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Microemulsions: A Novel Approach to Enhanced


Drug Delivery

Article · February 2008


DOI: 10.2174/187221108786241679 · Source: PubMed

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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


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

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


Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 239

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 between ordinary emulsions (macro emulsions) and micro-
capsule which contains a mixture of drug dissolved in oil and emulsions are shown in Table 1.
surfactant [15-17]. It converts into an oil-in-water (o/w)
A self microemulsifying drug delivery system
microemulsion in situ in an aqueous environment in the
(SMEDDS) is an anhydrous system of microemulsions. It
stomach and the small intestine. Microemulsion formulation
has also been referred to as microemulsion preconcentrate by
made the bioavailability and plasma concentration profiles of
some researchers. It is composed of oil, surfactant and
the drug more reproducible which is clinically important in cosurfactant and has the ability to form o/w microemulsion
the case of drugs showing serious adverse effects. This is a
when dispersed in aqueous phase under gentle agitation. The
significant step forward in the delivery of poorly soluble
agitation required for the self-emulsification comes from
drugs. Microemulsion systems are also now being increa-
stomach and intestinal motility [33-35].The nanosized drop-
singly investigated for transdermal [18-22], ocular [23],
lets have very high surface to volume ratios which are able
nasal [24, 25], pulmonary [26], vaginal [27, 28], rectal [29,
to efficiently solubilize the drug. The drug is released in a
30] and intravenous drug delivery [31]. more reproducible manner which will become less dependent
This review focuses on recent developments in the field on the GI physiology and the fed/fasted state of the patient.
of microemulsion technology with respect to drug delivery.
Since the drug delivery system should be mild and
The article summarizes the recently introduced patents on
biocompatible, the choice of excipients is, however, limited.
microemulsion systems and explores their potential in the
Also a large amount of surfactant is required for micro-
delivery of poorly soluble drug compounds in particular in emulsion formation which is undesirable. Therefore, proper
addition to their novel applications.
selection of the components and their use concentration is
2. MICROEMULSIONS imperative for a wider acceptability. The field of existence of
microemulsion is generally narrow and their temperature
In 1959, Schulman et al. visualized the existence of small stability, particularly of nonionic surfactant containing
emulsion-like structures by electron microscopy and subse- microemulsions, can be limited.
quently coined the term “microemulsions” [32]. Micro-
emulsions are isotropic, thermodynamically stable trans- 2.1. Structure
parent (or translucent) systems of oil, water and surfactant,
Microemulsions are dynamic systems in which the
frequently in combination with a cosurfactant with a droplet
interface is continuously and spontaneously fluctuating [36].
size usually in the range of 20-200 nm. These homogeneous
Structurally, they are divided into oil-in-water (o/w), water-
systems, which can be prepared over a wide range of
in-oil (w/o) and bicontinuous microemulsions. In w/o micro-
surfactant concentration and oil to water ratio, are all fluids
emulsion, water droplets are dispersed in the continuous oil
of low viscosity. phase while o/w microemulsion is formed when oil droplets
Microemulsions as drug delivery tool show favourable are dispersed in the continuous aqueous phase. In systems
properties like thermodynamic stability (long shelf-life), where the amounts of water and oil are similar, a
easy formation (zero interfacial tension and almost sponta- bicontinuous microemulsion may result. In all three types of
neous formation), optical isotropy, ability to be sterilized by microemulsions, the interface is stabilized by an appropriate
filtration, high surface area (high solubilization capacity) and combination of surfactants and/or co-surfactants. The
very small droplet size. The small droplets also provide mixture of oil, water and surfactants is able to form a wide
better adherence to membranes and transport drug molecules variety of structures and phases depending upon the
in a controlled fashion. Microemulsions are easy to proportions of the components. The flexibility of the
administer to children and to people who have difficulty surfactant film is an important factor in this regard. A
swallowing solid oral dosage forms. The key differences 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 Talegaonkar et al.

Table 1. Comparison of Microemulsion with Conventional Emulsion

S. No Property Microemulsion Emulsion

1 Appearance Transparent (or translucent) Cloudy

2 Optical Isotropy Isotropic Anisotropic

3 Interfacial tension Ultra low High

4 Microstructure Dynamic (interface is continuously and spontaneously fluctuating) Static

5 Droplet size 20-200 nm > 500 nm

6 Stability Thermodynamically stable, long shelf-life Thermodynamically unstable (kinetically stable),


will eventually phase separate

7. Phases Monophasic Biphasic

8 Preparation Facile preparation, relatively lower cost for commercial production Require a large input of energy, higher cost

9 Viscosity Low viscosity with Newtonian behaviour Higher viscosity

bicontinuous structures, and therefore broaden the range of Lipophilic drugs are preferably solubilized in o/w
microemulsion existence. A very rigid surfactant film will microemulsions. The main criterion for selecting the oil
not enable existence of bicontinuous structures which will phase is that the drug should have high solubility in it. This
impede the range of existence. Besides microemulsions, will minimize the volume of the formulation to deliver the
structural examinations can reveal the existence of regular therapeutic dose of the drug in an encapsulated form.
emulsions, anisotropic crystalline hexagonal or cubic phases,
Surfactants
and lamellar structures depending on the ratio of the
components. The surfactant chosen must be able to lower the
The internal structure of a microemulsion vehicle is very interfacial tension to a very small value which facilitates
dispersion process during the preparation of the micro-
important for the diffusivity of the phases, and thereby also
emulsion and provide a flexible film that can readily deform
for the diffusion of a drug in the respective phases.
around the droplets and be of the appropriate lipophilic
Researchers have been trying zealously to understand the
character to provide the correct curvature at the interfacial
complicated phase behaviour and the various microstructures
region. It is generally accepted that low HLB surfactants are
encountered in the microemulsion systems [37].
favoured for the formulation of w/o microemulsion, whereas
2.2. Components of Microemulsion Formulations surfactants with high HLB (>12) are preferred for the
formation of o/w microemulsion. Surfactants having HLB
A large number of oils and surfactants are available
greater than 20 often require the presence of cosurfactants to
which can be used as components of microemulsion systems
reduce their effective HLB to a value within the range
but their toxicity, irritation potential and unclear mechanism
required for microemulsion formation.
of action limit their use. One must choose materials that are
biocompatible, non-toxic, clinically acceptable, and use Cosurfactants
emulsifiers in an appropriate concentration range that will
In most cases, single-chain surfactants alone are unable
result in mild and non-aggressive microemulsions. The
to reduce the o/w interfacial tension sufficiently to enable a
emphasis is, therefore, on the use of generally regarded as
microemulsion to form [39-42]. The presence of cosur-
safe (GRAS) excipients.
factants allows the interfacial film sufficient flexibility to
Oil Phase take up different curvatures required to form microemulsion
over a wide range of composition [38, 43-45]. If a single
The oil component influences curvature by its ability to
surfactant film is desired, the lipophilic chains of the
penetrate and hence swell the tail group region of the
surfactant should be sufficiently short, or contain fluidising
surfactant monolayer. Short chain oils penetrate the tail
groups (e.g. unsaturated bonds). Short to medium chain
group region to a greater extent than long chain alkanes, and
length alcohols (C3-C8) are commonly added as cosur-
hence swell this region to a greater extent, resulting in
factants which further reduce the interfacial tension and
increased negative curvature (and reduced effective HLB) increase the fluidity of the interface.
[38]. Saturated (for example, lauric, myristic and capric acid)
and unsaturated fatty acids (for example, oleic acid, linoleic 2.3. Method of Preparation
acid and linolenic acid) have penetration enhancing property
2.3.1. Phase Titration Method
of their own and they have been studied since a long time.
Fatty acid esters such as ethyl or methyl esters of lauric, Microemulsions are prepared by the spontaneous
myristic and oleic acid have also been employed as the oil emulsification method (phase titration method) and can be
phase. depicted with the help of phase diagrams. Construction of
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 241

