Int J Pharm Bio Sci 2012 July; 3(3): P 1 – 13

Review Article Pharmaceutics

ISSN
International Journal of Pharma and Bio Sciences 0975-6299

OPHTHALMIC MICROEMULSION: A COMPREHENSIVE REVIEW

KALE MOHAN1*,SURUSE PRAVIN1 AND BODHAKE ATUL2

1*
Sharad Pawar College of Pharmacy, Wanadongri, Hingna Road, Nagpur- 441 110 (MS), India.
2*
Mahatma Jyoti Rao Phoole University and Research Scientist, Centaur Pharmaceuticals, Pune, Maharashtra 411027(MS),
India.

ABSTRACT
The design and development of new drug delivery systems with the intention of
enhancing the efficacy of existing drugs is an ongoing process in pharmaceutical
research. It is necessary for a pharmaceutical solution to contain a therapeutic dose of
the drug in a volume convenient for administration. In last decade, o/w micro/lipid
emulsions have been recognized as an interesting and promising ocular topical delivery
vehicle for lipophilic drugs. The aim of present review is to present the potential of o/w
and lipidmicroemulsions for ocular delivery of lipophilic drugs. The review covers an
update on the state of the art of incorporating the lipophilic drugs, a brief description
concerning the components and the classification of lipid/oil in water emulsions. The
ocular metabolism after topical instillation and the applications of micro/lipid emulsions
are thoroughly discussed.

KEYWORDS : o/w microemulsion, lipophilic drugs, ophthalmic drug delivery

KALE MOHAN
Sharad Pawar College of Pharmacy, Wanadongri, Hingna Road, Nagpur- 441 110
(MS), India.

*Corresponding author

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INTRODUCTION
For the treatment of different extra- and intra- has also been the focus of recent reviews
ocular etiological conditions such as glaucoma, (Ding, 1998;Marti-Mestreset al., 2002;
uveitis, keratitis, dry eye syndrome, Saettone et al., 2000). Thus, keeping in mind
cytomegalovirus retinitis, acute retinal necrosis, the potential of microemulsions, the purpose of
proliferative vitreoretinopathy and macular this review is to report on the most recent
degenerative disease, a lot of lipophilic and findings on the mode of ocular active lipophilic
poorly water soluble drugs have become drug incorporation into lipid emulsions, to
available in recent years. However, most of the classify the microemulsions, to describe briefly
traditional ophthalmic dosage forms are clearly the major components needed to formulate
not only uncomfortable for the patient but also ocular compatible o/w microemulsions, to
not efficient in combating some of the current relate the ocular metabolism or concomitant
virulent ocular diseases. Furthermore, in protective mechanism factors faced by lipid
ophthalmology, the low viscosity topical emulsions following ocular topical application,
formulations either in aqueous-based eye to offer a short overview on safety assessment
drops or in liquid retentive suboptimal forms is made so far with regard to the ocular topical
generally preferred to provide local drug route and finally to describe the ocular topical
concentrations in the precorneal or aqueous delivery of lipophilic drugs through o/w type
humor part of the eye. lipid emulsions. The size and the size
In the last decade, oil-in-water (o/w) type lipid distribution of the submicron emulsions
emulsions, primarily intended for parenteral obviously depend on the specific formulation.
applications have been investigated and are Irrespective of the formulation, most of the lipid
now exploited commercially as a vehicle to emulsions exhibit a narrow size distribution
improve the ocular bioavailability of lipophilic range which may vary from 50 to 700 nm with
drugs (Ding, 1998;Tamilvanan et al., 2002; a mean droplet size of about 200 nm.
Marti-Mestreset al., 2002). The natural
biodegradability, nanometer droplet size range, Addition of lipophillic drug into oil/lipid:
sterilizability and substantial drug solubilization There are three different approaches to add
either at the innermost oil phase or at the o/w and dissolve lipophilic drugs into the lipid
interface and improved ocular bioavailability emulsions.
are thus making the microemulsion a promising
ocular delivery vehicle. For the first time, an (A) Extemporaneous drug addition
anionic lipid emulsion containing Cyclosporine When looking for a new galenic presentation
A 0.05% (Restasis, Allergan, Irvine, USA) was form for Amphotericin B with better ocular
approved for clinical use by the FDA in tolerance over the commercial Fungizone eye
December 2002, and is now available in the drops, incorporated the drug directly to the
US for the treatment of chronic dry eye disease preformed 20%emulsion, Intralipid(Cohenet
(available at www.restasis.comand al.,1996). However, after addition of the solid
www.dryeye.com). Furthermore, an over-the- drug particles or drug solution, several physical
counter product that features a non-medicated changes such as phase separation,
(blank) anionic emulsion formulation(Refresh nanoprecipitation or creaming may occur within
Endura) has been launched in the US market lipid emulsions thus limiting such practices in
for eye lubricating purposes in patients ocular lipid emulsion preparations. Therefore,
suffering from moderate to severe dry-eye ocular active lipophilic agents are not normally
syndrome (Sasakiet al., 1996;Rieger, incorporated into the lipid emulsions by this
1990).Furthermore, as one of the noninvasive, extemporaneous addition method.
topical drug delivery vehicles to treat ocular
pathologies, the efficacy of o/w microemulsions

