advances in the topical ocular drug delivery

Review

10.1586/17469899.2.2.309 © 2007 Future Drugs Ltd ISSN 1746-9899 309www.future-drugs.com

Advances in the topical ocular drug deliveryYasmin Sultana†, M Aqil, Asgar Ali and Abdus Samad

†Author for correspondenceHamdard University, Department of Pharmaceutics, Faculty of Pharmacy,New Delhi 110062, [email protected]

KEYWORDS: collagen shields, dendrimers, in situ gelling systems, lipid emulsions, lyophilisates, microemulsions, mucoadhesive polymers, ocular drug delivery, ocular inserts, ocular iontophoresis, prodrugs, soft drugs, thiolated polymers, vesicular systems

Technology for delivering active moieties to the eye has shown many advancements in recent years, from primitive eye drops to iontophoretic drug delivery, in situ gelling systems, dendrimers, penetration enhancers, lipid emulsions, ocular inserts, mucoadhesive polymers, thiolated polymers, collagen shield, soft drugs and site-specific drug delivery systems. The drawbacks of conventional therapy are largely circumvented by these advanced ocular drug delivery systems. However, so far, very few drug delivery systems have made their way to the market. Nevertheless, there has been extensive progress in the development of ocular delivery systems.

Expert Rev. Ophthalmol. 2(2), 309–323 (2007)

Historically, the ophthalmology sector hasreceived little attention from the pharma-ceutical industry. Recently, there has beenan exponential growth in the number of newcompounds entering the mainstream for thetreatment of ophthalmic indications, whichhas resulted in an intensification of competi-tion within the ophthalmic drug deliverysector.

Drug delivery to the eye has always posed aconsiderable problem as less than 10% bioa-vailability in the anterior chamber can beachieved using eye drops and drug delivery toposterior chamber is not provided by any top-ical marketed formulation. This clearlymeans that there is a strong need for topicaltreatments for unresolved ocular pathologies.

There are formulation difficulties withophthalmic preparations as only hydrophiliccompounds can usually be formulated asdrops and over half of all ophthalmic drugsare lipophilic in nature. One of theapproaches to resolve this problem is cat-ionic emulsions, which can be formulatedusing lipophilic compounds. NovagaliPharma has pioneered the cationic emulsiontechnology invented by Professor SimonBenita of the Hebrew University, Jerusalem,Israel. The basis of the technology is theelectrostatic attraction that occurs betweendroplets of positively charged emulsions

loaded with active ingredient and negativelycharged cell membranes. From a pharmaco-logical point of view, cationic emulsionsincrease bioavailability through bioadhesionof the active to the membranes and promo-tion of endocytosis. On a physiological level,since tissues of the cornea and conjunctivaare negatively charged, the electrostatic phe-nomenon can enhance bioavailability uponophthalmic administration.

Despite extensive research efforts, very fewophthalmic delivery systems are on the mar-ket. Ocusert® [1] and Lacrisert® representocular inserts that failed to deliver on initialpromise. This is partly owing to patients’unwillingness to place the object in theireyes and also because of high end cost to theconsumer.

Propine®, developed by Allergan, containsdipivefrin 0.1%, a prodrug of epinephrinethat is converted to epinephrine in thehuman eye, leading to a decrease in aqueoushumor production. It has fewer side effectscompared with conventional epinephrinetherapy. Timoptic XE®, developed by Merck& Co., which contains 0.25 and 0.5%timolol maleate, is indicated in the treatmentof elevated intraocular pressure (IOP) [2].

The advances and innovations in the topi-cal ocular drug delivery are discussed in thetext and a summary is presented in TABLE 1.

CONTENTS

Penetration enhancers

Corneal shields

Ocular iontophoresis

Microparticles & nanoparticles

Ocular inserts

Mucoadhesive polymers

In situ gelling systems

Dendrimers

Site-specific chemical delivery systems & soft drugs

Lipid emulsions

Expert commentary & five-year view

Key issues

References

Affiliations

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Sultana, Aqil & Ali

310 Expert Rev. Ophthalmol. 2(2), (2007)

Penetration enhancersOne of the major obstacles in ocular drug delivery is poor per-meability of the cornea, which results in absorption of approxi-mately 10% or less of the applied dose into the anterior segmentof the eye. Two major categories of ocular penetration enhancersare paracellular (diffusive and convective transport occurringthrough intercellular spaces and tight junctions) and trans-cellular (cell/tissue partitioning/diffusion, channel diffusion andcarrier-mediated transport).

Ethylenediaminetetraacetic (EDTA) improves the paracellulartransport by its calcium ions chelating effect, which results in thewidening of tight junctions as calcium ions are involved inproper functioning of tight junctions [3].

A wide range of ocular penetration enhancers have been studiedfor over 10 years but, owing to their nonspecific actions (whichinclude permanent damage to ocular membranes and tight junc-tions), they have a low safety profile and, consequently, they arenot approved by the US FDA [4]. Recently, many penetrationenhancers were studied, such as cyclodextrins, that acted as truecarriers but were not capable of modifying permeability of a bio-logical barrier. Drug absorption is limited by release of drug fromdrug–cyclodextrin complex [5]. Cyclodextrins can be used to formaqueous eye drop solutions with lipophilic drugs, such as steroidsand some carbonic anhydrase inhibitors. The cyclodextrinsincrease the water solubility of the drug, enhance drug absorptioninto the eye, improve aqueous solubility and reduce local irritation.

Methazolamide is a carbonic anhydride inhibitor that is notbeing successfully formulated as an eye drop. In a double-blindclinical trial it was concluded that, through cyclodextrin complexa-tion, it was possible to produce topically active methazolamide eyedrops that lower IOP [6].

Azone® 0.1% can enhance corneal penetration of hydrophiliccompounds by 20-fold but inhibit corneal penetration oflipophilic compounds. It was speculated that Azone acted byloosening of tight junctions and alteration of membrane charac-teristics [7]. Saponin was also evaluated for ocular penetratingeffect and it acted by detergent action [8]. Pz-peptide is anothernovel penetration enhancer that reversibly opens tight junctionsand it demonstrated pronounced in vitro effect and lesser in vivoeffect. Pz-peptide failed to enhance ocular absorption of pro-pranolol, which might be due to binding of Pz-peptide to mucinand other ocular proteins [9].

Other excipients that were explored for ocular penetration-enhancing effect were colloidal systems, polyacrylates and bio-adhesive polymer. Although a number of approaches were tried,their utility will depend on their freedom from nonspecific actionsand their safety issues for the eye.