phase diagram is a useful approach to study the complex curvature of the surfactant from initially stabilizing a w/o
series of interactions that can occur when different com- microemulsion to an o/w microemulsion at the inversion
ponents are mixed. Microemulsions are formed along with locus. Short-chain surfactants form flexible monolayers at
various association structures (including emulsion, micelles, the o/w interface resulting in a bicontinuous microemulsion
lamellar, hexagonal, cubic, and various gels and oily disper- at the inversion point.
sion) depending on the chemical composition and con-
centration of each component. The understanding of their 2.4. Characterisation
phase equilibria and demarcation of the phase boundaries are The characterization of these systems is highly chal-
essential aspects of the study. lenging due to their small droplet size with fluctuating
As quaternary phase diagram (four component system) is boundaries and complex structure. Basic components in a
time consuming and difficult to interpret, pseudo ternary- physicochemical characterization of microemulsion systems
phase diagram is often constructed to find the different zones are:
including microemulsion zone, in which each corner of the 1. Phase stability and phase behavior,
diagram represents 100% of the particular component Fig.
2. Microstructure, dimension (size and size distribution),
(2). The region can be separated into w/o or o/w micro-
shape and surface features (specific area, charge, and
emulsion by simply considering the composition that is
whether it is oil rich or water rich. Observations should be distribution),
made carefully so that the metastable systems are not inclu- 3. Local molecular arrangements, interactions and
ded. The methodology has been comprehensively discussed dynamics.
by Shafiq-un-Nabi et al. [46].
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
Fig. (2). Pseudoternary phase diagram of oil, water and surfactant investigating the internal physicochemical states of
showing microemulsion region. microemulsions [40, 56, 68-71].
Viscosity measurement can indicate the presence of rod-
2.3.2. Phase Inversion Method like or worm-like reverse micelles while conductivity
Phase inversion of microemulsions occurs upon addition measurement provides a means of determining whether a
of excess of the dispersed phase or in response to tempe- microemulsion is oil-continuous or water-continuous as well
rature. During phase inversion drastic physical changes provide a means of monitoring phase inversion phenomena
occur including changes in particle size that can affect drug [43]. Dielectric measurements are a powerful means of pro-
release both in vivo and in vitro. These methods make use of bing both the structural and dynamic features of micro-
changing the spontaneous curvature of the surfactant. For emulsion systems. Pulsed field gradient NMR is also used
non-ionic surfactants, this can be achieved by changing the extensively to measure self-diffusion coefficients of the
temperature of the system, forcing a transition from an o/w various components and yields information on the mobility
microemulsion at low temperatures to a w/o microemulsion and microenvironment.
at higher temperatures (transitional phase inversion). During 3. MICROEMULSIONS IN DRUG DELIVERY
cooling, the system crosses a point of zero spontaneous
curvature and minimal surface tension, promoting the During the last two decades, microemulsions have been
formation of finely dispersed oil droplets. This method is extensively researched because of their tremendous potential
referred to as phase inversion temperature (PIT) method. in many applications. The role of microemulsions in drug
Instead of the temperature, other parameters such as salt delivery and the patents granted shall be discussed
concentration or pH value may be considered as well instead comprehensively herein.
of the temperature alone. 3.1. Oral Delivery
Additionally, a transition in the spontaneous radius of
The development of the effective oral delivery systems
curvature can be obtained by changing the water volume
has always been the main goal because drug efficacy can be
fraction. By successively adding water into oil, initially severely limited by instability or poor solubility in the
water droplets are formed in a continuous oil phase. Increa-
gastrointestinal fluid. Biopharmaceutical Classification
sing the water volume fraction changes the spontaneous
242 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Talegaonkar et al.

System (BCS) is a useful guidance by US FDA and it takes administration of a commercial product, Taxol® (Bristol
into account contributions of three major factors, dissolution, Myers Squibb) showed approximately 10-fold lower Cmax
solubility, and intestinal permeability, which affect oral drug than that obtained with their composition in rats.
absorption. According to the BCS, drug substances are
Farah et al. in US Patent 6054136 provided a SMEDDS
classified as follows: capable of forming a microemulsion in situ with the
Class I - High Permeability, High Solubility physiological fluid of the stomach and intestine for the
enhancement of drug bioavailability [76]. The SMEDDS
Class II - High Permeability, Low Solubility
consisted of an active constituent, a lipophilic phase, a
Class III - Low Permeability, High Solubility surfactant and a cosurfactant. The lipophilic phase consisted
Class IV - Low Permeability, Low Solubility of a mixture of C8-C18 polyglycolized glycerides having a
HLB of less than 16. Surfactant was chosen from the group
Knowledge of BCS help the formulation scientists to comprising saturated C8-C10 polyglycolized glycerides and
develop a dosage form based on mechanistic, rather than oleic esters of polyglycerol also having an HLB of less than
empirical approaches. Drug substances are considered highly 16 (e.g. Labrasol®, Labrafac CM 10®) and cosurfactant was
soluble when the largest dose of a compound is soluble in chosen from the group comprising lauric esters of propylene
<250 mL of water over a range of pH from 1.0 to 7.5 and glycol (Lauroglycol®), oleic esters of polyglycerol and ethyl
highly permeable when they show >90 percent absorption of diglycol (Transcutol®). The surfactant/cosurfactant ratio was
the administered dose [1, 72]. In contrast, compounds with between 0.5 and 6. The composition being free from aqueous
solubility below 0.1mg/mL provide significant dissolution phase would facilitate packaging in hard gelatin capsules.
related problems, and often, even compounds with solubility The US Patent 6312704 granted to the same inventors was
below 10mg/mL present difficulties related to solubilization the extension of their earlier patent [77]. In that there was an
during formulation. A major technological hurdle for routine additional claim in which it was said that lipophilic phase
clinical use of many drugs is their very poor solubility in was obtained by esterification of polyethylene glycol and
water. glycerol with fatty acids, or by mixing of glycerol esters and
Microemulsions have the potential to enhance the condensates of ethylene oxide with fatty acids. The
solubilization of the poorly soluble drugs and overcome the surfactant was selected from the group consisting of oleic
dissolution related bioavailability problems. This is parti- esters of polyglycerol or a product obtained by esterification
cularly important for the BCS class II or class IV drugs. The of glycerol and polyethylene glycol with caprylic acid and
successful formulation of such drugs is highly dependent on capric acid, or by mixing of glycerol esters and condensates
the performance of the formulated product. Microemulsions of ethylene oxide with caprylic acid and capric acid.
act as super solvent of these drugs and can be optimized to The use of rapamycin (macrolide antibiotic) and its
ensure consistent bioavailability. In addition, they can be structurally similar analogs are limited by their very low
used for the delivery of hydrophilic drugs including solubility, low and variable bioavailability and their high
macromolecules such as proteins and peptides. This is due to toxicity. They have potent immunosuppressive activity and
the existence of polar, nonpolar and interfacial domains also antitumor and antifungal activity. Fricker et al. taught a
which allow encapsulation of drugs with varying solubility. microemulsion preconcentrate carrier medium for their
Moreover, these systems have been reported to protect the effective oral delivery [78]. The carrier medium comprised a
incorporated drugs against oxidation, enzymatic degradation reaction product of a castor oil and ethylene oxide; a
[73] and enhance the membrane permeability [74]. Presently, transesterification product of a vegetable oil and glycerol
Sandimmune Neoral® (Cyclosporine A), Fortovase® comprising predominantly linoleic acid or oleic acid, mono-,
(Saquinavir), Norvir® (Ritonavir), etc. are the commercially di-, and triglycerides or a polyoxyalkylated vegetable oil; 1,2
available SMEDDS formulations. -propylene glycol; and ethanol. When administered orally
A detailed illustration of their role in oral drug delivery is high and consistent absorption was obtained. Therefore, the
discussed in this section. macrolide might be administered in lower doses, which
might alleviate toxicity problems. Earlier they had described
3.1.1. Bioavailability Enhancement of Poorly Water a microemulsion preconcentrate for their delivery com-
Soluble Drugs prising hydrophilic component (Transcutol®, Glycofurol,
Paclitaxel, an anticancer drug, has poor aqueous solu- 1,2-propylene glycol, or their mixtures), a lipophilic
bility and therefore, formulation of paclitaxel has proven to component selected from the group consisting of fatty acid
be difficult. Gao et al. disclosed self emulsifying compo- triglycerides (Miglyol®, Captex®, Capmul®, etc.), mixed
sitions that generated a supersaturated paclitaxel micro- mono-, di-,and tri-glycerides and transesterified ethoxylated
emulsion upon contact with water in vivo that permitted its vegetable oils (e.g. Maisine®), and a surfactant which was
rapid and efficient absorption resulting in improved oral selected from the group consisting of polyethyleneglycol,
bioavailability [75]. The composition comprised of a solvent, natural or hydrogenated castor oils (Cremophor EL®, Cre-
a surfactant, a substituted cellulosic polymer (e.g. hydroxy- mophor RH40®), polyethylene-sorbitan fatty acid esters
propyl methyl cellulose, hydroxypropyl cellulose, hydroxy- (Tweens), polyoxyethylene fatty acid esters (Myrj),
ethyl cellulose, methyl cellulose, etc.), and optionally a P- polyoxyethylene-polyoxypropylene co-polymers, and block
glycoprotein inhibitor. Paclitaxel and surfactant were present co-polymers (Pluronic, Polaxamers) [79]. The composition
in a ratio of from about 1:3 to about 1:20 by weight; and the on dilution with water gave a microemulsion having an
substituted cellulosic polymer and paclitaxel were present in average particle size of <150 nm.
a ratio of from about 50:1 to about 0.1:1 by weight. The oral
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 243