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(B) De novo emulsion preparation speed mixers. Further homogenization takes

In principle, the drug molecules should be place to obtain the needed small droplet size
incorporatedby a de novo process. Thus, the range of the emulsion. A terminal sterilization
drug is initially solubilizedor dispersed together by filtration or steam then follows. The lipid
with an emulsifier in suitable single oilor oil emulsion thus formed contains most of the
mixtures by means of slight heating. The water drug molecules within its oil phase. This is a
phase containing the osmotic agent with or generally accepted and standard method to
without an addition alemulsifier is also heated prepare lipophilic drugloaded lipid emulsions
and mixed with the oil phase bymeans of high for ocular use as shown in Fig.1.

Figure.1
Manufacturing using high pressure homogenization

(C) Interfacial incorporation approach using in an organic solvent, instead of oil. Following
Phospholipid the solvent evaporation, the obtained
Since many drugs of commercial interest phospholipids/ drug co-mixture is used in the
including ocular therapeutic agents generally de novo production of the lipid emulsions
have a solubility that is too low in FDA (Davis and Washington, 1988). However, this
approved oils, proposed a method to approach suffers from possible drug
incorporate such drugs into the interfacial o/w nanocrystal formation inside the lipid emulsions
layer of the emulsion droplets (Lance et al., and from the use of organic solvent during the
1988). This can be achieved by initially emulsion preparation process. To overcome
dissolving the drug along with the phospholipid such drawbacks, a novel SolEmul technology

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has been developed in which an additionalhigh Excipients for the manufacturing of ocular
speed homogenization step is included to mix compatible lipid emulsion:
the drug with lipid emulsions. The drug This section is a comprehensive presentation
particles are in fact micronized to the nanosize of the general considerations concerning
range prior to incorporation into the lipid excipient selection and optimum
emulsions. By this technique, concentrations mainly in relation to the oil
adequateamounts of lipophilic drugs can be phase, the aqueous phase and the emulsifiers.
substantially incorporated into the lipophilic
core or intercalated betweenthe selected (A) Oils and Lipids
emulsifier molecular films at the o/w interface Prior to the formulation design of the lipid
of the lipid emulsions. The drugs reported to emulsions data are needed concerning the
have been incorporated by this novel approach drug solubility in the oil vehicle. Additionally,
are Amphotericin B, Carbamazepine prerequisite information is needed on
andItraconazole(Buttle et al., 2002;Muller and compatibility of the oil vehicle with other
Schmidt, 2002;Akkar and Muller, 2003; Akkar, formulation additives and the established
et al., 2003). ocular tissues-oil vehicle matching before the
dosage form can be prepared.

