic acid, glyceryl monostearate,
sorbitan esters, etc.) component and an aqueous phase [157].
The droplet size ranged from 10-100 nm. They had found the
composition to be useful for propofol, a short-acting
intravenous anesthetic. Micromulsion would emulsify or
partition propofol into the non-aqueous phase and preclude
(or markedly reduce) stinging and allow painless injection.
Dennis et al. in their invention taught a intravenous
microemulsion delivery system comprising a long polymer
chain surfactant component and a short fatty acid surfactant
component, and an aqueous phase, wherein the amounts of
the long chain polymer and short chain fatty acid surfactant
components were selected to provide for spontaneous
formation of thermodynamically stable microemulsion drop-
lets of the oil phase having a particle size from 10-100 nm
and the interfacial tension of the drug with the emulsifier
combination was less than 0.1 dynes per cm [158]. This
work was an extension of an earlier patent granted to the
same inventors [157].
Microemulsions are generally not dilutable with aqueous
fluids, such as certain bodily fluids and buffer solutions, and
form emulsions upon contacting such fluids. Various
microemulsions are also sensitive to temperature and are not
stable outside of room temperature conditions. US Patent
6245349 provided drug delivery compositions in both
concentrated and diluted forms for use as vehicles in the
administration of various active agents [159]. The concen-
trated drug delivery compositions were formulated with a
phospholipid component, a component selected from
propylene glycol or certain polyethylene glycol compounds,
a high HLB surfactant, and the drug component, with water
and/or an optional oil component. The concentrated drug
delivery compositions could be diluted with an aqueous fluid
to form an o/w microemulsion. These o/w microemulsions
were characterized by their small particle size and their wide
range of temperature stability, typically from about -20o-
50oC. They could be administered by intravenous, intra-
arterial, intrathecal, intraperitoneal, intraocular, intra-
articular, intramuscular or subcutaneous injection.
According to the invention of the Wretlind et al. paren-
teral administration of water-insoluble active agents was
enhanced when the agents were administered in the lipoid
phase of a carrier microemulsion [160]. The microemulsion
comprised of a finely dispersed lipoid in an aqueous phase
with a mean particle size below 1 micron. Higher
concentration of the agent (diagnostic or therapeutic) could
be achieved and hence a lower dose whereby a rapid onset of
the pharmacological effect was accompanied by a reduced
incidence of injury to body tissues. As the agents were
present in a dissolved state in the hydrophobic phase, there
was no need of affecting the pH or the osmotic pressure of
the aqueous phase. Because of this, the method of adminis-
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 251
tration according to the invention would cause a lower
occurrence of injuries to the body tissues.
US Patent 7157099 described stable, biologically
compatible w/o microemulsions, for the sustained release by
parenteral administration of hydrophilic active ingredients
[161]. Microemulsions could be formulated particularly for
peptide active ingredients (LHRH analogs such as Leup-
rolide acetate, Goserelin, Triptorelin, Somatostatin or its
analogs such as Octreotide and Lanreotide acetate, etc.) or
biologically active oligo- or polysaccharides (unfractioned
heparin or low molecular weight heparins), which provides
protection against immediate attack by the hydrolytic
enzymes as well as sustained release to avoid repeated
administrations. The microemulsions consisted up to 20% of
an internal hydrophilic aqueous phase containing the active
ingredient, 30 to 98% of a hydrophobic external phase and
up to 50% of a surfactant alone or in admixture with a co-
surfactant. Another technology already used for the sustained
release of peptides involved the use of bioerodible polymers
like polymers based on glycolic acid and lactic acid [162].
Drawbacks of using polymers include their higher cost and
the issues of environmental impact and safety of the
pharmaceutical formulation as organic, in particular
chlorinated, solvents are used during their preparation. Also,
these microemulsion formulations did not cause persistent
granulomas which were reabsorbed during the time in which
the medicament was effective and did not induce local
ulcerogenicity.
Vigne et al. disclosed microemulsions suitable for
parenteral administration of fat soluble vitamins (vitamins E,
A, D, and K) and hydrophobic drugs [163]. The micro-
emulsions were comprised of a naturally occurring amphi-
patic substance and a hydrophobic lipid along with the active
ingredient and were size selected for 30-100 nm pseudo-
micelles. According to them, the composition had the unique
property of delivering fat soluble substances to the plasma in
a form and distribution which mimicked the natural uptake
in normal subjects.