Liang et al. disclosed self-emulsifying formulations of improved the systemic bioavailability of the active molecule.
fenofibrate or fenofibrate derivatives having an improved The self micro-emulsfying carrier included a lipophilic
oral bioavailability and/or reduced food effect when phase, which was a mixture of glycerol mono-, di- and
compared to commercial available formulations such as triesters and of PEG mono- and diesters with at least one
Lipanthyl® (Groupe Fournier) or TriCor®. (Abbott Labo- fatty acid chosen from the group comprising C8 - C18 fatty
ratories) [80].The particle size of the active agent was not acids (LabrafilM1944CS®), a surfactant phase which is a
critical to the bioavailability of the product. Fenofibrate or mixture of glycerol mono-, di- and triesters and of PEG
fenofibrate derivative was dissolved in a solubilizer that mono- and diesters with caprylic acid (C8) and capric acid
allowed the complete dissolution of the fenofibrate or a (C10) (Capryol 90®), a co-surfactant phase which was an
fenofibrate derivative and prevented or minimized the ester of a polyvalent alcohol with at least one fatty acid
crystallization of fibrate in the formulation. With the chosen from the group comprising caprylic esters of
complete dissolution of the fibrate, the fibrate solution propylene glycol, lauric esters of propylene glycol and oleic
allowed for an increase in absorption of the fibrate by the esters of polyglycerol. The ratio of surfactant/cosurfactant
patient. Some of the earlier strategies for increasing the varied between 0.2 and 6.
bioavailabilty included the use of micronized fenofibrate
The object of the invention of von Corswant was to
[81-84], use of diethylene glycol monoethyl ether as
provide a vehicle which increased the solubility of
solubilizer [85], etc. compounds having a low solubility in water and at the same
Bioavailability for orally administered conventional time being non-toxic [90]. In that direction he presented a
crystalline or amorphous forms of cholesterol ester transfer non-toxic o/w or bicontinous microemulsion which was
protein (CETP) inhibitors is quite low, often having absolute comprised of a polar phase comprising water and a
bioavailabilities of less than 1%. Gumkowski et al. provided component for adjusting the polarity of the polar phase, a
self-emulsifying or self-microemulsifying compositions for surfactant film modifier which is a monohydric alcohol with
the improved solubility and bioavailability of CETP inhi- 2-3 carbon atoms (e.g. ethanol), a non-polar phase comp-
bitors [86]. The formulation had a CETP inhibitor, a cosol- rising oil, and a mixture of a hydrophilic surfactant and a
vent, a surfactant having an HLB of 1 to 8, a surfactant hydrophobic surfactant which was selected from the group
having an HLB of over 8 to 20, and optionally a digestible consisting of lecithin, sphingolipids and galacto lipids. The
oil. inventors had found that by using at least two types of
Lambert et al. provided a composition which could be a modifiers for adjusting the polarity it was possible to
minimize the amount of the surfactant and thus, also the
emulsion or a microemulsion having oil and a water phase
toxicity was minimized.
for improving the solubility of poorly soluble drugs [87].
Chemotherapeutic agent could be a taxoid, a taxane, or a Chen et al. described a microemulsion of pyranone
taxine, preferably paclitaxel. Alpha-tocopherol or a toco- protease inhibitor compounds that was free of alcohol and
pherol polyethylene glycol succinate was also incorporated propylene glycol comprising a pyranone protease inhibitor,
in the oil phase. The resulting formulation was inexpensive, surfactant, and a polyethylene glycol solvent having a mean
sterilizable by either heat or filtration, stable for at least a molecular weight of greater than 300 but lower than 600, and
year and accommodated a wide variety of water insoluble a lipophilic component comprising medium chain mono- and
and poorly soluble drugs and was ethanol-free. Non-aqueous di-glycerides, and optionally a basic amine [91]. The
solvents and solubilizers such as alcohol used in pharma- formulations of this invention provided for improved
ceutical formulations may extract toxic substances, for solubilization, stability and/or bioavailability of the pyranone
example plasticizers, from their containers. This may cause drug and permit less arduous manufacturing processes to be
adverse reactions such as respiratory distress. This problem undertaken in the fill process and allow the capsules to be
could be circumvented by their invention. The US Patent stored at room temperature.
6660286 described a similar composition which in addition
Gao et al. provided pharmaceutical compositions in a
claimed a composition consisting of paclitaxel, one or more
self-emulsifying formulation which permitted a high loading
tocopherols or their derivatives, a tocopherol polyethylene of lipophilic compounds (up to about 400 mg/g) in addition
glycol derivative, polyethylene glycol, a polyoxypropylene-
to good oral bioavailability [92]. The novel composition
polyoxyethylene glycol nonionic block polymer, and an
comprised a lipophilic drug , a mixture of diglyceride and
aqueous phase [88].
monoglyceride in a ratio of from about 9:1 to about 6:4 by
Benameur et al. have found that the incorporation of an weight wherein the diglyceride and monoglyceride are
active agent, particularly statins, into a self-micro- mono- or di- unsaturated fatty acid esters of glycerol having
emulsifying system made it possible to reduce the first sixteen to twenty-two carbon chain length, solvent and
intestinal passage effect, and thus improve the systemic surfactant. The composition might be in the form of liquid
bioavailability of the active molecule [89]. Earlier SMEDDS for soft elastic capsules or hard gelatin capsules for oral
had been reported to improve the solubility of the water- application and might also be in the form of a liquid solution
insoluble active principles but there was no knowledge on for oral, parenteral, rectal or topical application. In their
the action of SMEDDS on intestinal metabolism. The earlier patent they had mentioned the use of pyranone
inventors had found surprisingly that the incorporation of an compound as the active agent [93]. They also provided a
active principle (statins) with a strong first intestinal passage formulation for pyranone compounds which was based on
effect into a self-microemulsifying system made it possible the use of a particular amount (0.1% to about 10% by
to reduce the first intestinal passage effect, and thus
244 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Talegaonkar et al.

