1461-5347/98/$ – see front matter ©1998 Elsevier Science. All rights reserved. PII: S1461-5347(98)00087-X

▼ Most conventional ophthalmic dosage formsare simplistic. It is usual that water-soluble drugsare delivered through topical administration inan aqueous solution1, and water-insoluble drugsare administered topically as an ointment oraqueous suspension. The major deficiencies ofthese conventional dosage forms include poorocular drug bioavailability, pulse-drug entry aftertopical administration, systemic exposure be-cause of nasolacrimal duct drainage, and a lackof effective systems for drug delivery to the pos-terior segment of ocular tissue.

Poor ocular drug bioavailability is the result ofocular anatomical and physiological constraints,which include the relative impermeability of thecorneal epithelial membrane, tear dynamics,nasolacrimal drainage2, and the high efficiencyof the blood–ocular barrier3. It is standard foronly 1% or less of a topically applied dose to beabsorbed across the cornea and thus reach theanterior segment of the eye4,5.

Pulse entry is a common, and yet highly un-desirable, pharmacokinetic characteristic associ-ated with eye drops6. The initial high drug con-centration found in tears, followed by a rapiddecline, poses a potential risk of toxicity, andsuggests a requirement for frequent dosing.Attempts to overcome the toxicity associated

with the high initial concentration without a requirement for frequent dosing form a challeng-ing task, particularly in the case of potent drugs.

Nasolacrimal drainage is the major factor forprecorneal drug loss that leads to poor ocularbioavailability. It is also the major route of entryinto the circulatory system for drugs that are applied through topical administration7,8. Forpotent drugs, the systemic exposure through na-solacrimal drainage after topical administrationcan be sufficiently high to cause systemic toxicity.A recognized example is timolol; systemic tox-icity has been reported for the ophthalmic solu-tion of timolol following topical administration9.

The delivery of drugs to the posterior segmentof ocular tissue is prevented by the same factorsthat are responsible for the poor ocular bioavail-ability. In addition, the blood–retinal barrier lim-its the effectiveness of the intravenous route inposterior drug delivery.To date, the most accept-able method for posterior drug delivery is intra-vitreal injection, and yet although effective, theintravitreal injection procedure is associated witha high risk of complications3.

Early attemptsA considerable amount of effort has been madein ophthalmic drug delivery since the 1970s.Thevarious approaches attempted in the early stagescan be divided into two main categories:bioavailability improvement and controlled re-lease drug delivery.The former was attempted bythe methods listed in Table 1, and the latter wasattempted by various types of inserts (Table 2)and nanoparticles. After initial investigations,some approaches were dropped quickly, whereasothers were highly successful and led to mar-keted products.

Bioavailability improvementViscosity enhancers. Attempts to increase the viscosityof the formulation, in order to prolong precornealresidence time and improve bioavailability,

Recent developments in ophthalmicdrug delivery Shulin Ding

Shulin DingAllergan

2525 Dupont DriveIrvine, CA 92623

USAtel: 11 714 246 6218fax: 11 714 246 6981

e-mail:Ding_Shulin@Allergan.com

reviews research focus

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Recent research efforts in ophthalmic drug delivery have mainly

focused on systems in which drugs may be administered in the form

of eye-drops. As a result of these efforts, significant advancements

have been made in the following areas: in situ-forming gels, oil-

in-water emulsions, colloidal drug delivery systems (liposomes and

nanoparticles) and microparticulates. Protein and peptide delivery,

posterior drug delivery and non-aqueous vehicles are three new

areas of interest in ophthalmic drug delivery, and this review will

discuss recent progress and specific development issues relating to

these drug delivery systems.

formed a popular strategy in the early research stages of oph-thalmic drug delivery. The viscosity enhancers were often hy-drophilic polymers, such as various celluloses, polyvinyl alcohol and polyacrylic acid.The conceptual simplicity, ease ofmanufacture, and initially promising data in animal modelsmeant that, despite the lack of human data, in the 1980s manyof the viscosity enhancers could be incorporated into eye-dropformulations. Subsequently, the effect of these viscosity en-hancers on drug bioavailability was demonstrated to be mini-mal in humans10, and their clinical significance was modest atbest11. In rabbits, it was found that the effect was more pro-nounced, and reached a maximum level at a viscosity of ap-proximately 15–150 cps12. A review of the research efforts inthis area was presented by Lee and Robinson in 19864. Today,hydrophilic polymers continue to be used in formulations ofophthalmic products, but their function is more for patientcomfort and/or reasons of bioadhesion rather than viscosityenhancement.