Corneal shieldsCorneal collagen shields were initially designed to promotewound healing but could be used to deliver drugs to the eye.Although the bioavailability is comparable with eye drops, theycould be considered as a technological improvement in drugdelivery. Most commonly the shields are used during surgery;however, a number of experimental studies reported use of corneal

shields for delivering drugs to the eye, particularly antibiotics,antifungal agents, anti-inflammatory agents, anticoagulants,antiviral agents and immunosuppressive agents. Collagen shieldswere found to deliver antibiotics more effectively after cataractsurgery compared with subconjunctival injections [10]. Collagenshields are manufactured from porcine or bovine collagen andthree different collagen shields are currently available with disso-lution times of 12, 24 and 72 h. The theoretical, experimentaland clinical evidence supports a role for corneal collagen shieldsas a drug delivery device and in the promotion of epithelial andstromal healing [11].

Collagen shields presoaked in solutions of gatifloxacin andmoxifloxacin showed good penetration of drugs into the anteriorchamber with no adverse reaction to the cornea [12]. A presoakedcollagen shield demonstrated a lower aqueous humor moxifloxacinlevel compared with eye drops but it offers the advantage of beingdissolved at the site of application [13].

Ocular iontophoresisOcular iontophoresis is a viable alternative delivery system forsubstances that are not amenable to topical application and thosethat require repeated administration over an extended period oftime. Current trends in ophthalmic research are towards resolvingproblems associated with iontophoretic techniques.

Iontophoresis of the various classes of drugs (antibiotics, anti-virals, antifungals, antimetabolite, adrenergic, steroids, anestheticsand dyes) can be delivered by two approaches: transcorneal ionto-phoresis, which delivers a high concentration of drug to the ante-rior segment of the eye, and transscleral iontophoresis, which canproduce significantly high and sustained drug concentrations inthe vitreous and retina [14].

Transscleral iontophoresis has advantages over transcornealdelivery [15], including the large surface area of the sclera com-pared with the cornea, enhanced transfer of drugs to the posteriorchamber and less chance of systemic absorption.

The duration of time during which iontophoresis is applied isalso a critical factor in therapy. It has been observed in some stud-ies that short (1–4 min) iontophoretic treatments have potentialclinical value [16].

Successful transcorneal delivery of insulin to the eye is beneficialin potentially lessening the severity of diabetic retinopathy. It wasfound that, on iontophoretic administration, insulin primarilyentered the conjunctiva and diffused into the sclera to enterintraocular tissues before it reached and accumulated in the opticnerves [17].

Ocular iontophoresis is fast, painless, safe and, in most cases,results in the delivery of a high concentration of drug to a specificocular site. Ocular iontophoresis has been used to introduce genesinto the anterior and posterior segments of the eye. A short, low-current, noninvasive iontophoretic treatment [18] using dexametha-sone-loaded hydrogels has potential clinical value in increasingdrug penetration to the anterior and posterior chamber [19].

The highest concentration of gentamicin sulphate was reachedafter iontophoresis with current intensity of 1.5 mA applied for60 s. The delivery of gentamicin to the eye through iontophoresis

Advances in the topical ocular drug delivery

www.future-drugs.com 311

with solid hydroxyethyl methacrylate/ethyene glycol dimethacrlatehydrogels seems to be a promising method, achieving high concen-tration of drug in the ocular tissues. In another study, delivery ofgentamicin to the rabbit eye by drug-loaded hydrogel iontophore-sis was found to be well tolerated and there was no statisticallysignificant difference between treatment and control groups [20].

Microparticles & nanoparticlesCurrently, only one microparticulate ophthalmic delivery system,Betoptic S®, containing betaxolol 0.25%, has been approved forcommercial use in the USA. The microparticulate technology pro-vides the dual benefits of improved patient compliance andextended drug release.

Particles ranging from 100 µm to the order of severalhundred micrometers are called microparticles [21] and aredivided into two groups: microcapsules, which are almostspherical entities of the order of several hundred micrometersin diameter, where the drug particles or droplets are trappedinside a polymeric membrane, and microspheres, which arepolymer–drug combinations where the drug is homogenouslydispersed in the polymer matrix. Particles of size smaller than1 µm are called nanoparticles. Nanocapsules are small reser-voirs consisting of a central cavity surrounded by a polymericmembrane. Nanospheres are small solid monolithic spheresconstituting a dense solid polymeric network, which developsa large surface area.

Table 1. Research advances in ophthalmic drug delivery.

Ocular drugdelivery system

Drug/target disease Polymers/bases/excipients

Ophthalmic research Ref.

Penetrationenhancers

Hydrocortisone/ocular inflammationLevobunolol/glaucoma

Cyclodextrins,Azone®

Cyclodextrins act as true carriers by complexation between hydrophobic molecules and inner hydrophobic cores of cyclodextrins. Azone® 0.1% can enhance corneal penetration of hydrophilic compounds but inhibit corneal penetration of lipophilic compounds

[5,7]

Collagenshield

Gatifloxacin and moxifloxacin/ocular infection

Collagen shield Collagen shields presoaked in solutions of drugs showed good penetration of drugs into the anterior chamber with no adverse reaction in the cornea

[12]

Oculariontophoresis

Dexamethasone Hydrogel matrix and iontophoresis device

Iontophoresis using dexamethasone-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior and posterior chamber

[19]

Microparticles/nanoparticles

Tobramycin/ocular infection

Solid lipid nanoparticles in the colloidal size range (average diameter below 100 nm; polydispersity index below 0.2)

Nanoparticles produced a significantly higher bioavailability in the aqueous humor compared with an aqueous solution of the drug

[30]

Ocularinserts

Fluorescein/dye Thiolated polyacrylic acid

Thiolated polyacrylic acid inserts demonstrated better ocular retention compared with nonthiolated polymer inserts

[41]

Mucoadhesivepolymers

Sodium hyaluronate/dry eye disorder

Sodium hyaluronate

Diluted solutions of sodium hyaluronate have been employed successfully as tear substitutes in severe dry eye disorders

[61]

In situ gelling system

Timolol maleate/ glaucoma, pefloxacin mesylate/ocular infection,Pilocarpine

Gelrite® (deacetylated gellan gum [DCG]) Alginates with high G content (>65%)

Gelrite® solution has shown superior bioavailability when formulated with a number of ocular drugs. Alginates with high G content demonstrated instant gelation at low concentration (0.5%)

[76,77,93]

Dendrimers Pilocarpine nitrate/ glaucoma and tropicamide

Polyamido amine (PAMAM) dendrimer

Demonstration of bioadhesive properties and interaction between dendrimer and surface of cornea

[104]

Lipidemulsions

Cyclosporin A/antifungal Cationic lipid emulsion

Cationic lipid emulsion of cyclosporine A demonstrated enhanced bioavailability compared with anionic formulation owing to the electrostatic attraction between the cationic oil droplets and anionic corneal surface moieties

[117]

Ocularinserts

Thiolated polyacrylic acid

Thiolated polyacrylic acid inserts demonstrated better ocular retention compared with nonthiolated polymer inserts

[26]

Sultana, Aqil & Ali


Polymers used in the preparation of microparticulates may beerodible, biodegradable, nonerodible or ion exchange resins [22].Nonbiodegradable polymers are either digested by enzymes ordegraded in vivo through a chemical pathway. The utility ofnanoparticles as an ocular drug delivery system may depend on [23]:

• Optimizing lipophilic–hydrophilic properties of thedrug–polymer system

• Optimizing rates of biodegradation in the precorneal pocket

• Increasing retention efficiency in the precorneal pocket

It is desirable to produce nanoparticles with bioadhesive prop-erties. Without biadhesion, nanoparticle would be eliminated asquickly as aqueous solution from the precorneal site.