weight) of the basic amine along with solvents, surfactants intestine could be circumvented. Further, the work of Rudnic
and oil [94]. et al. described a pharmaceutical preparation comprising a
stable, surface-active emulsion or dispersion of a
The invention of Bauer et al. included o/w micro-
pharmaceutical agent incorporated into an emulsion having a
emulsion containing one polyglycerol ester as the emulsifier
and lipophilic substance as the internal phase [95]. The hydrophobic discontinuous phase of a long chain carboxylic
acid (e.g. lauric acid, capric acid, myristic acid, behenic acid,
emulsifier contained a triglycerol monofatty acid ester (e.g.
etc.) or ester (glyceryl monostearate, glyceryl monopal-
triglycerol monolaurate, triglycerol monocaprylate) and the
mitate, etc.) or alcohol thereof dispersed in an aqueous phase
lipophilic substance was selected from the group consisting
or having a hydrophilic discontinuous phase dispersed in a
of carotenoids, vitamins A, D, E and K and their derivatives
hydrophobic phase of a long chain carboxylic acid or alcohol
and polyunsaturated fatty acids. The emulsifiers used were
non-toxic and such microemulsions could also be used in thereof [100]. The materials when combined in accordance
with the invention to form a w/o microemulsion gave
foodstuffs in addition to the pharmaceutical field.
enhanced absorption capabilities.
Mishra et al. described self-emulsifying microemulsion
Melatonin is a hormone synthesized in the epiphysis, in
or emulsion preconcentrate formulations containing omega-3
the retina and, presumably in the chromaffinic cells of the
fatty acid oil and a hydrophobic drug [96]. The drug was
soluble in the omega-3 fatty acid oil and the preconcentrates intestinal tract. It has immunostimulant and immuno-
modulatory effects. An attempt had been made by Graziella
were free of or contain only minor amounts of a hydrophilic
et al. to improve the oral bioavailability of melatonin [101].
solvent system. US Patent 4678808 described the use of
They described a microemulsion containing melatonin, L-
these oils to treat disorders associated with arachidonic acid
alpha-phosphatidylcholine (emulsifier) and a solvent mixture
metabolites, including autoimmune syndromes, acute and
consisting of ethanol, propylene glycol and water in which
chronic inflammatory diseases, atherosclerosis, etc. [97]. The
omega-3 fatty acid oil and drug can exert an additive or the weight ratio of L-alpha-phosphatidylcholine to melatonin
was about 1:1.
synergistic therapeutic effect or the omega-3 fatty acid oil
counteracts the negative side effects of the therapeutic agent. Eugster et al. taught in their invention a spontaneously
For example, cyclosporines are soluble in omega-3 fatty acid dispersible concentrate which formed an ultramicroemulsion
oil and capable of exerting an additive or synergistic when diluted with water or a glucose solution [102]. The
therapeutic effect in various autoimmune and inflammatory concentrate contained sterolester and/or sterolphosphor
diseases. In addition, the omega-3 fatty acid oil mediated the compounds, surfactant, vitamin or provitamin, free fatty acid
adverse side effects, such as nephrotoxicity, of a cyclos- and a carrier or diluent. They had found that the newly syn-
porine such as cyclosporine A by reduction of its dose. The thetised sterolesters and sterolphosphatides had a pronoun-
composition could be administered in soft or hard gelatin ced antitumour activity, particularly if these compounds
capsule. were being incorporated into spontaneously dispersible
Crison et al. taught a self-microemulsifying formulation concentrates.
for increasing the bioavailability of a drug which included Ecanow proposed drug delivery systems which included
oil/ lipid material, a surfactant, and a hydrophilic co-surfac- one or more monomeric or polymerized surface active agents
tant [98]. HLB of hydrophilic co-surfactant was greater than (e.g. polymerized lecithin) which allowed for rapid
8. The self-microemulsifying formulation could also include dissolution and smooth liberation of the incorporated drug
the addition of an aqueous solvent such as triacetin. They [103]. Stable microemulsions could be produced by encasing
had found that a more hydrophilic co-surfactant not only the microemulsions in a coacervate phase matrix and/or film.
increased the dissolution of poorly water-soluble drugs but,
Table 2 shows the utilization of the microemulsion
that it also increased their in vivo bioavailability.
technology to improve the solubility and bioavailability of
Orally administered acyclovir (in tablet, capsule or some of the poorly water soluble drugs.
suspension form) is slowly and erratically absorbed with 15- 3.1.2. Controlled and Sustained Release of Drugs
30% bioavailability. For improved patient compliance an
acyclovir preparation is required which would permit lower US Patent 7147867 disclosed a sustained-release dosage
dosing and less frequent administration. In one embodiment form for the delivery of a progestogenic steroid comprising
of their invention Burnside et al. provided a pharmaceutical of a capsule, a self-emulsifying drug formulation contained
preparation comprising a w/o emulsion, preferably a within a first portion of the capsule, an expandable layer
microemulsion, containing an oil phase (such as a long chain contained within a second portion of the capsule [104]. The
carboxylic acid or ester or alcohol thereof), a surfactant expandable layer was so positioned that the self-emulsifying
(such as poloxamer) and an aqueous phase containing the drug formulation could be expelled from the capsule upon
drug acyclovir [99]. It was found that microemulsions were expansion of the expandable layer and a semipermeable
ideal for oral acyclovir delivery since they contain membrane is formed over at least a portion of an outer
homogeneous and uniform droplet size of approximately 20- surface of the capsule Fig. (3). The semipermeable mem-
40 nm and had the ability to dissolve relatively large brane comprised of a thermoplastic polymer composition
amounts of polar solutes in an overall oily environment. The having a softening point of 40- 180oC. The aqueous fluid
outer oily phase of the microemulsion was able to dissolved the gelatin capsule and the imbibed fluid caused
incorporate into the intestinal cell matrix, thus creating the push-displacement layer to expand and push the
channels (either paracellularly or transcellularly) through emulsified formulation through an orifice at a controlled
which the acyclovir could pass. Thus, malabsorption in the 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, blended, liquid mixture consisting essentially of a drug, a
improved bioavailability, sustained release and inhibition of surfactant, and a member selected from the group consisting
crystal growth during storage thereby providing improved of a mono- and di-glyceride to provide a liquid self-emul-
stability. sifying drug formulation, (e) adding the drug formulation
formed in step (d) to a capsule, (f) adding the sprayed
Gattefosse had been assigned a patent for a composition
composition of step (c) to the capsule, (g) coating the
with sustained release of active agent which was capable of
capsule with a semipermeable composition to provide a
forming a microemulsion with an external hydrophilic phase,
for example physiological fluid or water [105]. The membrane permeable to an aqueous fluid and providing an
exit in the membrane for delivering the drug formulation at a
composition comprised of an inert polymeric matrix which
sustained-release and controlled rate over an extended period
couldn’t be ionised at physiological pH, dispersed in the
of time.
microemulsion forming system. After ingestion, polymeric
matrix on contacting the physiological fluid formed a gelled 3.1.3. Manufacturing Improvements
polymeric matrix. The gelled barrier controlled the pene-
tration of water from the outside inwards, making possible SMEDDS based formulations require filling into soft or
hard gelatin capsules. Some of the problems encountered in
the gradual release of the microemulsified active principle by
the processing of liquid SMEDDS include leaching and
diffusion, in a continuous and prolonged manner. Figure (4).
leakage of the formulation, interaction with capsule shell
shows the functioning of the polymer matrix dispersed in a
components and handling difficulties for the manufacturers.
SMEDDS formulation, the composition obtained being in
It is therefore of interest to incorporate the self micro-
the form of gel capsule.
emulsifying vehicles into a powder to produce solid dosage
ALZA Corporation had been assigned a patent for a forms which may provide an attractive alternative to filled-
sustained release self emulsifying formulation to enhance the capsule preparations. The proper excipients selection,
solubility, the dissolution, and the bioavailability of the drug however, is crucial when formulating dry adsorbed solid
[106]. The formulation process involved the following steps: formulations. A comprehensive review on these systems
(a) blending an osmotic hydrogel and an osmotically focusing on formulation considerations, selection and func-
effective solute, (b) blending a hydroxyalkylcellulose and tion of solidifying excipients and techniques of preparation
water to provide a granulation solution, (c) spraying the has been published recently [107].
granulation solution of step (b) onto the composition
provided in step (a) to provide granules, (d) forming a
246 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 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
Fig. (3). Dosage form comprising a capsule made of two parts handling problems to the manufacturers. Capsules leakage is
consisting of a body portion and a cap portion in which capsule a common problem. Presentation of microemulsions in a
contains a drug microemulsion formulation and an expandable solid dosage form provided a more robust, stable dosage that
composition. 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.
Fig. (4). Functioning of the polymer matrix dispersed in a One preferred embodiment of the invention of Burnside
SMEDDS formulation. et al. comprised of a microemulsion containing an oil phase
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 247

(such as a long chain carboxylic acid or ester or alcohol tant enhanced the uptake of the active material upon
thereof), a surface active agent (such as a poloxamer) and an administration [114].
aqueous phase containing the insulin [111]. They had
Desai described a microemulsion formulation for oral
attempted to increase the intestinal absorption of the
administration, in which a liquid polyol solvent (propylene
hormone which had met with only limited success earlier. glycol or polyethylene glycol) and lipid cosolvent containing
The hydrophobic material formed the continuous phase and
a proteinaceous medicament, e.g., insulin formed a micro-
the hydrophilic material formed the discontinuous phase in
emulsion in the gastrointestinal tract at sites of absorption
which the hydrophilic material was emulsified (w/o). A large
i.e. villi of the intestinal tract [115]. A vital ingredient in the
amount of polar solutes could be dissolved in an overall oily
formulation was the protease inhibitor which inhibited or
environment by using w/o microemulsion thereby creating
prevented the degradation of the proteinaceous material.
an oral delivery system for oral delivery of insulin. Earlier preparations contained ethanol which might cause
Cho et al. taught in US Patent 5656289 that oral pro- protein denaturation.
teinaceous compositions comprising w/o microemulsions
Poli et al. presented compositions in the form of
could form chylomicra or provide chylomicra to sites of
microemulsions or liposomic dispersions for the transmu-
absorption in the gastrointestinal tract [29]. It is believed that
cosal administration of therapeutic proteins or peptidic
when a biologically active material is administered in asso- substances [116]. They contained in addition a thermosetting
ciation with chylomicra or the constituents of chylomicra, it
agent (Pluronic F127®) which differentiated them from the
is targeted to the villae and microvillae of the intestinal wall,
known liposomic or microemulsified compositions. The
from where it is secreted into the lacteals and intestinal
composition had a low viscosity at room temperature which
lymph and then drained into the thoracic duct and, ulti-
helped in the distribution of finely absorbed divided product
mately, the circulating bloodstream. Therefore, proteina-
on a larger surface and the viscosity increased on reaching
ceous active agents administrable only parenterally can be the mucous as a result of structural change took place as a
given by the more preferred oral or rectal route. Formu-
function of the body temperature.
lations of the invention were suitable for the oral
administration of insulin in the treatment of diabetes. w/o Ekwuribe et al. prepared hydrophilic and lipophilic
formulation for proteinaceous compounds comprised of a balanced microemulsion formulations of free-form and/or
hydrophilic phase dispersed in a lipophilic phase to form an conjugation-stabilized therapeutic agents such as insulin
emulsion/microemulsion wherein hydrophilic phase [117]. Microemulsion described was w/o type and had a
comprises water, a biologically active substance and lecithin HLB value between 3 and 7. In one particular aspect, the
or a lecithin precursor comprising a phospholipid, and lipo- composition comprised insulin covalently coupled with a
philic phase comprises oil, a phospholipid and a lipophilic polymer, a linear polyalkylene glycol moiety and a lipophilic
surfactant [30]. Lecithin can integrate into chylomicra, moiety, wherein the insulin, the linear polyalkylene glycol
particularly into their membranes and ultimately carries the moiety and the lipophilic moiety are conformationally
protein with it into general circulation. arranged in relation to one another such that the insulin in
the composition had an enhanced in vivo resistance to
The invention of Cho et al. provided pro-micelle
enzymatic degradation, relative to insulin alone. HLB value
compositions (microemulsion or liposome) comprising a
of less than 7 provided a stable formulation for incorporating
pharmaceutically active agent encapsulated with a membrane
free form insulin and/or insulin conjugates suitable for oral
of esterified C12 -C18 fatty acids wherein the concentration of
administration. The microemulsion compositions could also
fatty acid is less than 15 weight % [112]. In the intestine, be employed for non-therapeutic purposes, e.g., diagnostic.
exposure to C12 -C18 fatty acids resulted in conversion of the
pro-micelle to a stable micelle that effectively delivered the 3.1.4.1. Cyclosporine Delivery
pharmaceutically active agent to the systemic circulation.
Cyclosporine delivery has remained a challenge for the
The membrane could be further encapsulated with a film
formulation scientists. It is an immunosuppressive agent and
coating or an enteric coating to provide a minicapsule. They
is widely used in recipients of organ transplants and in
could be used to deliver acid labile molecules such as insulin various autoimmune diseases. It exerts potent immuno-
and other peptides by oral route and drugs showing
suppressive activity by inhibiting the growth and
inadequate oral absorption.
differentiation of T cells. The inherent insolubility of the
Owen et al. provided a highly stable w/o microemulsion cyclosporine provides the major hurdle for the low and
which readily converted to an o/w emulsion by the addition variable bioavailability and there is variability in inter- and
of aqueous fluid [113]. Proteins and peptides could be stored intra-patient dose response and low formulation stability
for long periods of time at room temperature and above by during storage. It is, therefore, necessary to monitor
using the w/o microemulsion. When required for use blood/blood-serum levels of patients receiving cyclosporine
aqueous fluid was added which converted the microemulsion therapy at regular and frequent intervals which is time
to an o/w emulsion and released the protein. US Patent consuming and inconvenient and adds to the overall cost of
5688761 described the extension of the above mentioned therapy. Due to poor bioavailability, higher doses may be
work in which the same assignee (LDS Technologies, Inc) needed which may result in undesirable adverse side effects
had included high purity short chain monoglyceride such as nephrotoxicity and renal side effects which can be
surfactant as the preferred low HLB surfactant after finding troublesome and may lead to an ineffective therapy. On
that the use of C9-13 monoglycerides as the low HLB surfac- 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 Talegaonkar et al.