3.3. Topical Delivery
Microemulsion systems are now being investigated
zealously for topical delivery which is evident from the
numerous publications coming up every year. They have
been reported to enhance the transdermal permeation of
drugs significantly compared to conventional formulations
such as solutions, gels or creams [164,165]. They are able to
incorporate both hydrophilic (5-fluorouracil, apomorphine
hydrochloride, diphenhydramine hydrochloride, tetracaine
hydrochloride, methotrexate) and lipophilic drugs (estradiol,
finasteride, ketoprofen, meloxicam, felodipine, triptolide)
and enhance their permeation [18-22, 166-170]. Since the
microemulsion is a multicomponent system and its formation
requires high surfactant concentration, the skin irritation
aspect must be considered especially when they are intended
to be applied for a longer period. Several plausible mecha-
nisms have been proposed to explain the advantages of
microemulsion for the transdermal delivery of a drug:
1. A large amount of drug can be incorporated in the
formulation due to the high solubilizing capacity that
252 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
might increase thermodynamic activity towards the skin
[171].
2. The permeation rate of the drug from microemulsion
may be increased, since the affinity of a drug to the
internal phase in microemulsion can be easily modified
to favour partitioning into stratum corneum, using
different internal phase, changing its portion in
microemulsion [172].
3. The surfactant and co surfactant in the microemulsions
may reduce the diffusional barrier of the stratum
corneum by acting as penetration enhancers [21].
4. The percutaneous absorption of drug will also increase
due to hydration effect of the stratum corneum if the
water content in microemulsion is high enough [173].
Due to the small droplet size and large amount of inner
phase in microemulsions, the density of droplets and their
surface area are assumed to be high. Therefore, droplets
settle down to close contact with the skin providing high
concentration gradient and improved drug permeation.
Moreover, low surface tension ensures good contact to the
skin. Also, the dispersed phase can act as a reservoir making
it possible to maintain an almost constant concentration
gradient over the skin for a long time [19].
The liquid, transparent, multicomponent systems accor-
ding to the invention of Muller et al. contained the active
agents in a solution of an oily and optionally an aqueous
component in the presence of surfactants and cosurfactants
[174]. Under certain conditions, the cosurfactants can serve
as oil components or vice-versa. The efficacy of the active
agents applied in the form of the multicomponent systems
according to the invention was much better than that of
active agents applied in the form of known multicomponent
systems. The multicomponent systems could be used in
pharmaceutical products for cutaneous, peroral, vaginal and
parenteral administration of pharmaceutical active agents.
The invention of Protopapa et al. referred to depilatory
preparations containing proteolytic enzymes solubilized in
microemulsions, formed with lecithin, aliphatic hydrocarbon,
alipathic alcohol and buffer solution (pH 7-9) to be applied
for permanent enzymic depilation [175]. The invention
introduced the use of microemulsions as a medium for the
facilitated penetration of the enzymic activity in the
epithelial cells of the skin. In addition, their invention
referred to a depilation method that applied the preparations
of microemulsion containing the enzyme alpha-chymo-
trypsin, or the enzyme trypsin, for the depilation of any type
of skin (fatty-resistant or dry-sensitive). The application of
these preparations provided more permanent depilation than
the one resulting from other depilatory methods.
3.4. Opthalmic Delivery
In conventional ophthalmic dosage forms, water soluble
drugs are delivered in aqueous solution while water-
insoluble drugs are formulated as suspensions or ointments.
Low corneal bioavailability and lack of efficiency in the
posterior segment of ocular tissue are some of the serious
drawbacks of these systems. Recent research efforts have
therefore focused on the development of new and more
Talegaonkar et al.
effective delivery systems. Microemulsions have emerged as
a promising dosage form for ocular use [176].
Bowman et al. disclosed sustained release emulsions
(macroemulsions and microemulsions) in which particles of
the dispersed phase were dispersed and stably maintained in
physical separation by lightly crosslinked, water swellable
polymers (carboxyvinyl polymers, polyvinyl pyrolidone,
etc.) present in an aqueous polymeric system formulated for
administration to the eye in drop or ribbon form [23].
Medicament was dissolved in dispersed phase and was
delivered over a sustained release period. Rather than using
large quantities of the polymer, the invention relied on
including an amount of the polymer sufficient to stably
maintain that physical separation of the particles of the
disperse phase of the emulsion within the aqueous polymeric
system. The advantages of the invention included enhanced
bioavailability of the sparingly soluble drug in water,
inhibition of the tendency of oily medicaments to separate
and/or agglomerate in aqueous media and sustained action.
Chloramphenicol, an antibiotic used in the treatment of
trachoma and keratitis, in the common eye drops hydrolyzes
easily. Lv et al. investigated chloramphenicol microemulsion
composed of Span 20, Tween 20, isopropylmyristate and
water as potential drug delivery systems for eye drops [177].