Nanoparticles made of polyacrylamide or polymethyl meth-acrylate (PMMA) do not degrade either biologically or enzym-atically, which makes them less popular for ophthalmic use [24].Polyacrylcyanoacrylate (PACA) has been used for decades in sur-gery and is considered free from toxicity and safe for ocular use.Its biodegradation and bioadhesion make it an attractive carrierfor controlled ocular delivery [25].

To prepare PACA nanoparticles, monomer at a concentrationof 0.1–0.3% is added to an aqueous system of the drug solu-tion. Alkyl cyanoacrylate particles polymerize according to ananionic mechanism in an aqueous medium using hydroxyl ionsas the initiators. Starting with the polymeric reaction in anacidic medium and varying the pH of the medium during thepolymerization process, the velocity of polymerization andmolecular weight of the resultant polymer can be controlled,which influences the particle size of the nanoparticles formedby this reaction [26].

Another significant advantage with this polymer is that theseparticles do not require high energy input for the polymeriza-tion process and there is no effect on the stability of theabsorbed drug. However, PACA nanoparticles penetrate intothe outer layer of corneal epithelium, causing disruption of cellmembrane [27].

Another polymer, poly-å-caprolactone produced betterresults in terms of ocular bioavailability [28]. The colloidal parti-cles are taken up preferentially by the corneal epitheliumthrough an endocytotic mechanism in inflammed conditioncompared with the healthy tissue and this accounts for theimproved bioavailability of nanoparticles under inflammatoryconditions [29].

Solid lipid nanoparticles in the colloidal size range (averagediameter <100 µm; polydispersity index <0.2) and containing2.5% tobramycin as ion–pair complex with hexadecyl phosphateproduced a significantly higher bioavailability in the aqueoushumor compared with an aqueous solution of the drug [30].

Technological results of a study with Eudragit retard(Eudragit RS 100 and Eudragit RL 100) nanopaticle suspen-sion containing cloricromene revealed enhanced bioavailabilityand improved shelf life of the drug [31]. A nanoparticle systemwith polymer Eudragit RL 100 only and containing cloricro-mene showed interesting size distribution, surface charge val-ues and increased ocular bioavailability of the drug [32]. Ocular

tolerability of Eudragit RS 100 and RL 100 nanoparticles wasevaluated in the rabbit eye using a modified Draize test and itwas found to be free from any irritant effect on the cornea, irisand conjunctiva up to 24 h after application [33].

Eudragit RS 100 nanoparticle suspensions loaded with ibu-profen indicated an increase in pharmacological activity andocular bioavailability of drug [34]. Controlled delivery of ibu-profen was achieved by loading in Eudragit RS 100 nano-suspension and the delivery system did not show toxicity onocular tissues [35].

Flurbiprofen (FB)-loaded acrylate polymer nanosuspensionsdemonstrated freedom from ocular toxicity and enhanced bio-availability of the drug [36]. Poly(lactic/glycolic) acid nano-particles incorporating FB were prepared by the solvent dis-placement technique using poloxamer 188 as a stabilizer toimprove the availability of the drug for the prevention of theinflammation caused by ocular surgery. These formulationsshowed an appropriate average size for ophthalmic administra-tion (232.8 and 277.6 µm, respectively) and a good yield ofentrapment efficiency (94.60 and 93.55%, respectively). Therelease behavior of FB from the developed nanoparticles wascomplete and exhibited a biphasic pattern. Formulations did notshow toxicity on ocular tissues [37].

Ocular insertsOcular inserts are the solid devices that are placed in thecul-de-sac or the cornea, and present the advantage of avoidinga pulsed release owing to multiple applications and providingincreased residence time. The ocular inserts are classified intothree major categories based upon their solubility behaviour [38]:insoluble, soluble and bioerodible inserts. The insoluble insertshave been classified in three groups: diffusional systems,osmotic systems and hydrophilic contact lenses. The diffusionalsystems are composed of the central reservoir of the drugenclosed in specially designed semipermeable or microporousmembrane. The osmotic inserts are generally composed of acentral part surrounded by a peripheral part. The central partconsists of either a single reservoir (composed of drug with orwithout an additional osmotic solute dispersed though the pol-ymeric matrix) or two compartments (one compartment ofdrug reservoir containing drug surrounded by an elastic imper-meable membrane and another osmotic solute reservoir con-taining osmotic solute surrounded by a semipermeable mem-brane). Contact lenses are a group of insoluble ophthalmicdevices that need removal after use. Refojo subdivided contactlenses into five groups: rigid, semi-rigid, elastomeric, softhydrophilic and biopolymeric [39]. Soluble ocular inserts offerthe advantage of being entirely soluble so that they do not needto be removed from their site of application. They are madefrom natural and synthetic or semisynthetic polymers. Thebioerodible inserts are composed of homogenous dispersion of adrug included into a hydrophobic coating that is substantiallyimpermeable to the drug. The main components of such insertsare called bierodible polymers, that is, materials that undergohydrolysis of chemical bonds and, hence, dissolution.



Unmedicated hydroxypropyl cellulose matrices are used inthe treatment of keratitis sicca (Lacrisert, Merck, Sharp andDohme). Soluble ophthalmic drug inserts (SODIs) are madefrom polymers of polyacrylamide, ethylacrylate and vinyl-pyrrolidone and are prepared as thin, elastic, oval plates. Theywere endorsed for use in ophthalmic practice in the USSR in1971 [40].

The Ocusert therapeutic system, developed by Alza Corpora-tion, is a device that releases the drug at a rigorously constantand reproducible rate for over 1 week. The Ocusert and Lacri-sert are the two ocular inserts that are marketed in Westerncountries but they have not gained popularity until now owingto patient and clinician unwillingness to administer unfamiliarmedication and also owing to therapeutic failures that couldoccur due to unnoticed expulsion of insert from the eye andrupture of membrane.

Thiolated polyacrylic acid 450 kDa (PAA450–cysteine conju-gate) was prepared by direct compression and provided suffi-cient fluorescein concentration in the tear film for more than8 h. By contrast, a rapid drainage of the tracer was measuredafter application of inserts based on unmodified polyacrylic acidinserts or an aqueous reference solution [41]. Thiomer inserts arebioadhesive, insoluble and are generally well tolerated in the eye.