Table1
Common emulsion excipients

Lipid/oil Emulsifier Cationic lipids and Others

polysaccharides
Sesame oil Cholesterol Stearylamine Glycerol
Castor oil Phospholipid Oleyamine Xylitol
Soya oil Polysorbate 80 Chitosan Sorbitol
Paraffin oil Transcutol P Thiomersal
Paraffin light Cremophor RH EDTA
Lanolin Ploxamer 407 Methyl Paraben
Vaseline Polaxamer 188 Propyl Paraben
Corn oil Miranol C2M
Glycerin Tyloxapol
Monostearate

Medium chain
Monoglycerides

Medium chain
triglycerides

Table 1 enlist the common emulsion excipients Tocopherol (0.001–0.002% w/w) should be
and the oils suitablefor dissolving or dispersing included in a typical lipid emulsion formulation
lipophilic drugs of ocular interests. Since fatty for ocular use. The final oil phase
oils are triglycerides, care must be taken to concentration in ocular lipid emulsions is now
minimize or eliminate oxidation.α-Tocopherol is widely accepted at or even below 5% (w/w)
a good example of an antioxidant used to taking into account that the lipid emulsion must
obtain a desired stabilized lipid emulsion under be kept in a low viscosity range, of between 2
prolonged storage conditions. Therefore, α- and 3 cp, which is considered an adequate

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viscosity for ocular preparations (Lee and chlorocresol, parabens etc. are regularly
Robinson, 1986). Sometimes, a mixture of oils included in ophthalmic lipid emulsions to
rather than single oil is employed since drug prevent microbial spoilage of multi-dose
solubilization in the oil phase is a prerequisite ophthalmic lipid emulsions. The presence of
to exploit the lipid emulsion advantages. components of natural origin like lecithin or oils
Jumaa and Muller reported the effect of mixing with high calorific potential render the
castor oil with medium chain triglycerides on lipidemulsion a good medium to promote
the viscosity of castor oil(Jumaa and Muller, microbial growth when it is packed in multi-
1998;Jumaaet al., 1999). The oil combination, dose containers. Sznitowska et al. studied the
at the ratio of 1:1 (w/w) led to a decrease in the physicochemical compatibility between the
viscosity of castor oil and simultaneously to a lecithin-stabilized lipid emulsion and 12
decrease in the interfacial tension of the oil antimicrobial agents over 2 years of storage at
phase. This was related to the free fatty acids room temperature. Preliminary
contained in castor oil, which can act as a co- physicochemical screening results indicate that
emulsifier resulting in lower interfacial tension addition of chlorocresol, phenol, benzyl
and, simultaneously in a more stable alcohol, thiomersal, chlorhexidine gluconate
formulation in comparison with the other oil and bronopol shouldbe avoided due to the
phases. occurrence of an unfavourable pH change
followed by the coalescence of the
(B) Emulsifier lecithinstabilized droplets of the lipid emulsion.
Traditionally, lecithin or phospholipids have Despite a good physicochemicalcompatibility,
been theemulsifiers of choice to produce ocular neither parabens nor benzalkonium chloride
lipid emulsions. However, emulsifier of this kind showed satisfying antibacterial efficacy in the
is not suitable to produce submicron sized lipid emulsion against thetested
emulsion droplets or to withstand the heat microorganisms and consequently did not pass
during steam sterilization. Therefore, additional the test. Therefore, higher concentrations of
emulsifiers preferably dissolved in the aqueous antimicrobial agents or their combination may
phase are usually included in the lipid emulsion be required for efficient preservation of the
composition. A typical example of the aqueous lecithin-stabilized lipid emulsions probably
soluble emulsifiers is non-ionic surfactants because of unfavorable phase partitioning of
(e.g. Tween 20) after taking into consideration the added antimicrobials within the different
their non-irritant nature when compared to ionic internal structures of the lipid emulsions.
surfactants. The non-ionic block copolymer of
Polyoxyethylene-Polyoxypropylene, Pluronics Ocular metabolism of lipid emulsions after
F68 (Poloxamer 188), is included to stabilize instillation
the lipid emulsion through strong steric Considerations of ocular drug delivery are not
repulsion. However, amphoteric surfactants, detailed in this section. Pertinent information
Miranol MHT (Lauroamphodiacetate and concerning factors affecting drug permeation or
Sodium tridecethsulfate) and Miranol C2M retention as well as eyes anatomy and
(Cocoamphodiacetate) were also used in an physiology can be found in several reviews
earlier ophthalmic lipid emulsion(Muchtar and (Stjernschantz and Astin, 1993; Lee, 1993;
Benita, 1994). It should be added that Jarvinenet al., 1995; Prausnitz andNoonan,
Restasise contains only polysorbate 80 and 1998;Washingtonet al., 2001). From a medical
carbomer 1342 at alkali pH to stabilize the point of view, lipid emulsions for ophthalmic
Cyclosporin-A loaded anionic lipid emulsion. use aim to enhance drug bioavailability either
by providing prolonged delivery to the eye or
(C) Preservatives by facilitating transcorneal/transconjunctival
Additives other than antioxidants such as penetration. Drugs incorporated in o/w type
preservatives like benzalkonium chloride, lipid emulsions are lipophilic in nature and,