Chloramphenicol was entrapped in the o/w microemulsion
free of alcohol. Its stability was determined in the accele-
rated experiments of three months. The authors revealed that
the content of glycol (main hydrolysis product) in the
microemulsion formulation was much lower than that in the
commercial eye drops at the end of the accelerated
experiments. Thus, a remarkable increase in the chloram-
phenicol stability was observed in the microemulsion
formulations.
Fialho et al. prepared microemulsion based dexa-
methasone eye drops which showed better tolerability and
higher bioavailability [178]. The formulation showed greater
penetration in the eye which allowed the possibility of
decreasing the number of applications per day. This might be
useful in achieving improved patient compliance.
Habe et al. formulated water-continuous microemulsions
for ocular application of pilocarpine [179]. in vitro Studies
showed a prolonged pilocarpine release from the
microemulsions with lecithin. The authors found micro-
emulsions to be favourable for ophthalmological use.
3.5. Nasal Delivery
Microemulsions are now being studied as a delivery
system to enhance uptake across nasal mucosa. Addition of a
mucoadhesive polymer helps in prolonging the residence
time on the mucosa. Nasal route for administration of
diazepam might be a useful approach for the rapid onset of
action during the emergency treatment of status epilepticus.
For this microemulsion was formulated comprising of ethyl
laurate (15%), Tween 80:propylene glycol:ethanol at 1:1:1
weight ratio (70%) and water (15%). The nasal absorption of
diazepam was found to be fairly rapid at 2 mg kg-1 dose with
maximum drug plasma concentration reached within 2-3
min. The bioavailability (0-2 h) after nasal spray compared
to i.v. injection was about 50% [24].
Microemulsions in Drug Delivery
3.6. Periodontal Delivery
Periodontal disease is a collective term for a number of
progressive oral pathological afflictions like inflammation
and degeneration of the gums, periodontal ligaments,
cementum and its supporting bone. It is a major cause of
tooth loss. The invention of Brodin et al. included a novel
pharmaceutical composition comprising local anaesthetic in
oil form, surfactant, water and optionally a taste masking
agent [180]. The composition was in the form of an emulsion
or microemulsion and had thermoreversible gelling proper-
ties i.e. it was less viscous at room temperature than after
introduction onto a mucous membrane of a patient. The
surfactant in the formulation imparted the thermoreversible
gelling properties. Preferred surfactants were Poloxamer
188®, Poloxamer 407® and Arlatone 289®. The composition
could be used as a local anaesthetic for pain relief within the
oral cavity in conjunction with periodontal scaling and root
planning and overcame the problem with the existing topical
products (jelly, ointment or spray) such as lack of efficacy
due to inadequate depth of penetration, too short duration
and difficulties in administration due to spread, taste etc.
3.7. Drug Targeting
Drug targeting has evolved as the most desirable but
elusive goal in drug delivery. By altering the pharma-
cokinetics and biodistribution of drugs and restricting their
action to the targeted tissue increased drug efficacy with
concomitant reduction of their toxic effects can be achieved.
Drug targeting to diseased cells can be achieved by
exploiting the presence of various receptors, antigens/
proteins on the cell membrane which may be uniquely
expressed or over expressed in these cells as compared to the
normal cells. Specific antibodies to the surface proteins and
ligands for the receptors can be used to target specific cells.
Submicron size range of these systems confers excellent
opportunities to overcome the physiological barriers and
enables efficient cellular uptake followed by intracellular
internalization.
3.7.1. Cellular Targeting
Nucleic acids delivered to cells are promising
therapeutics. The invention of Monahan et al. included
insertion of nucleic acid into a reverse micelle for cell
delivery [181]. They referred w/o microemulsions to as
reverse micelles. The reverse micelle had the property to
compact the nucleic acid for easier delivery. To further
enhance the delivery, other molecules such as a surfactant
having a disulfide bond or a polyion might be added to the
nucleic acid-micelle complex. Another advantage of the
invention was the use of reverse micelles for gene delivery to
the cells. The micelle containing the compacted polynuc-
leotide could be utilized as a reaction vesicle in which
additional compounds such as polycation could be added to
the DNA. Additionally, the polynucleotide/reverse micelle
system was used as a vesicle for template polymerization of
the DNA or caging of the DNA in which the polycation was
crosslinked. Another advantage was that the micelle might
be cleaved under physiological conditions involved along the
transfection (process of delivering a polynucleotide to a cell)
pathway. Better recovery and purification of the bio-
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 253
molecules could be achieved by utilizing cleavable reverse
micelles which was difficult earlier.