Mucoadhesive polymers, such as acrylates and polyethyleneoxide (PEO), are used to prepare ocular mini-tablets and erodi-ble inserts, respectively. Recent studies on the mini-tablets,PEO and thiomer inserts proved that small, well-toleratedmucoadhesive devices are promising drug delivery systems inthe treatment of external and intraocular eye infections and dis-eases requiring frequent eye drop instillation to maintain thera-peutic drug levels. Bupivacaine was formulated as soluble ocu-lar insert using hyaluronic acid (HA) and its effectiveness wasassessed in healthy volunteers. Bupivacaine 1 mg was found tobe a safe and effective dose [42].

Mucoadhesive erodible ocular inserts of ofloxacin were pre-pared using PEO by powder compression and the effect of chi-tosan hydrochloride (Ch-HCL) on drug release was examined.It was found that addition of 10, 20 or 30% medicated Ch-HCL microparticles to ocular inserts produced changes therein,which accelerated insert erosion and drug release from theinserts [43].

The release mechanism of different drugs, namely, pred-nisolone (PDS), oxytetracycline hydrochloride (OTH) and gen-tamicin sulphate (GTS) from erodible ocular inserts based onPEO was studied. It was found that release of an approximately50% GTS dose was controlled by diffusion owing to the highwater solubility of the drug, accompanied by weak drug–PEOinteractions, whereas PDS and OTH were released with erosion-controlled kinetics [44].

Effects of the molecular weight of polymer PEO on the prop-erties of ofloxacin inserts were examined. It was found thatmucoadhesion was dependant on molecular weight and maxi-mum mucoadhesion was observed with PEG 400. PEG 2000was not suitable as a material for ocular insert due to its excessivetendency to swell, which results in spillage from the eye [45].

Gel-forming ocular inserts of ofloxacin were prepared usinghigh molecular-weight (400 kDa) linear PEO. The erosiontime scale was varied by compounding PEO with EudragitL100 (EUD), 17% neutralized (EUD Na17) or 71% neutral-ized (EUD Na71). Immediately after instillation in the eye,the insert-based nonplain PEO, PEO- EUD Na17 or EUDNa71 formed mucoadhesive gels. The gel residence time in theprecorneal area was in the order EUD Na17 < PEO < EUDNa71 [46].

Various sustained-release mini-tablet (2 mm, 6 mg) formulaeconsisting of sodium fluorescein as model drug and bioadhesivepowders (drum-dried waxy maize starch [DDWM], Amiocastarch, carbopol 74P) were manufactured at a compressionforce of 1.25 kN. It was found that slower release was obtainedwith formulae containing cospray-dried Amioca with 15%(with water [w/w]) carbopol 974P and the formulation did notproduce any mucosal irritation and released the model drug for12 h after application in the fornix [47].

Prolonged-release ciprofloxacin-containing ocular gellingmini-tablets were evaluated in volunteers. The ocular mini-tab-let applied in the fornix was generally well tolerated by healthyvolunteers [48].

The efficiency and tolerance of the Mydriasert® ocular inserton pupil dilation were evaluated. The size of maximal mydriasisobtained when using the insert was significantly greater thanthat obtained using eye drops, regardless of the frequency ofinstillation (p < 0.04) [49].

The usefulness of molecular imprinting technology to obtaintherapeutic soft contact lenses capable of prolonging the per-manence of timolol in the precorneal area compared with con-ventional contact lenses and eye drops was evaluated. Timolol-release studies carried out in rabbits showed that soft contactlenses made by the molecular imprinting method providedmeasurable timolol concentrations in the tear fluid for two- andthreefold longer than nonimprinted contact lenses and eyedrops [50].

The influence of the composition of soft contact lenses onthe achievement of a significant increase in drug loading andcontrol release was evaluated. Four types of timolol-imprintedlenses were prepared by UV irradiation of N, N-diethylacryla-mide (DEAA), 2-hydroxyethylmethacrylate (HEMA), 1-(trist-rimethyl-siloxysilylpropyl)-methacrylate (SiMA) and N, N-dimethylacrylamide (DMAA) (50:50 v/v), or methylmeth-acrylate (MMA) and DMAA (50:50 v/v) solutions, to whichfunctional monomer, methacrylic acid (MAA, 100 mM), crosslinker, ethyleneglycol dimethacrylate (EGDMA, 140 mM) andtimolol maleate (25 mM) were previously added. The resultsindicate that, by modulating the composition of the lenses, it ispossible to adapt the drug loading and release behavior of thelenses to the treatment requirements of specific pathologicalprocesses [51].

The utility of molecular imprinting for improving the loadingcapacity of weakly cross-linked hydrogels for subsequent use assoft contact lenses for administration of timolol was evaluated.Imprinted hydrogels were prepared considering preformulation

Sultana, Aqil & Ali


of complexes between methacylic acid (functional monomers)and timolol (target molecules) and polymerization with N,DEAA and EGDMA (cross-linker) after injection in molds(0.3 mm thickness) and UV irradiation at room temperature.The results indicated that absorption sites capable of capturingthe target molecules were encoded effectively into the polymernetwork by the molecular imprinting technique and improvedthe drug loading capacity of the gels [52].

The influence of the composition and the application of theimprinting technique on the loading capability of HEMAhydrogels, with a view to their use as reloadable soft contactlenses for administration of timolol, was investigated. Theresult of the study indicated that the incorporation of MAA ascomonomer increases the timolol loading capacity to thera-peutically useful levels, while retaining appropriate releasecharacteristics [53].

In an attempt to reduce drug loss and side effects associatedwith conventional therapy, dimyristol phosphatidylcholine(DMPC) liposomes were dispersed in lens material (poly-2-hydroxyethyl methacrylate{p-HEMA}hydrogels) [54]. Theresults of this study showed that the p-HEMA gels loaded withliposomes were transparent and released drug for a period ofapproximately 8 days [55].

Mucoadhesive polymersThe mucoadhesive approach, which was successful in oral andbuccal drug delivery, was extended to ocular drug deliverybased on the presence of mucin in the eye. Some mucoadhesivepolymers showed not only good potential to increase bio-availability of the applied drugs but also protective and healingproperties to epithelial cells [56].

Mucus consists of glycoproteins, proteins, lipids, electrolytes,enzymes, mucopolysaccharides and water. The primary compo-nent of mucus is mucin, a high molecular-mass glycoproteinwith subunits containing a protein core, approximately800 amino acids long, of which 200 are bearing polysaccharideside chains. As the polysaccharide side chains usually terminatein either fucose or sialic acid (N-acetylmeuraminic acid,pKa = 2.6), the glycoprotein is negatively charged at the physi-ological pH. The preferential uptake of cationic liposomes bythe cornea is probable evidence to support the hypothesis ofelectrostatic interactions between the mucins and cationicmucoadhesives. In the case of anionic polymers, a hydrogenbonding mechanism is suggested for mucoadhesion [57].