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depending on the extent of lipophilicity, either ophthalmic drugs are believed to gain access
the corneal or the conjunctival/sclera route of to the internal ocular structures. Relatively little
penetration may be favored (Lee, 1993). For attention has been given to alternate routes
the more lipophilic drugs the corneal route was through which drugs may enter the eye.
shown to be the predominant pathway for
delivering drugs to the iris, whereas the less Ocular delivery of lipophilic drugs by lipid
lipophilic drugs underwent the emulsions
conjunctival/scleral penetration for delivery into For convenience, we have divided this section
the ciliary body (Chien et al., 1990). Thus, into two parts based on the charge of the
transcorneal permeation has traditionally been emulsified oil droplets:
the mechanism by which topically applied

Table 2
Non-exhaustive list of oil-in-water (o/w) submicron lipid emulsion for ocular drug delivery

Emulsion type Drug used

Anionic emulsion D8-THC (Osborneet al., 1995)
Anionic emulsion Pilocarpine base and Indomethacin
(Zurowska-Pryczkowskaet al., 1999)
Anionic emulsion Adaprolol maleate
(Navehet al., 1994; Zurowska-Pryczkowskaet al., 1999)
Anionic emulsion Indomethacin
(Calvoet al., 1996; Osborneet al., 1995; Navehet al., 1994)
Anionic emulsion Synthetic HU-211 and Pilocarpine base
(Muchtaret al., 1994; Klanget al., 1999; Stevensonet al., 2000)
Anionic emulsion Pilocarpine base
(Sznitowskaet al., 1999; Navehet al., 2000; Navehet al., 1994;
Zurowska-Pryczkowskaet al., 1999; Melamedet al., 1994)
Anionic emulsion Cyclosporin-A
(Stevenson, 2000; Dinget al., 1995; Ding and Olejnik 1997;
Acheamponget al., 1999; Sallet al., 2000; Turneret al., 2000;
Kunertet al., 2000; Brignoleet al., 2001; Smallet al., 2002;
Galatoireet al., 2003)
Cationic emulsion Piroxicam(Muchtaret al., 1992)
Cationic emulsion Indomethacin(Klanget al., 2000)
Cationic emulsion Miconazole(Yang and Benita, 2000)
Cationic emulsion Cyclosporin A(Tamilvanan, 2001; Abdulrazik, 2001)

Anionic lipid emulsions applications pilocarpineloadedanionic lipid emulsions lasted

The in-vivo data obtained from studies of early for more than 29 h inalbino rabbits whereas
formulations confirmed that anionic lipid that of the generic pilocarpine lastedonly 5 h
emulsions can be effective topical ophthalmic (Zurowska-Pryczkowskaet al., 1999).
drug delivery systems (Muchtar et al., Zurowska-Pryczkowska et al., studied how lipid
1992)with a potential for sustained drug emulsions as a vehicle influence chemical
release Navehet al., 2000. Naveh andco- stability of pilocarpine, as well as how the drug
workers have also noted that the IOP-reducing may affect the physical stability of lipid
effectof a single, topically administered dose of emulsions. In a subsequent work from the