systems for cyclosporine which can provide a suitable concentrate composition comprising a cyclosporine, 1,2-
uniform dosage and appropriate bioavailability. propylene glycol, a mixed mono-, di-, tri-glyceride and a
hydrophilic surfactant [121]. They claimed a trans-
Initially, cyclosporine was commercially available as a
esterification product of corn oil and glycerol (Maisine® )
cyclosporine drink solution which provided an average
absolute bioavailability of 30% only, with marked variation. comprising a) a free glycerol content of less than 10%, b)
less than 1% of palmitic acid and stearic acid mono-, di- and
The commercial product that had been sold under the name
tri-glycerides; and c) 85% or more of linoleic acid and oleic
Sandimmune® (Sandoz Ltd.) was made according to US
acid mono-, di- and tri-glycerides all parts by weight which
Patent 4388307 [118]. The Sandimmune formulation con-
they didn’t claim in their previous patent [122]. Further
tained cyclosporine in olive oil with the surfactant Labrafil
earlier the same assignee claimed an o/w microemulsion and
and ethanol. However, the resulting liquid formulation was
administered as an aqueous dilution (solution or emulsion) microemulsion concentrate for the delivery of Cyclosporine
A [123, 124]. The microemulsion had a particle size of less
which was not convenient for the subject and might provide
than 2000Aº while the microemulsion concentrate upon
a non-uniform dosage for oral administration. In Sandi-
dilution with water spontaneously formed microemulsion
mmun® soft capsule a large amount of ethanol was used as a
which also had a particle size of less than 2000 Aº.
cosurfactant in order to solubilize the cyclosporine. How-
ever, since ethanol permeates the gelatin shell of the capsule Novartis AG in US Patent 5866159 described a micro-
and is volatile, its content may greatly vary during storage emulsion pre-concentrate of cyclosporin A comprising a
and may in turn result in crystallization of the cyclosporine hydrophilic component, triglyceride lipophilic component
which may lead to variation in the bioavailability. Sandoz and polyoxyethylene glycolated natural or hydrogenated
Ltd. introduced an improved formulation later under the vegetable oil surfactant (Cremophor RH40®, Cremophor
trademark Neoral® according to the composition disclosed in RH60®, Cremophor EL®, etc.) [125].The composition upon
US Patent 5342625 [119]. The Neoral formulation was a dilution to 5 parts by weight of water spontaneously formed
microemulsion pre-concentrate which contained cyclos- an o/w microemulsion having average particle size of less
porine in an anhydrous oily vehicle, medium chain trigly- than about 200 nm. Use of alkanols, e.g. ethanol, as hydro-
cerides, surfactants, glycerol and alcohol which exhibited philic phase was less preferred. In an especially preferred
better and more consistent bioavailability. The preparation embodiment the hydrophilic phase of compositions would
showed that cyclosporin bioavailability was almost not consist of Transcutol, Glycofurol and/or 1,2-propylene
affected by food, bile secretion, etc. Therefore, frequent glycol. Effective cyclosporin dosaging with concomitant
monitoring of the plasma level of patient was not needed, enhancement of resorption/bioavailability levels, as well as
and hence was a remarkable improvement. reduced variability in resorption/bioavailability levels could
be achieved both for individual patients receiving
A recent patent assigned to Novartis AG was concerned
cyclosporin therapy as well as between individuals.
with the delivery of cyclosporines (excluding cyclosporine
A) [120]. It included microemulsions and microemulsion Novartis AG in US Patent 7205279 described a micro-
pre-concentrate composition comprising of a hydrophilic emulsion pre-concentrate comprising a hydrophilic phase
component, lipophilic component containing cyclosporine which comprises dimethylisosorbide and/or a lower alkyl
and hydrophilic surfactant. The hydrophilic phase comprised alkanoic ester, a lipophilic phase, and a surfactant for the
of C1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low delivery of cyclosporine and lactam macrolide [126]. The
molecular weight mono- or poly-oxy-alkanediol (e.g. composition could also be in the form of microemulsion. The
Transcutol® , Glycofurol®); or 1,2-propyleneglycol. The compositions provided good bioavailability and reduce
composition upon dilution with adequate water sponta- variability in inter- and intra-patient dose response.
neously produced an o/w microemulsion having an average
Novartis AG had been granted a patent which described a
particle size of less than about 0.15 microns. The compo-
cyclosporine containing composition in the form of a capsule
sitions permitted the preparation of solid, semi-solid and
comprising a polyoxyethylene sorbitan fatty acid ester, a
liquid preparations containing a cyclosporine in sufficiently
reaction product of a natural or hydrogenated castor oil and
high concentration which allowed convenient oral ethylene oxide, a sorbitan fatty acid ester, and ethanol [127].
administration while at the same time achieving improved
efficacy., e.g. in terms of bioavailability characteristics and Mulye described an approach to deliver cyclosporine in a
there was reduced intra and inter individual variability. The carrier comprising a fatty acid solubilizer having 6-22 carbon
compositions were non-alkanol based, e.g. which may be atoms and a non-ionic surfactant (HLB value greater than
free or substantially free of ethanol. Earlier ethanol based 10) which form an emulsion (emulsion or microemulsion) on
formulations presented a number of problems. Evaporation exposure to water [128]. The inventor had suprisingly found
of the ethanol, e.g. from capsules or from other forms, e.g. that the use of a carrier system comprising a non-ionic
when opened, resulted in the development of a cyclosporine surfactant in conjunction with a cyclosporin solubilizing
precipitate. Encapsulation of cyclosporine in soft gelatin agent consisting of C6-C22 fatty acids overcame the problems
encapsulated form necessitated packaging in an air-tight of limited solubility and resulting bioavailability associated
compartment, for example an air-tight blister or aluminium- with cyclosporin.
foil blister-package. This in turn rendered the product both Bhalani and Patel described a polar lipid self-emulsifying
bulky and more expensive to produce. Their compositions drug delivery system (PLSEDDS) of cyclosporine which
eliminated or reduced the packaging difficulties which were instantly forms a fine emulsion when brought into contact
encountered with alkanolic compositions. In their earlier with an aqueous medium [129]. The composition consisted
patent, the assignee had described a microemulsion pre-
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 249