The mechanism by which mucoadhesion takes place hasbeen said to have two stages; the contact (wetting) stage fol-lowed by the consolidation (establishment of the adhesiveinteractions) stage. The relative importance of each stage willdepend on the individual application. For example, adsorptionis a key stage if the dosage form cannot be applied directly tothe mucosa of interest, while consolidation is important if theformulation is exposed to significant dislodging stresses. Adhe-sive joint failure will inevitably occur as a result of over-hydration of a dosage form or as a result of epithelia or mucusturnover [58]. It has been demonstrated by several research

groups that charged polymers, both cationic and anionic, pos-sess better mucoadhesive property in comparison with nonioniccellulose ethers or polyvinyl alcohol [59,60].

HA is an important constituent of the extracellular matrixthat may play a role in inflammation and wound healing andmay promote corneal epithelial cell proliferation. Diluted solu-tions of sodium hyaluronate have been employed successfully astear substitutes in severe dry-eye disorders. The beneficialeffects are attributed to viscoelasticity and biophysical proper-ties similar to mucins providing long-lasting hydration andretention [61,62].

Chitosan (CS) is biodegradable, biocompatible and non-toxic. It possesses antimicrobial and wound-healing propertiesand exhibits pseudoplastic and viscoelastic behaviour [63]. CSis used as a viscosity-enhancing agent in artificial tear formula-tions owing to its excellent tolerance after topical application,bioadhesive properties, hydrophilicity and good spreadingover the entire cornea. A cationic biopolymer is endowed withgood wetting properties, as well as an antibacterial effect thatis desirable in cases of dry eye, which is often complicated bysecondary infections.

The effect of Ch-HCL and of N-carboxymethylchitosan(CMCh), formulated in ophthalmic solutions, on the ocularpharmacokinetics of ofloxacin, was studied in rabbits. Ch-HCLsignificantly enhanced intraocular drug penetration withrespect to an isoviscous drug solution containing polyvinylalcohol and commercial ofloxacin eye drops. This effect, whichresulted in an approximately 190% increase of the peak con-centration in the aqueous, was ascribed to an increased cornealpermeability [64].

N-trimethyl chitosan (TMC) polymers differing in quar-ternization degree (QD) and molecular weights were preparedfrom two CS 90% deacetylated, one of higher molecular weight(1460 kDa) (TMCH), the other of low molecular weight(580 kDa) (TMCL), by one, two or three reductive methyl-ation steps. TMC polymers of intermediate QD, at the concen-tration of 0.001% w/v, produced significant permeabilityenhancement, independent of polymer molecular weight [65].

A long-lasting pilocarpine-loaded CS/Carbopol® nanoparticleophthalmic formulation was developed and showed the mostsignificant long-lasting decrease in the pupil diameter of rabbitsin an in vivo miotic study. The advantages of CS and Carbopolare good biocompatibility, biodegradability and low toxicity [66].γ-scintigraphic studies demonstrated that CS formulationsremain on the precorneal surface as long as commonly usedcommercial artificial tears (Protagent collyrium® andProtagent-SE® unit-dose), having a fivefold higher viscosity [67].

Lele and Hoffman have developed a new mucoadhesive drugdelivery formulation based on an ionic complex of partiallyneutralized polyacrylic acid (PAA) and a highly potentβ-blocker drug, levobetaxolol × hydrochloride (LB x HCl), foruse in the treatment of glaucoma [68]. Thin films of the com-plexes dissociated to release the drug by ion exchange with syn-thetic tear fluid. The films shrunk continuously during releaseof the drug and dissolved completely in 1 h.



Mucoadhesive eyedrops containing tetrahydrozoline hydro-chloride (TZ), a decongestant drug, were based on a ternaryinteraction drug–polymer–polymer. The anionic polymersassessed were the anionic HA and PAA, the cationic CS (HCS)and the polyelectrolyte gelatin (G). Formulations based on theternary systems TZ/G/HA, TZ/HCS/HA, TZ/G/PAA andTZ/HCS/PAA at the stoichiometry ratios between cationic andanionic polymers and containing a ten- and 20-fold excess ofthe anionic polymers were prepared [69].

Numerous polysaccharides were evaluated as mucoadhesivesophthalmic vehicles [70–74]: polygalactouronic acid [75], xylo-glucan [70], xanthan gum [71], gellan gum [76,77], pullulan, guargum, scleroglucan [78] and carrageenan [74]. Polysaccharidesformed macromolecular ionic complexes with drugs thatimproved bioavailability and lengthened the therapeutic effectcompared with drug solutions.

Xyloglucan, due to its mucin like structure, has cell protectiveproperties and reduced drug-related toxicity, and is well toler-ated by conjunctival cells [70]. Xanthan gum interacts moder-ately with mucins and delays the clearance of the instilled solu-tions. However, the effect of gelation mechanism of gellan gumis superior to xanthan gum, especially at the later time points.The performances of a mucoadhesive polysaccharide from tama-rind seed (xyloglucan or tamarind seed polysaccharide [TSP]) asan adjuvant for ophthalmic vehicles containing timolol wereevaluated. The polymer under investigation, in spite of a com-paratively low viscosity, produced high timolol concentrations inthe ocular tissues and a low systemic absorption. The perform-ances of the TSP vehicle were comparable to those of a referencein situ gelling formulation (Timoptic XE®) [79].

In an attempt to improve bioadhesion, polyacrylates, CS,alginate, deacetylated gellan gum and cellulose derivativeswere synthesized with immobilized thiol group [80–83]. Theresulting polymers, called thiolated polymers or thiomers, arecapable of forming covalent bonds with mucins, whereas othermucoadhesive polymers discussed above formed noncovalentbonds or physical entanglements. The extensive cross-linkingof the thiomers resulted in a tremendous increase in viscosityand mucoadhesion, independent of pH or ionic strength ofthe medium.

It has also been demonstrated that thiomers possesspermeation-enhancing properties for the paracellular uptake ofdrugs [84]. This is achieved by the opening of tight junctions.Thiomers could be useful additives in artificial tear formula-tion owing to their antioxidant and free radical scavengingproperties [85]. The formation of disulfide bonds with mucinsleads to strong mucoadhesion, prolonged residence time andprotective effect for the corneal/conjunctival epithelium. Thein situ gelling, mucoadhesive, permeation-enhancing propertyof thiomers makes them a viable ocular drug delivery system.