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same group on in- vivo evaluation using penetration into intraoculartissues was much
normotensiverabbits, it was shown that anionic lower and absorption into bloodwas minimal
lipid emulsionsformulated with pilocarpine (Acheampong et al., 1999). The oil canthen
hydrochloride at pH 5.0 couldbe indicated as a migrate towards the lower lid where it may
preparation offering prolonged residelonger than aqueous fluids and
pharmacologicalaction (miotic effect) together supplement the lipid layer inthe tears. This
with satisfactorychemical stability(Sznitowskaet indicates that lipids containing eye drops
al., 2001) . However, the ocular suchas lipid emulsions have moved a step
bioavailabilityarising from such a formulation closer to natural tearseven in terms of ocular
did not improve significantlywhen compared to tolerability and therefore should notbe
an aqueous solution of the samedrug. On the expected to produce any ocular discomfort
other hand, Calvo et al., observed an (Rieger, 1990). Indeed,the lipid substances
improvement in indomethacin ocular bio normally present in tears, such as
availability when the drug was incorporated in phospholipids, saturated and unsaturated fatty
a lipid emulsioncompared to the commercial acids andtriglycerides, are currently used in the
aqueous drops followingtopical application into preparation of mostlipid emulsions. Therefore,
rabbit eye.Beilin et al., showed as previously the lipid emulsions closelycorrespond to the
mentionedthat a lipid emulsion increased natural tear fluid and seem to participate in
ocular residence time incomparison to eye formation of physiological tear film.
drops, correlated the delayed
pharmacologicalaction to the delayed Cationic lipid emulsions applications
residence time. Anselem et al., and Melamed The potential of a cationic submicron emulsion
et al., prepared an anioniclipid emulsion suitablefor ocular application of piroxicam was
containing Adaprolol maleate, a novel softb- reported (Klang et al., 1994). It wasshown that
blocking agent and observed a delayed IOP the Piroxicam positively charged emulsion
depressant effect in human volunteers. A wasthe most effective formulation in lowering
similar pharmacologicaleffect was also the ulcerativecornea score following alkali burn
observed in ailing human volunteers by Avivet of rabbit corneas. Anincreased uptake of the
al., using pilocarpine base-loaded lipid positive oil droplets by thenegatively charged
emulsion.A novel anionic lipid emulsion cornea is a plausible explanation forthe
incorporating theimmunomodulatory agent resulting enhancement of the lipophilic drug
Cyclosporine-A was developedand its clinical oculardisposition. Furthermore, the blank
efficacy was investigated for the treatment emulsions showed a very rapid healing rate
ofmoderate to severe dry eye disease in over the first three days, with a breakdown on
animals and humans(Dinget al., 1995;Ding and day 14 and then complete re-epithelialization
Olejnik, 1997; Acheamponget al., 1999). The on day 28.Regardless of the preparation
novel Cyclosporine-A ophthalmic dosage instilled, the highest concentrationof
formrepresents a breakthrough in the Indomethacin was achieved in the
formulation of a complex,highly lipophilic cornea,followed by conjunctiva, sclera retina
molecule such as Cyclosporine-A within and aqueous humor.However, the cationic
ananionic lipid emulsion.Ding and Coll, have emulsion provided significantlyhigher drug
developed a castor oil in wateremulsion levels than the control solution and
stabilized by Polysorbate 80. The Cyclosporine anionicemulsion only in the aqueous humor
penetrated into rabbit extraocular tissues and sclera-retina. The stability and
(cornea, lachrymalglands and conjunctiva) at oculartolerance following topical instillation into
concentrations adequate for eye ofthese cationic lipid emulsion vehicles
localimmunosuppression activity while were investigated(Klang et al., 1994; Klang et