of cyclosporine dissolved in a polar lipid, such as a medium diluted in an aqueous media to form a spontaneous emulsion.
chain monoglyceride of C6-C12 fatty acids having a Polyoxyethylene glycerol trioleate was used as a surfactant
monoglyceride content of at least 50% and a surfactant. They which is non-toxic and well tolerated physiologically. The
had found that medium chain monoglyceride as a component formulation provided a self-emulsifying delivery system in
prevented crystallization of cyclosporine under storage which the droplets are preferably from 50 to 150 nm and
conditions and cyclosporine A exhibited superior self- higher bioavailability was achieved.
emulsification ability when dissolved in certain polar lipids
Meinzer et al. provided oil-free pharmaceutical
as mentioned above. The encapsulated dosage form of this
compositions containing cyclosporinA [135]. A hard gelatin
composition did not require a hydrophilic component (like
capsule dosage form containing cyclosporin A in a mixture
ethanol, propylene glycol, or polyethylene glycol) which
with a surfactant of HLB value of at least 10 and hydrophilic
require specialized packaging, such as aluminum foil blister. phase being a polyethylene glycol and/or a lower alkanol
Formulation could be inexpensively packaged such as in
provided that any lower alkanol, if present, is less than 12%
glass or OHD polyethylene bottles. The same inventors in
of the total weight of the composition excluding the hard
their next patent provided PLSEDDS of lipophilic drugs in
gelatin capsule weight. Their earlier patent was similar
addition to cyclosporine dissolved in a polar lipid as men-
except in that they had specifically claimed a poly-
tioned earlier and containing surfactants and triglycerides
ethyloxylated castor oil having an HLB value of at least 10
[130]. instead of a surfactant of HLB value of at least 10 [136].
Naicker et al. provided microemulsion or microemulsion They found that the compositions were compatible with
preconcentrate of cyclosporine analogs that are structurally tenside materials, e.g. bile salts, present in the gastro-
similar to cyclosporine A consisting of Vitamin E TPGS intestinal tract and were fully dispersible in aqueous systems
(Vitamin E-alpha-tocopheryl polyethylene glycol 1000 comprising such natural tensides and are capable of
succinate), medium chain triglyceride oil, an emulsifier and providing microemulsion systems in situ which were stable
ethanol [131]. The formulations provided superior drug and do not exhibit precipitation.
bioavailability and reduced adverse effects.
Stuchlik et al. described cyclosporine compositions in
Chakravorty et al. described a self emulsifiable formu- which the concentration of cyclosporine was higher than
lation consisting of cyclosporine, hydrophilic agent, 10% and provided high bioavailability [137]. Polar solvents
lipophilic agent, surfactants, antioxidant and preservative had been omitted in the compositions which might cause
[132]. Lipophilic system consisted of a medium chain compatibility problems with the capsule shell. The carrier
triglyceride of caprylic acid and capric acid. Labrasol served was composed of partial esters of C16-22 fatty acids with a
as a surfactant, which was combined with other selected glycerol derivative selected from diglycerol to decaglycerol
surfactants, like cremophor RH 40 and/or polysorbate 80. and partial esters of C8-16 fatty acids with pentaglycerol to
The formulation was filled in a soft-gelatin shell capable of pentadecaglycerol in mutual weight ratios of 1:1.
rupturing in less than 12 minutes to provide quick release of Singh et al. taught in US Patent 6187747 substantially
the formulation in the upper part of the gastrointestinal tract.
alcohol free composition of cyclosporine which comprised a
Domb provided a dispersible concentrate for the adminis- cyclosporine in a hydrophilic carrier medium comprising
tration of a cyclosporine which included a hydrophilic propylene glycol, esters of propylene glycol with C4 to C12
solvent comprising a lower alkyl ester of hydroxyalkanoic fatty acids and polyoxyethylene hydrogenated castor oils
acid or a lower alkyl ester of N-alkyl pyrrolidone and [138]. On dilution with the gastrointestinal fluids the
surfactant [133]. Surfactant was preferably a combination of hydrophilic end of the surfactant and the cosurfactant were
a surfactant with high HLB of at least about 8 and a oriented towards hydrophilic environment of gastrointestinal
surfactant with low HLB of less than about 5. The charac- fluid and the drug molecules were entrapped in the
teristic feature of the concentrate was that it formed, upon hydrophobic portions of the surfactant micelles. The drug
contact with an aqueous solution, particles of a size of less was released leading to improved absorption, thus providing
than about 100 nm. Other ingredients were optional, such as an increased and less variable bioavailibility. In their later
a fatty acid ester such as tricaprin, a phospholipid, and an patent they have broadened the claim by extending the
ethoxylated fat such as cremophor. The ethoxylated fat could percentage range of propylene glycol, esters of propylene
be optionally substituted for the surfactant. Their formu- glycol and polyoxyethylene hydrogenated castor oils [139].
lations did not require stabilizers, such as anti-oxidants, for
Hong et al. taught a solid-state microemulsion of cyclos-
good stability. They hypothesized that the excellent stability
porin prepared by dispersing of cyclosporin microemulsion
compared to some of the earlier formulations was due to the in enteric carrier [140]. The carrier prevented the release of
use of hydrophilic solvents such as ethyl lactate. Ethyl
cyclosporin in the acidic condition, while allowing a rapid
lactate is miscible in both organic and inorganic solvents,
release in the upper part of the small intestine thereby
since it is more hydrophobic than ethanol and has higher
forming the microemulsion. The composition could maintain
storage stability than ethanol owing to latter’s high volatility.
the plasma therapeutic level of cyclosporine for about 1 day
Egbaria et al. taught a pharmaceutical composition by only once daily dosing.
comprising a spontaneous emulsion of cyclosporine, ethanol,
Hong et al. developed a cyclosporine containing micro-
polyoxyethylene glycerol trioleate, and an oil component
emulsion preconcentrate, which comprised lipophilic
[134]. A method for their preparation involved dissolving
solvent, surfactant and oil [141]. Lipophilic solvent was
cyclosporine in ethanol. Then polyoxyethylene glycerol
typically comprised of alkyl ester of polycarboxylic acid
trioleate and an oil component were added, mixed and
250 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Talegaonkar et al.

(e.g. triethyl citrate, tributyl citrate) and/or carboxylic acid does not have any toxicity problem of the solvent in
ester of polyols (e.g. triacetin). They reported that using comparison to the soft capsule using ethanol, transcutol,
lipophilic solvent was advantageous instead of hydrophilic propylene glycol, glycofurol, dimethylisosorbide, etc., in the
solvent which causes pharmaceutical instability and can prior compositions. The composition could be dissolved in
overcome the various problems of the prior formulations. an external phase such as water, artificial gastric juice and
Lipophilic solvents used in the invention were odorless and intestinal juice, etc. to form a self-emulsion with mild
colorless oils in liquid state, and had high boiling point of stirring and therefore, by appropriately adjusting the
more than 250°C. They did not volatilize at the condition of constitutional ratio of each component the diameter of
high temperature during the procedure for soft capsule particles in the inner phase of the emulsion formed could be
preparation as well as during storage at room temperature, controlled to 100 nm or less. The composition was suggested
and therefore, could ensure the stability of preparation to be formulated into the oral preparations such as soft
comprising them. Moreover, they did not show such severe capsules, hard capsules sealed with gelatin bending at the
hygroscopic property as glycols showed, did not dissolve the conjugated portion, oral liquid preparations, etc.
gelatin shell, and did not induce the compositional change
The invention of Woo was concerned with a micro-
due to non-volatility and non-permeability for gelatin shell.
emulsion concentrate containing cyclosporine as an active
Sherman described pharmaceutical compositions in the ingredient, dimethylisosorbide as a cosurfactant, oil and a
form of an emulsion preconcentrate or microemulsion surfactant where cyclosporine, dimethyl isosorbide, oil and
preconcentrate comprising cyclosporine, acetylated mono- surfactant were present in the ratio of 1:1-5:1-5:2-10 by
glyceride (Myvacet®) as lipophilic solvent, a surfactant, and weight [146]. The composition was suitable for the
optionally a hydrophilic solvent [142]. In comparison to formulation of a soft capsule for oral administration. Since
other ingredients used as lipophilic solvent in some of the dimethylisosorbide has no membrane permeation property,
previous formulations, they found that acetylated mono- the soft capsule preparation was stable in comparison with
glycerides offered various advantages such as low cost, good the soft capsules containing ethanol, propylene glycol,
solvent properties for cyclosporines, thus reducing the transcutol, glycofurol, etc., as a cosurfactant in the prior dis-
amount of lipophilic solvent required and/or reducing the closures. Furthermore, appearance and composition content
need for a hydrophilic co-solvent to maintain the cyclo- of the soft capsule according to the present invention were
sporine in a stable solution and ready miscibility with not changed.
preferred hydrophilic co-solvents such as polycarbonate and Earlier, the same inventor provided a cyclosporine soft
ready dispersibility into emulsions or microemulsions upon
capsule composition comprising cyclosporine as an active
inclusion of a suitable surfactant. In his earlier patent, the
ingredient, dimethylisosorbide as a cosurfactant, components
inventor described a pharmaceutical composition in the form
of an esterified compound of fatty acid and primary alcohol,
of a microemulsion preconcentrate comprising a cyclo-spo-
medium chain fatty acid triglyceride and fatty acid
rine dissolved in a solvent system comprising of a
monoglyceride (e.g. Nikkol VF-E®, Miglyol 812®) as an oil
hydrophobic component, a hydrophilic component, and a component, and a surfactant having an HLB value of 10 to
surfactant, wherein either the hydrophobic component was
17 [147]. Another patent granted to the same inventor
selected from tocol, tocopherols, tocotrienols, and deriva-
described a cyclosporine containing soft capsule composition
tives thereof, or the hydrophilic component was selected
which comprised cyclosporine as an active ingredient,
from propylene carbonate or polyethylene glycol having an
polyethylene glycol having a molecular weight of 200 to 600
average molecular weight of less than 1000 [143]. In a
as a cosurfactant, a mixture of an esterified compound of
subsequent patent, the same inventor taught pharmaceutical fatty acid and primary alcohol, medium chain fatty acid
compositions in the form of an emulsion preconcentrate or
triglyceride and fatty acid monoglyceride as an oil com-
microemulsion preconcentrate of cyclosporine comprising
ponent, and a surfactant having HLB value of 10 to 17 [148].
propylene carbonate as hydrophilic solvent, glycerides as
Polyethylene glycol is non-volatile, does not permeate the
lipophilic solvent, and a surfactant [144]. The disclosed
gelatin membrane of the soft capsule, and has a high
lipophilic solvents such as Vitamin E in his earlier patent
solubility for cyclosporine and is therefore advantageous for
were relatively expensive. He found that when propylene administration of the composition in a soft capsule dosage
carbonate was used as hydrophilic solvent, excellent
form.
emulsion preconcentrate and microemulsion preconcentrates
could be made using relatively inexpensive glycerides as 3.2. Parenteral Delivery
lipophilic solvent, and without the use of ethanol.
The formulation of lipophilic and hydrophobic drugs into
Kim et al. described pharmaceutical composition con- parenteral dosage forms has proven to be difficult. O/w
taining cyclosporine, an oil component, a hydrophilic cosur- microemulsions are beneficial in the parenteral delivery of
factant consisting of propylene carbonate or a mixture of sparingly soluble drugs where the administration of suspen-
propylene carbonate and polyoxyethylene-polyoxypropylene sion is not desirable. They provide a means of obtaining
block copolymer (pluronics, poloxamers), and a surfactant relatively high concentration of these drugs which usually
[145]. The use of the above mentioned hydrophilic cosur- requires frequent administration. Other advantages are that
factant provided a solubilizing effect sufficient for cyclos- they exhibit a higher physical stability in plasma than
porine and also provided some advantages that it did not liposomes or other vesicles [149] and the internal oil phase is
cause the change in capsule appearance and the precipitation more resistant against drug leaching. Several sparingly
of cyclosporine due to the change in solvent content, reduced soluble drugs have been formulated into o/w microemulsion
the manufacturing cost to provide an economical effect and for parenteral delivery [31, 149-156]. Microemulsions can
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 251