In situ gelling systemsGelation is a gel form of coacervate, which is obtained by theagglomeration and coalescence of particles in large numbersinduced by any process that destabilizes the pseudolatex (a

dispersion of an already formed polymer in water). Destabiliz-ation of pseudolatex is effected by physical agents or by chemi-cal coacervants. Physical destabilization can be induced byincreasing the frequency or energy of the collisions betweennanoparticles. Several concepts for the in situ gelling systemshave been investigated. These systems can be triggered by pH,temperature or by ions present in the tear fluid.

pH-mediated in situ gelling systems are based on the conceptof the alkali-induced thickening phenomenon of anionic lat-tices due to the presence of a carbonic buffer system regulatingthe pH of tears, as described by Ibrahim [86]. Nanodispersionswith a low viscosity and containing a large amount of poly-meric material exhibit an increase in viscosity when neutralizedwith a base. Wesslau described this effect as an inner thicken-ing, which is due to the swelling of the particles from theneutralization of the acid groups contained in the polymerchain and the absorption of water [87]. The pH of the tears isnormally approximately 7.2–7.4. The dispersion of an anionicpolymer in water typically shows a very low viscosity up to pH5 and will coacervate in contact with the tear fluid, forming agel. Examples of these types of polymers are cellulose acetatephthalate (CAP) and Carbopol.

The in situ gelling system formulated with CAP increased thehalf-life of residence on the rabbit corneal surface to 400 s com-pared with 40 s for solution [88]. However, this system is charac-terized by a high polymer concentration, (30% CAP) and thelow pH of the instilled solution may be a discomfort (irritant)for the patient.

Temperature-mediated in situ gelling systems exhibit thermo-reversible gelation at the temperature of the eye (33–34°C).Examples are pluronics, tetraonics and ethyl hydroxyethyl cel-lulose. A number of studies demonstrated thermoreversible gel-ling properties of pluronics but these polymers are character-ized by high polymer concentration (25% poloxamer), inaddition to the surfactive properties of the poloxamer, whichmay be detrimental to the ocular tolerance [89]. Ions mediatedin in situ gelling system gels in the presence of cations presentin the tear fluid and are exemplified by Gelrite® and alginate.

Gelrite (deacetylated gellan gum [DCG]) solutions haveshown superior bioavailability when formulated with a numberof ocular drugs [76,77,90]. It requires very low polymer concentra-tion (0.6%), is well tolerated by the eye, possesses optical clarityand is capable of withstanding heat during autoclaving.Shibuya and colleagues compared two gel-forming timololmaleate ophthalmic solutions, Timoptol XE and Lizmon TG®,with regard to efficacy and tolerability in patients with glau-coma or ocular hypertension by means of a patient-masked,prospective, randomized crossover study [91]. A total of29 patients (78.4%) preferred to use gel-forming timolol solu-tions rather than twice-daily timolol ophthalmic solution. Thepresence of concurrently used ophthalmic solutions did notaffect the incidences of subjective symptoms. The incidences ofobjective adverse effects were not significantly differentbetween two gel-forming timolol ophthalmic solutions. To fur-ther improve in situ gelling behavior, Krauland and colleagues

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thiolated DCG, which provided dual benefits of cation-dependant sol-gel transition of DCG and the oxidation-basedin situ gelation of thiomers [92]. The net result was stronglyimproved viscous and elastic properties.

Alginates with high guluronic acid content (>65%) demon-strated instant gelation compared with polymer with low Gcontent and the gelation of polymer with high G contentoccurred at low polymer concentration (0.5%). In the eye, algi-nate cross-linked to bivalent cations and also formed complexwith proteins to form a polyelectrolyte complex, which precipi-tates out of the solution. An example of such a complex is algi-nate-poly(L-Lysine) complex [93]. It was shown that matricesbased on these polyelectrolyte complexes were less sensitive todilution or ion-exchange reactions and maintained their struc-ture under physiological conditions. Furthermore, alginateswith high G contents have demonstrated adequate gel strengthwhich enables them to withstand shear forces in the eye. Intheir study using alginate as carrier for ocular delivery of pilo-carpine, Cohen and colleagues have concluded that alginateshave excellent tolerance, are easy to administer in the eye andform a low-viscosity, free-flowing liquid that will be convertedto gel form in the cul-de-sac of the eye [93].

Joshi and colleagues first used a combination of polymers toobtain enhanced in situ gelling effects [201]. Later on, carbopoland hydroxyl propyl methyl cellulose [94], carbopol and methylcellulose [95], alginate and pluronic [96] and carbopol andpluronic [97] were used in combination to provide improvedin situ gelling in the eye.

DendrimersDendrimers are the class of polymers that have a dendriticmacromolecular architecture due to their branching structuresimilar to that of the trees. Tomalia and colleagues developedthe first dendrimer, named the starburst TM polyamidoamine(PAMAM) dendrimer owing to its dendritic branches and con-trolled starburst growth [98]. This macromolecule is built on anammonia core with extending branches of alternating methylacrylate and ethylene diamine molecules [99]. The cascade iscontinued by adding methyl acrylate moieties onto the reactiveends of the ethylene diamine molecules and then ethylenediamine moieties onto the methyl acrylate. Each addition cre-ates another branched layer, referred to as generation. Eachgeneration causes an exponential increase in the surface reactivesites that may have functional implications [100]. The dendrimerpossesses a remarkably cell-like construction consisting of alow-density core and modifiable internal and external surfaces,making it a perfect container or scaffolding for drugs, DNAand protein [101].

Uppuluri and colleagues have shown that the PAMAM den-drimers solutions exhibited typical Newtonian flow behavior[102]. In a neutral medium, the mucin molecule is negativelycharged (pKa = 2.6) and behaves like an anionic polyelectrolyte.It repels the negatively charged dendrimers, resulting in amarked decrease in mucoadhesion [103]. Vandamme and Brobeckdemonstrated the bioadhesive properties of dendrimers, which

also contributed to the increase in bioavailability of oculardrugs [103]. They concluded that the interactions between den-drimers and the surface of the cornea can lead to a structure withmore rigid behavior that traps some of the instilled solution.The release of this trapped solution will be slower because thesolutes have to diffuse through this macromolecular structure.

Site-specific chemical delivery systems & soft drugsTailor-made drugs and delivery systems are required for manydiseases of the eye. As the therapeutic ratio of the majority ofocular drugs is low, it is necessary to design drugs specifically forthe eye with emphasis on safety and efficacy [104]. Chemicaldelivery systems and soft drugs are designed with the objective ofimproving the therapeutic index without compromising its activ-ity, by taking into account the anatomical, physiological andmetabolic considerations. The ultimate goal of drug delivery is toconjugate the drug with the carrier to modify the pharmacoki-netic profile and make it site specific. The carrier can be anothersmall molecule or a macromolecular system. In both cases, theconjugate must be able to regenerate the active species throughchemical or enzymatic hydrolysis, preferably at the site of action.

The concept of a chemical delivery system based on predict-able enzymatic (metabolic) activation processes was proposedto overcome the transport-related problems in the delivery ofactive compounds to the target sites in the body. A CDS, whendelivered, will undergo several predictable, stepwise enzymatictransformations and finally result in selective delivery of drug tothe site of action, thereby leaving the rest of the body free fromactive drug. The site specificity of CDS is by virtue of eithertrapping of precursor in a specific organ, such as the brain, ordue to the presence of some specific enzyme systems at the siteof action [105–108].