The invention of Wheeler et al. was related to cell
delivery of hydrophobic compounds in microemulsion
carriers [182]. Microemulsion was comprised of a mixture of
oil, a hydrophobic compound, and a polyethylene glycol-
linked lipid. The purpose of polyethylene glycol-linked lipid
was to enhance the stability of the microemulsion compo-
sitions. The hydrophobic compound resided in an oil
environment which was surrounded by a monolayer of a
polar lipid. The polar head of the lipid faced outwards to
provide compatibility with the external aqueous environment
and the nonpolar tail faced the internal oil environment. A
targeting moiety such as biotin, avidin, streptavidin or
antibodies might be covalently or noncovalently attached to
the lipid monolayer. The composition could also be used for
diagnostic and therapeutic purposes.
3.7.2. Tumour Targeting
Maranh ao suggested the utility of microemulsions as
vehicles for the delivery of chemotherapeutic or diagnostic
agents to neoplastic cells while avoiding normal cells [183].
They claimed a method for treating neoplasms, wherein
neoplasms cells have an increased number of LDL (low
density, lipoprotein) receptors compared to normal cells. The
microemulsion comprised of a nucleus of cholesterol esters
and not more than 20% triglycerides surrounded by a core of
phospholipids and free cholesterol and contained a
chemotherapeutic drug. Microemulsions were similar in
chemical composition to the lipid portion of low density
lipoprotein (LDL), but did not contain the protein portion.
These artificial microemulsion particles incorporated plasma
apolipoprotein E (apo E) on to their surface when they were
injected in the bloodstream or incubated with plasma. The
apolipoprotein E served as a linking element between the
particles of the microemulsion and the LDL receptors. The
microemulsions could then be incorporated into cells via
receptors for LDL and delivered the incorporated molecules.
Thus, higher concentration of anticancer drugs could be
achieved in the neoplastic cells that have an increased
expression of the receptors. In this way toxic effects of these
drugs on the normal tissues and organs could be avoided. In
human subjects, they observed no change in the plasma
kinetics of the radioactively labeled microemulsion
containing carmustine or cytosine-arabinoside thereby
confirming that the incorporation of these drugs did not
diminish the capacity of the microemulsion to incorporate
apo E in the plasma and bind to the receptors.
Shiokawa and coworkers reported a novel microemulsion
formulation for tumour targeted drug carrier of lipophilic
antitumour antibiotic aclacinomycin A (ACM) [184]. Their
findings suggested that a folate-linked microemulsion is
feasible for tumour targeted ACM delivery. The study
showed that folate modification with a sufficiently long PEG
chain on emulsions is an effective way of targeting emulsion
to tumour cells.
3.7.3. Brain Targeting
Intranasal administration confers a simple, practical, cost
effective, convenient and noninvasive route of adminis-
tration for rapid drug delivery to the brain [185-187]. It
254 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
allows a direct transport of drugs to the brain circumventing
the brain barriers [188, 189]. Vyas et al. prepared muco-
adhesive microemulsion for an antiepileptic drug clona-
zepam [25]. The aim was to provide rapid delivery to the rat
brain. Brain/blood ratio at all sampling points up to 8h
following intranasal administration of clonazepam muco-
adhesive microemulsion compared to i.v. was found to be 2-
fold higher indicating larger extent of distribution of the drug
in the brain.
CURRENT & FUTURE DEVELOPMENTS
The full potential of microemulsion systems is yet to be
realized. A lot of innovations are expected to come in the
field of microemulsion technology. The role of micro-
emulsion systems is of paramount importance in providing
novel solutions to overcome the problems of poor aqueous
solubility of highly lipophilic drug compounds and provide
high, more consistent and reproducible bioavailability.
Furthermore, these formulations can be easily scaled up
which is important from industrial standpoint considering the
relative cost of commercial production. In addition to oral
drug delivery, a lot of topical products employing the
microemulsion technology are likely to emerge. This is
significant not only from the view point of drug delivery but
also from the huge and lucrative cosmetic market prospects.
Microemulsions can also be used to achieve drug targeting
however challenges remain, primarily because of the layers
of barriers that these systems need to overcome to reach to
the target. Recent research work is focused on the production
of safe, efficient and more compatible microemulsion
constituents which will further enhance the utility of these
novel vehicles. A considerable amount of work still needs to
be performed to characterize the physicochemical behaviour
of the microemulsions. Despite the caveat associated with
this therapeutic system, the current scientific interest seems
to be directed at recognizing its full potential as a novel drug
delivery tool.
ACKNOWLEDGEMENTS
One of the authors, A. Azeem is highly grateful to the
University Grants Commission, Government of India for
providing financial assistance in the form of research
fellowship.
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