also be used as intravenous delivery systems for the fat tration according to the invention would cause a lower
soluble vitamins and lipids in parenteral nutrition [156]. occurrence of injuries to the body tissues.
Dennis et al. patented an intravenous microemulsion US Patent 7157099 described stable, biologically
delivery system for water insoluble or sparingly water compatible w/o microemulsions, for the sustained release by
soluble drugs that comprised an oil phase comprising the parenteral administration of hydrophilic active ingredients
drug, a long polymer chain surfactant (e.g. lecithin, gelatin [161]. Microemulsions could be formulated particularly for
casein, tweens, macrogol ethers, etc.) component and a short peptide active ingredients (LHRH analogs such as Leup-
fatty acid surfactant (e.g. stearic acid, glyceryl monostearate, rolide acetate, Goserelin, Triptorelin, Somatostatin or its
sorbitan esters, etc.) component and an aqueous phase [157]. analogs such as Octreotide and Lanreotide acetate, etc.) or
The droplet size ranged from 10-100 nm. They had found the biologically active oligo- or polysaccharides (unfractioned
composition to be useful for propofol, a short-acting heparin or low molecular weight heparins), which provides
intravenous anesthetic. Micromulsion would emulsify or protection against immediate attack by the hydrolytic
partition propofol into the non-aqueous phase and preclude enzymes as well as sustained release to avoid repeated
(or markedly reduce) stinging and allow painless injection. administrations. The microemulsions consisted up to 20% of
an internal hydrophilic aqueous phase containing the active
Dennis et al. in their invention taught a intravenous
microemulsion delivery system comprising a long polymer ingredient, 30 to 98% of a hydrophobic external phase and
up to 50% of a surfactant alone or in admixture with a co-
chain surfactant component and a short fatty acid surfactant
surfactant. Another technology already used for the sustained
component, and an aqueous phase, wherein the amounts of
release of peptides involved the use of bioerodible polymers
the long chain polymer and short chain fatty acid surfactant
like polymers based on glycolic acid and lactic acid [162].
components were selected to provide for spontaneous
Drawbacks of using polymers include their higher cost and
formation of thermodynamically stable microemulsion drop-
lets of the oil phase having a particle size from 10-100 nm the issues of environmental impact and safety of the
pharmaceutical formulation as organic, in particular
and the interfacial tension of the drug with the emulsifier
chlorinated, solvents are used during their preparation. Also,
combination was less than 0.1 dynes per cm [158]. This
these microemulsion formulations did not cause persistent
work was an extension of an earlier patent granted to the
granulomas which were reabsorbed during the time in which
same inventors [157].
the medicament was effective and did not induce local
Microemulsions are generally not dilutable with aqueous ulcerogenicity.
fluids, such as certain bodily fluids and buffer solutions, and
Vigne et al. disclosed microemulsions suitable for
form emulsions upon contacting such fluids. Various
parenteral administration of fat soluble vitamins (vitamins E,
microemulsions are also sensitive to temperature and are not
A, D, and K) and hydrophobic drugs [163]. The micro-
stable outside of room temperature conditions. US Patent
emulsions were comprised of a naturally occurring amphi-
6245349 provided drug delivery compositions in both
concentrated and diluted forms for use as vehicles in the patic substance and a hydrophobic lipid along with the active
ingredient and were size selected for 30-100 nm pseudo-
administration of various active agents [159]. The concen-
micelles. According to them, the composition had the unique
trated drug delivery compositions were formulated with a
property of delivering fat soluble substances to the plasma in
phospholipid component, a component selected from
a form and distribution which mimicked the natural uptake
propylene glycol or certain polyethylene glycol compounds,
in normal subjects.
a high HLB surfactant, and the drug component, with water
and/or an optional oil component. The concentrated drug 3.3. Topical Delivery
delivery compositions could be diluted with an aqueous fluid
to form an o/w microemulsion. These o/w microemulsions Microemulsion systems are now being investigated
were characterized by their small particle size and their wide zealously for topical delivery which is evident from the
range of temperature stability, typically from about -20o- numerous publications coming up every year. They have
50oC. They could be administered by intravenous, intra- been reported to enhance the transdermal permeation of
arterial, intrathecal, intraperitoneal, intraocular, intra- drugs significantly compared to conventional formulations
articular, intramuscular or subcutaneous injection. such as solutions, gels or creams [164,165]. They are able to
incorporate both hydrophilic (5-fluorouracil, apomorphine
According to the invention of the Wretlind et al. paren- hydrochloride, diphenhydramine hydrochloride, tetracaine
teral administration of water-insoluble active agents was hydrochloride, methotrexate) and lipophilic drugs (estradiol,
enhanced when the agents were administered in the lipoid finasteride, ketoprofen, meloxicam, felodipine, triptolide)
phase of a carrier microemulsion [160]. The microemulsion and enhance their permeation [18-22, 166-170]. Since the
comprised of a finely dispersed lipoid in an aqueous phase microemulsion is a multicomponent system and its formation
with a mean particle size below 1 micron. Higher requires high surfactant concentration, the skin irritation
concentration of the agent (diagnostic or therapeutic) could aspect must be considered especially when they are intended
be achieved and hence a lower dose whereby a rapid onset of to be applied for a longer period. Several plausible mecha-
the pharmacological effect was accompanied by a reduced nisms have been proposed to explain the advantages of
incidence of injury to body tissues. As the agents were microemulsion for the transdermal delivery of a drug:
present in a dissolved state in the hydrophobic phase, there
was no need of affecting the pH or the osmotic pressure of 1. A large amount of drug can be incorporated in the
the aqueous phase. Because of this, the method of adminis- formulation due to the high solubilizing capacity that
252 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Talegaonkar et al.