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al., 1996; Wehrle et al., 1996). The promising penetrationof drugs into ocular surface tissues
results obtained with Cyclosporine-A loaded through an endocyticmechanism (Calvo,1996;
cationic lipid emulsions paved the way for Sznitowska, 2000). The endocytic effect is
theformulation to recently obtain approval from probably morepronounced with the cationic
regulatoryauthorities to undergo Phase-I emulsion as suggested (Yang, and Benita,
clinical study for the freedrug cationic lipid 2000).All these studies stress the effectiveness
emulsion (Etheridge, 2003). Furthermore, it of cationic lipidemulsions, which promote
isinteresting to note that the cationic emulsion ocular drug absorption viainternalization
is promotingthe penetration of Indomethacin possibly through an endocytic process.
and of Cyclosporin-Ato ocular tissues of the
posterior segment followingone single topical
CONCLUSION
instillation (Klang et al., 2000; Abdulrazik et al.,
2001). It can be noted thatthe concentration of
The o/w type lipid emulsion seems to offer a
the respective drugs in the sclera/retinaand in
number of advantages in the treatment of
the optic nerve was higher with the cationic
various ocular pathologies by providing an
emulsionthan with the anionic emulsion. Such
altered ocular pharmacokinetics profile of the
relatively highconcentrations in the posterior
lipophilic drug incorporated in lipid emulsion
segment can be reachedonly by diffusion of the
following topical instillation into the eye. The
drugs through one of the followingpathways:
potential role of lipid emulsions in the ocular
transcorneal, transconjunctival or through
topical delivery of lipophilic drugs to the
theblood circulation secondary to the systemic
posterior segment of the eye is currently under
absorption.Since aqueous humor and blood
investigation. Attempts were being made to
levels of Cyclosporine werefound to be low,
optimize the lipid emulsion formulations to elicit
while with Indomethacin the
adequate therapeutic concentrations of
cornealconcentrations of the anionic and
effective drugs for the treatment of
cationic emulsions werenot significantly
virulent eye pathologies especially in the
different and the blood levels were alsolow,
posterior segment of the eye.
only the transconjunctival route can represent
aplausible approach for the increased
Recent trends in ophthalmic microemulsion
concentrations of thedrugs in the posterior
Most of the early investigational ophthalmic
segment as previously suggested.However, a
emulsions mimicthe formulations of parenteral
direct transscleral access to some ocular
emulsions, and use phospholipidsand pluronics
tissuesin the back of the eye cannot be
as emulsifiers. Because phospholipids are
excluded. Further studiesare needed to
sensitiveto oxygen, antioxidants are
elucidate the mechanism by which drugs
incorporated into these emulsionformulations
canreach the posterior segment of the eye.A
to improve their shelf-life. Even with
cationic lipid emulsion based on an association
antioxidants,however, the phospholipid-
ofPoloxamer 188 and Chitosan was also
containing emulsions are still limitedin room
prepared andexhibited interesting
temperature stability.
physicochemical properties regardingstability
The in vivo data obtained from studies of these
and charge effects (Jumaaet al.,1999;Calvo et
early formulations confirm that emulsions can
al., 1997). A remarkable fact fromthe data
be effective topical ophthalmicdrug delivery
reported in the present review is that
systems (Garty et al., 1994; Muchtar et al.,
irrespective ofthe drug, the cationic emulsion
1992), with a potential for sustained drug
provided higher drug levelsthan the anionic
release (Naveh et al., 1994; Barilanet al.,
emulsion formulation. There are evidencesthat
1994).Naveh and co-workers noted that the
colloidal delivery systems can facilitate the
intra ocular pressure-reducing effect of a

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single, topically administered doseof minimized by the water in the external phase.
Pilocarpine emulsion lasted for more than 29 h Furthermore, the concentration of the drug in
in albino rabbits, whereas that of the generic the oil phase can be adjusted to maximize
Pilocarpine solution lasted only five hours thermodynamic activity, thus enhancing drug
(Naveh et al., 1994). Oil-in-water emulsions are penetration.As technologies have advanced,
particularly useful in the delivery of water- the obstacles preventing the development of
insoluble drugs. Previously, ointments and ophthalmic emulsions have gradually been
suspensions were the only two available removed. The improvements in both machinery
options, but the former suffered from poor and aseptic processing allow for the
patient acceptance because of blurred vision reproducible manufacture of a sterile product
and matted eyelids, and the latter appeared to with greater assurance than was previously
have problems with particle irritation, poor possible. Moreover, new types of emulsifiers
bioavailability, and changes in polymorphism that are safe, non-irritating and chemically
and particle size upon storage. The newly unique have become available. Some of these
developed oil-in-water emulsion offers a third emulsifiers have demonstrated a remarkable
option that has the advantages of an ointment ability to stabilize emulsions. Using novel
without its drawbacks. polymeric emulsifiers, a newly formulated
In the oil-in-water emulsion, the water-insoluble Cyclosporine ophthalmic emulsion
drug is solubilized in the internal oil phase, demonstrates excellent room temperature
thereby remaining in the preferred solution stability and extremely low ocular irritation
state. By keeping the drug in solution, the issue (Ding et al., 1995; Ding and Olejnik, 1997).
ofpotential absorption because of slow This emulsion is in Phase-III clinical studies for
dissolution of solid drug particles is avoided. In the treatment of dry eye disease.
addition, the blurred vision caused by oils is

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