A soft drug can be defined as a biologically active compoundcharacterized by a predictable and controllable in vivo destruc-tion (metabolism) to a nontoxic product (metabolite) after ithas achieved its therapeutic effect. Inactive metabolite approachfor ocular drugs was most effective for designing ocular drugs.The design process starts with a known or predicted metaboliteof the drug that is completely devoid of any activity. This inac-tive metabolite is structurally modified to the active drug,which is referred to as soft drug. The soft drug thus designedhas soft moieties, which are subject to a facile and predictablemetabolism, theoretically in a single step to the starting inactivemetabolite. This metabolism is generally hydrolytic in nature.As this predictable metabolic deactivation takes place every-where in the body, the desired activity is produced exclusively atthe target site at or near the site of application [109,110].

The principle of soft drug design is to avoid the formation oftoxic metabolites for a given drug. A soft drug with a relativelyshort half-life is the best candidate to be formulated into con-trolled/sustained release systems for local administration intothe eye.

The prodrug approach reduces toxicity selectively by changingthe pharmacokinetic aspects of drug delivery. A prodrug is inac-tive and is transformed into active drug in vivo. The inactive



derivatives of drug molecules are better able to penetrate thecornea. After entering the cornea, the prodrug can be changedinto active form either hemically or enzymatically. Davis andcolleagues worked on recent advances in surgical techniquesand therapeutic approach (prodrug) material science, whichmade the revolution in ocular therapies [111].

Tirucherai studied corneal permeation of gancyclovir, an anti-viral drug with low ocular bioavailability [112]. He studied themechanism of gancyclovir permeation, enhanced by acyl esterprodrug design, and found that bioavailabilities are increased byprodrug design . Juntunen investigated the in vitro corneal per-meation of cannabinoids and their water-soluble phosphateester prodrug [113]. According to this study, topically adminis-tered cannabinoids have been shown to reduce IOP by interfer-ing with the ocular cannabinoids receptor. The use of hydroxypropyl β-cyclodextrin (HP β−CD) demonstrated that the fluxincreases by 45–70% of their corresponding parent compound.Lallemand also investigated the water soluble prodrug ofcyclosporin A for ocular application [114,115].

Lipid emulsionsOil in water (o/w)-type lipid emulsions have been investigatedas vehicle to improve bioavailability of ocular drugs.Cyclosporine A 0.05% lipid emulsion (Restasis®, Allergan,USA) is being marketed in the USA for the treatment ofchronic eye diseases. The novel cyclosporine A anionic lipidemulsion represents a breakthrough in the formulation of thiscomplex highly lipophilic molecule.

In a study with pilocarpine hydrochloride formulated as ananionic lipid emulsion [116], it was shown that, although theformulation has prolonged pharmacological action and satisfac-tory chemical stability, the ocular bioavailability has notimproved when compared with aqueous solution of the samedrug. It was suggested that inadequate precorneal residencetime of egg–lecithin stabilized lipid emulsion is the probablereason for such findings. Sasaki and colleagues have proposed amechanism for the better ocular tolerability of castor oil-basedemulsions [117]. When these emulsions interact with tears in theeye, electrolytes in the tears destabilize the emulsion, whichresults in release of oil. This oil supplements the lipid layer intears (consisting of phospholipids, saturated and unsaturatedfatty acids and triglycerides) and resides in the eye for longerperiods of time. These lipid emulsions closely correspond totear fluid and participate in forming a physiological tear film.

The cationic lipid emulsion of cyclosporine A demonstratedenhanced bioavailability compared with anionic formulation,owing to the electrostatic attraction between the cationic oildroplets and anionic corneal surface moieties [116]. Further-more, cationic lipid emulsions exhibited better ‘wettability’and, consequently, good spreading behavior over the pre-corneal area. It was found that the concentration ofcyclosporine A in the sclera-retina and in the optic nerve washigher with cationic emulsion than with anionic emulsion andit was concluded that the drugs’ diffusion occurred by thetransconjunctival route as aqueous humor and blood levels

were low. The suggested mechanism by which cationic emul-sions produced higher drug levels than the anionic emulsionswas penetration through endocytosis.

Vesicular systemVesicular systems have several advantages: improvement inocular residence time, sustainable action and minimization ofside effects. All these advantages lead to a reduction in dosesize and frequency of dosing and an increase in patient compli-ance. The vesicular systems are also used for targeting the drugcandidate [118].

LiposomeLiposomes are vesicular system of micron size composed of oneor more concentric lipid bilayers encapsulating the drug candi-date in an aqueous compartment. According to size, liposomesare categorized as small unilamellar vesicle (SUV), 10–100 µm,large unilamellar vesicle (LUV), 100–300 µm, giant unilamel-lar vesicle (GUV), more than 1 µm, oligo-lamellar vesicle(OLV), 0.1–1 µm, and multilamellar vesicle (MLV), more than0.5 µm.

The drugs that are poorly absorbed and have a low partitioncoefficient are formulated as a liposomal drug delivery systembecause the liposome is able to have ultimate contact with thecornea, which increase the probability of ocular drug absorp-tion. Liposome offers several advantages; it provides targetingto the tumor tissue, increases efficiency and increases stabilityvia encapsulation, has improved pharmacokinetics and iscompletely biodegradable.

Surface charge is important for the liposome behavior. Cati-onic liposome seems to be preferentially captured at the nega-tively charged corneal surface compared with neutral or nega-tively charged liposomes. Cortesi and colleagues studiedcationic liposome and reported that it is a potential carrier forocular administration of peptides with antiherpetic activity [119].

Chetoni and colleagues compared the liposome-encapsu-lated acyclovir with acyclovir ointment by determining thepharmacokinetic drug profile in rabbit aqueous humor aftertopical administration [120]. Monem and colleagues studied theprobability of using liposome as an ophthalmic drug deliverysystem for the lipophilic drug candidate, pilocarpine HCl, onthe eyes of normal and glaucomatous pigmented rabbits [121].They concluded that administration with neutral MLVs dis-played the most prolonged effect with respect to negativelycharged MLVs and free drug. The most common problemwith liposome is stability due to the presence of phospholipidbilayers, which leads to a short half-life.

NiosomesNiosomes are simply defined as the vesicular system, which canbe used as carrier for both hydrophilic and lipophilic drugs can-didate. Niosomes are a good alternative to liposomes because ofseveral advantages; more chemical stability, less oxidativedegradation of phospholipids and low cost. Aggarwal and col-leagues reported that there was improved pharmacodynamics of

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timolol maleate from a mucoadhesive niosomal ophthalmicdrug delivery system [122]. Guinedi and colleagues preparedand evaluated the reverse-phase evaporation and multilamellarniosome as an ophthalmic carrier of acetazolamide [123].