might increase thermodynamic activity towards the skin effective delivery systems. Microemulsions have emerged as
[171]. a promising dosage form for ocular use [176].
2. The permeation rate of the drug from microemulsion Bowman et al. disclosed sustained release emulsions
may be increased, since the affinity of a drug to the (macroemulsions and microemulsions) in which particles of
internal phase in microemulsion can be easily modified the dispersed phase were dispersed and stably maintained in
to favour partitioning into stratum corneum, using physical separation by lightly crosslinked, water swellable
different internal phase, changing its portion in polymers (carboxyvinyl polymers, polyvinyl pyrolidone,
microemulsion [172]. etc.) present in an aqueous polymeric system formulated for
administration to the eye in drop or ribbon form [23].
3. The surfactant and co surfactant in the microemulsions
may reduce the diffusional barrier of the stratum Medicament was dissolved in dispersed phase and was
delivered over a sustained release period. Rather than using
corneum by acting as penetration enhancers [21].
large quantities of the polymer, the invention relied on
4. The percutaneous absorption of drug will also increase including an amount of the polymer sufficient to stably
due to hydration effect of the stratum corneum if the maintain that physical separation of the particles of the
water content in microemulsion is high enough [173]. disperse phase of the emulsion within the aqueous polymeric
Due to the small droplet size and large amount of inner system. The advantages of the invention included enhanced
phase in microemulsions, the density of droplets and their bioavailability of the sparingly soluble drug in water,
surface area are assumed to be high. Therefore, droplets inhibition of the tendency of oily medicaments to separate
settle down to close contact with the skin providing high and/or agglomerate in aqueous media and sustained action.
concentration gradient and improved drug permeation. Chloramphenicol, an antibiotic used in the treatment of
Moreover, low surface tension ensures good contact to the trachoma and keratitis, in the common eye drops hydrolyzes
skin. Also, the dispersed phase can act as a reservoir making easily. Lv et al. investigated chloramphenicol microemulsion
it possible to maintain an almost constant concentration composed of Span 20, Tween 20, isopropylmyristate and
gradient over the skin for a long time [19]. water as potential drug delivery systems for eye drops [177].
The liquid, transparent, multicomponent systems accor- Chloramphenicol was entrapped in the o/w microemulsion
ding to the invention of Muller et al. contained the active free of alcohol. Its stability was determined in the accele-
agents in a solution of an oily and optionally an aqueous rated experiments of three months. The authors revealed that
component in the presence of surfactants and cosurfactants the content of glycol (main hydrolysis product) in the
[174]. Under certain conditions, the cosurfactants can serve microemulsion formulation was much lower than that in the
as oil components or vice-versa. The efficacy of the active commercial eye drops at the end of the accelerated
agents applied in the form of the multicomponent systems experiments. Thus, a remarkable increase in the chloram-
according to the invention was much better than that of phenicol stability was observed in the microemulsion
active agents applied in the form of known multicomponent formulations.
systems. The multicomponent systems could be used in Fialho et al. prepared microemulsion based dexa-
pharmaceutical products for cutaneous, peroral, vaginal and methasone eye drops which showed better tolerability and
parenteral administration of pharmaceutical active agents. higher bioavailability [178]. The formulation showed greater
The invention of Protopapa et al. referred to depilatory penetration in the eye which allowed the possibility of
preparations containing proteolytic enzymes solubilized in decreasing the number of applications per day. This might be
microemulsions, formed with lecithin, aliphatic hydrocarbon, useful in achieving improved patient compliance.
alipathic alcohol and buffer solution (pH 7-9) to be applied Habe et al. formulated water-continuous microemulsions
for permanent enzymic depilation [175]. The invention for ocular application of pilocarpine [179]. in vitro Studies
introduced the use of microemulsions as a medium for the showed a prolonged pilocarpine release from the
facilitated penetration of the enzymic activity in the microemulsions with lecithin. The authors found micro-
epithelial cells of the skin. In addition, their invention emulsions to be favourable for ophthalmological use.
referred to a depilation method that applied the preparations
of microemulsion containing the enzyme alpha-chymo- 3.5. Nasal Delivery
trypsin, or the enzyme trypsin, for the depilation of any type Microemulsions are now being studied as a delivery
of skin (fatty-resistant or dry-sensitive). The application of system to enhance uptake across nasal mucosa. Addition of a
these preparations provided more permanent depilation than mucoadhesive polymer helps in prolonging the residence
the one resulting from other depilatory methods. time on the mucosa. Nasal route for administration of
3.4. Opthalmic Delivery diazepam might be a useful approach for the rapid onset of
action during the emergency treatment of status epilepticus.
In conventional ophthalmic dosage forms, water soluble For this microemulsion was formulated comprising of ethyl
drugs are delivered in aqueous solution while water- laurate (15%), Tween 80:propylene glycol:ethanol at 1:1:1
insoluble drugs are formulated as suspensions or ointments. weight ratio (70%) and water (15%). The nasal absorption of
Low corneal bioavailability and lack of efficiency in the diazepam was found to be fairly rapid at 2 mg kg-1 dose with
posterior segment of ocular tissue are some of the serious maximum drug plasma concentration reached within 2-3
drawbacks of these systems. Recent research efforts have min. The bioavailability (0-2 h) after nasal spray compared
therefore focused on the development of new and more to i.v. injection was about 50% [24].
Microemulsions in Drug Delivery Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 253

3.6. Periodontal Delivery molecules could be achieved by utilizing cleavable reverse


micelles which was difficult earlier.
Periodontal disease is a collective term for a number of
progressive oral pathological afflictions like inflammation The invention of Wheeler et al. was related to cell
and degeneration of the gums, periodontal ligaments, delivery of hydrophobic compounds in microemulsion
cementum and its supporting bone. It is a major cause of carriers [182]. Microemulsion was comprised of a mixture of
tooth loss. The invention of Brodin et al. included a novel oil, a hydrophobic compound, and a polyethylene glycol-
pharmaceutical composition comprising local anaesthetic in linked lipid. The purpose of polyethylene glycol-linked lipid
oil form, surfactant, water and optionally a taste masking was to enhance the stability of the microemulsion compo-
agent [180]. The composition was in the form of an emulsion sitions. The hydrophobic compound resided in an oil
or microemulsion and had thermoreversible gelling proper- environment which was surrounded by a monolayer of a
ties i.e. it was less viscous at room temperature than after polar lipid. The polar head of the lipid faced outwards to
introduction onto a mucous membrane of a patient. The provide compatibility with the external aqueous environment
surfactant in the formulation imparted the thermoreversible and the nonpolar tail faced the internal oil environment. A
gelling properties. Preferred surfactants were Poloxamer targeting moiety such as biotin, avidin, streptavidin or
188®, Poloxamer 407® and Arlatone 289®. The composition antibodies might be covalently or noncovalently attached to
could be used as a local anaesthetic for pain relief within the the lipid monolayer. The composition could also be used for
oral cavity in conjunction with periodontal scaling and root diagnostic and therapeutic purposes.
planning and overcame the problem with the existing topical 3.7.2. Tumour Targeting
products (jelly, ointment or spray) such as lack of efficacy
due to inadequate depth of penetration, too short duration Maranh ao suggested the utility of microemulsions as
and difficulties in administration due to spread, taste etc. vehicles for the delivery of chemotherapeutic or diagnostic
agents to neoplastic cells while avoiding normal cells [183].
3.7. Drug Targeting They claimed a method for treating neoplasms, wherein
Drug targeting has evolved as the most desirable but neoplasms cells have an increased number of LDL (low
elusive goal in drug delivery. By altering the pharma- density, lipoprotein) receptors compared to normal cells. The
cokinetics and biodistribution of drugs and restricting their microemulsion comprised of a nucleus of cholesterol esters
action to the targeted tissue increased drug efficacy with and not more than 20% triglycerides surrounded by a core of
concomitant reduction of their toxic effects can be achieved. phospholipids and free cholesterol and contained a
Drug targeting to diseased cells can be achieved by chemotherapeutic drug. Microemulsions were similar in
exploiting the presence of various receptors, antigens/ chemical composition to the lipid portion of low density
proteins on the cell membrane which may be uniquely lipoprotein (LDL), but did not contain the protein portion.
expressed or over expressed in these cells as compared to the These artificial microemulsion particles incorporated plasma
normal cells. Specific antibodies to the surface proteins and apolipoprotein E (apo E) on to their surface when they were
ligands for the receptors can be used to target specific cells. injected in the bloodstream or incubated with plasma. The
Submicron size range of these systems confers excellent apolipoprotein E served as a linking element between the
opportunities to overcome the physiological barriers and particles of the microemulsion and the LDL receptors. The
enables efficient cellular uptake followed by intracellular microemulsions could then be incorporated into cells via
internalization. receptors for LDL and delivered the incorporated molecules.
Thus, higher concentration of anticancer drugs could be
3.7.1. Cellular Targeting achieved in the neoplastic cells that have an increased
Nucleic acids delivered to cells are promising expression of the receptors. In this way toxic effects of these
therapeutics. The invention of Monahan et al. included drugs on the normal tissues and organs could be avoided. In
insertion of nucleic acid into a reverse micelle for cell human subjects, they observed no change in the plasma
delivery [181]. They referred w/o microemulsions to as kinetics of the radioactively labeled microemulsion
reverse micelles. The reverse micelle had the property to containing carmustine or cytosine-arabinoside thereby
compact the nucleic acid for easier delivery. To further confirming that the incorporation of these drugs did not
enhance the delivery, other molecules such as a surfactant diminish the capacity of the microemulsion to incorporate
having a disulfide bond or a polyion might be added to the apo E in the plasma and bind to the receptors.
nucleic acid-micelle complex. Another advantage of the Shiokawa and coworkers reported a novel microemulsion
invention was the use of reverse micelles for gene delivery to formulation for tumour targeted drug carrier of lipophilic
the cells. The micelle containing the compacted polynuc- antitumour antibiotic aclacinomycin A (ACM) [184]. Their
leotide could be utilized as a reaction vesicle in which findings suggested that a folate-linked microemulsion is
additional compounds such as polycation could be added to feasible for tumour targeted ACM delivery. The study
the DNA. Additionally, the polynucleotide/reverse micelle showed that folate modification with a sufficiently long PEG
system was used as a vesicle for template polymerization of chain on emulsions is an effective way of targeting emulsion
the DNA or caging of the DNA in which the polycation was to tumour cells.
crosslinked. Another advantage was that the micelle might
be cleaved under physiological conditions involved along the 3.7.3. Brain Targeting
transfection (process of delivering a polynucleotide to a cell) Intranasal administration confers a simple, practical, cost
pathway. Better recovery and purification of the bio- 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 Talegaonkar et al.

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