Microemulsions Microemulsions (MEs) are an isotropic and thermodynam-ically stable multicomponent fluid system composed of water,oil, surfactant and/or cosurfactant. o/w microemulsions havebeen investigated for ocular administration, to dissolve poorlysoluble drugs, to increase absorption and to attend prolongrelease profile. Sakai and colleagues studied the stability oflatanoprost in an ophthalmic lipid emulsion using polyvinylalcohol, which showed good heat stability [124]. Lv and col-leagues studied the stability of chloramphenicol in ME free ofalcohols using span 20, tween 20, isopropyl myristate (IPM)and water, and concluded that the stability of chlorampheni-col increased remarkably [125]. Alany investigated o/w MEscapable of undergoing a phase transition to lamellar liquidcrystal (LC) or bicontinuous ME upon aqueous dilutionusing crodamol Eo, crill 1 and crillet 4, and alkanol or alkan-diol as cosurfactant, and water [126]. It was shown that phasetransition of ME to LC may be induced by tears and served toprolong precorneal retention.

Lyophilisate carrier systemLyophilisate carrier system is a recently used system in oculartherapy. It consists of freeze-dried products, free from water,applied to the eye. The ophthalmic lyophilisate carrier sys-tem (OLCS) has two important advantages, being easy toadminister and high tolerability, if the force of adhesionbetween lyophilisate and carrier strips and the structuralfirmness of the lyophilisate are well regulated. The OLCS is anovel dosage form for the delivery of pharmacologicallyactive ingredients or other substances, improving the struc-ture of the tear film in the eye. A drop of lyophilisate con-taining the drug and bulk forming water-soluble or swellingexcipients is attached to a flexible hydrophobic carrier [127].This lyophilisate system is prepared by using sodiumfluorescein 0.17%, which was dissolved in an aqueous solu-tion of hydroxypropylmethyl cellulose (HPMC) 1.0%,deposited on sterilized flexible hydrophobic poly tetra-fluoroethylene (PTFE) carrier strips and freeze dried underaseptic conditions. The fluorescein dose of the lyophilisatewas 68 µg, corresponding to a single conventional drop of40 µl fluorescein 0.17% solution. In a randomized, open-label study, 12 healthy volunteers applied the lyophilized flu-orescein to one eye and one drop of conventional fluoresceinophthalmic solution to the fellow eye. Fluorophotometrymeasurements of fluorescein concentrations in the anteriorsegment were performed with the Fluorotron Master IIbefore and +15, 30, 45, 60, 120 and 180 min after applica-tion [128]. Lux and colleagues studied the ocular bioavailabil-ity of a single application of a triple dose of sodium fluor-escein to the human anterior segment of the eye using

lyophilisate system, a novel drug delivery device containing afluorescein dose of 204 µg corresponding to three conven-tional, preservative-free eye drops of 40 µl Fluorescein SEThilo 0.17% (68 µg each) [129]. Single lyophilisate wasapplied to one eye of 22 healthy volunteers (+1 min) andthree conventional eye drops (+1, 16, 31 min) were applied totheir fellow eye. It was concluded that better bioavailabilitywas achieved in the corneal stroma midanterior chamber forup to 7 h using this new device. Steinfeld and colleaguesassessed the ocular bioavailability of fluorescein from a noveldrug delivery system compared with one single preservative-free eye drop and they concluded that a significantly betterbioavailability was achieved in human eyes by using lyophili-sate compared with the same dose from a conventional eyedrop [130]. Diestelhorst studied a new preservative-free, freeze-dried ophthalmic drug delivery system (lyophilisate). In hisfirst study, the safety and tolerability of the lyophilisate (pla-cebo) was compared with a conventional, preservative-freetear film substitute eye drop. The lyophilisate demonstrated avery good tolerability and excellent safety compared with theconventional eye drops containing the same polymer andelectrolytes. In Dry Drops, the active ingredient is incorpo-rated in a drop of hydrophilic polymer solution freeze driedon the tip of a soft hydrophobic carrier strip. Upon contactwith tear film and/or conjunctiva, the lyophilisate immedi-ately rehydrates and detaches from the carrier. The improvedchemical stability, exact dosing, reduced risk of lesions to theeye surface and good tolerability suggest that the new applica-tion device has promise for treatment in ophthalmology, aswell as in other medical subspecialties [131].

Flexible coilsAnother method of reducing the ocular bioavailability prob-lems is the use of device called OphthaCoil, which consists ofa drug-loaded adherent hydrogel coating on a thin metallicwire, which is coiled. The device was found to be well toler-ated and has good patient compliance. Pijls and colleaguesmonitored the release rate of anti-infective pradofloxacin inin vitro and in vivo experiments and showed that the Ophtha-Coil was capable of sustained drug delivery to the tear film indogs [132].

Expert commentary & five-year viewThere has been significant activity in the past 5 years in thefield of ocular drug delivery. Much of the research focus inthis area is aimed at improving bioavailability while retainingvisual acuity. Novel ocular drug delivery systems have beeninvestigated by many researchers for improvement in bioavail-ability, minimization of adverse effects and enhanced patientcompliance to ensure improved management of ocular patho-logical conditions. Despite a wide range of drug deliveryapproaches that have been employed, including penetrationenhancers, collagen shields, ocular iontophoresis, in situ gel-ling systems, dendrimers, lipid emulsions, ocular inserts,mucoadhesive polymers, thiolated polymers, soft drugs and



site-specific drug delivery systems, few of these have been ableto appear on the market. Some of the above approaches holdpromise as viable ocular drug delivery systems. Futureresearch may be directed towards techniques that are based onenhanced bioavailability yet also being patient friendly, such

as lipid emulsions, in situ gelling systems, iontophoresis,mucoadhesive and thiolated polymeric dosage forms. Sus-tained innovative research in this area may result in the entryof a significant number of technologically advanced oculardrug delivery systems onto the market.

Key issues

• Drug delivery to the eye is a complex process involving suppression of drug loss and enhancing ocular residence time of drugs.

• Enhancing ocular residence time of drugs is the main target of ocular drug delivery.

• Many of the ocular drug delivery systems described have been designed to achieve better ocular residence time and enhanced ocular tolerability.

• The bioavailability has been strongly enhanced by these systems.

• Few systems (in situ gelling system, ocular insert, microparticulate delivery system, lipid emulsions) have been approved and are in clinical use.

• Some of these systems, such as the in situ gelling system, thiolated mucoadhesive and thiolated in situ gelling system, lipid emulsions and dendrimer-based dosage forms, represent a breakthrough in ocular research.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Patent

201 Joshi A, Ding S, Himmelstein KJ. US Patent 5252318 (1993).

• First study on the use of combination of polymers to enhance in situ gelling effect in the eye.

Affiliations

• Yasmin Sultana, PhD

Hamdard University, Department of Pharmaceutics, Faculty of PharmacyNew Delhi 110062, [email protected]

• M Aqil, PhD

Hamdard University, Department of Pharmaceutics, Faculty of PharmacyNew Delhi 110062, India

• Asgar Ali, PhD


• Abdus Samad, BPharm


advances in the topical ocular drug delivery

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