Gels. Gel formation is an extreme case of viscosity enhance-ment through the use of viscosity enhancers. Many of the vis-cosity enhancers form a viscous gel at high concentrations inwater. Despite the extremely high viscosity, gels achieve only alimited improvement in bioavailability, and the dosing fre-quency can be decreased to once a day at most13. The high

viscosity, however, results in blurred vision and matted eyelids,which substantially reduce patient acceptability. To date, onlytwo ophthalmic gels are listed in the Physicians’ Desk Reference forOphthalmology: Pilopine HS® gel, commercialized in 1986 byAlcon, and more recently Merck’s Timoptic-XE®.

Penetration enhancers. In the early stages of ophthalmic drug de-livery research, chelating agents, preservatives, surfactants andbile salts were studied as possible penetration enhancers. Theeffort was soon diminished, however, due to the local toxicityassociated with the enhancers. Current research efforts are fo-cused first on developing an understanding of the mechanismsand regulations of drug transport, before proposing specificmethods for penetration enhancement14.

Prodrugs. The principle of prodrugs is to enhance cornealdrug permeability through modification of the hydrophilicity(or lipophilicity) of the drug. Prodrugs have proven to be ofvalue, but also difficult to design and develop, as evidenced bythe fact that only one ophthalmic prodrug,Allergan’s Propine®,has enjoyed successful development and commercialization.No new prodrug has been introduced to the ophthalmic mar-ket since the commercialization of Propine® in 1980.

Liposomes. The use of liposomes as a topically administered ocular drug delivery system began in the early stages of researchinto ophthalmic drug delivery.The results of early studies were

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Table 1. Early attempts to increase bioavailability

Approach Advantage Disadvantage Marketed product

Viscosity enhancers4,10–12 (such Droppable formulation Minimal effects in humans in Present in many current as hydroxylpropyl methyl-cellulose, Ease in manufacture terms of improvement in productscarboxylmethyl cellulose, polyvinyl Slight prolonged precorneal bioavailabilityalcohol, carbomers) residence time

Gels13 Slightly prolonged precorneal Limited value in terms of Pilopine HS® gelresidence time improvement in bioavailabilityReduced systemic exposure Blurred vision

Matted eyelidsPenetration enhancer4,14 Enhanced corneal drug penetration Ocular irritation and toxicity None

Prodrugs4 Enhanced corneal drug penetration Extensive pharmacokinetic and Propine®pharmacologic information isrequired for proper designProdrug is considered as a newdrug entity

Liposomes15–20 Droppable Low drug loading NoneBiocompatible Inadequate aqueous stabilityBiodegradable Manufacturing difficultiesPotential for bioavailability for sterile preparationsimprovement, toxicity reduction,sustained release, and site-specific delivery

favourable for lipophilic drugs15–17, but disappointing for hydrophilic drugs17–19. The physicochemical properties of theencapsulated drug apparently had a significant impact on thesubsequent penetration of the drug into tissues. When the en-capsulated drug was hydrophilic, the effectiveness of liposomesas drug carriers was compromised by the rapid escape of thedrug from the interior of the liposomes into the surroundingwater. Further studies revealed that liposomes must be adsorbedonto corneal and conjunctival surfaces for drugs to penetrateinto ocular tissues, and the number of contact sites on these sur-faces was limited17,20. It was concluded that liposomes may besuitable for ocular drug delivery, provided they had an affinityfor, and were able to bind to, ocular surfaces, and releasedtheir contents at optimal rates20. Since the discovery of contactsites on ocular surface tissues, the effect of liposome surfaceproperties on drug delivery has provided a focus for research,and new findings will be described in the section detailing recent developments.

Controlled drug deliveryNanoparticles.The potential use of polymeric colloidal particles asophthalmic drug delivery systems can be traced back to thelate 1970s. The first two systems studied in this area were thepilocarpine–cellulose acetate hydrogen phthalate (CAP) latexsystem4,21 and Piloplex4,22. The pilocarpine–CAP latex systemconsisted of pilocarpine adsorbed onto CAP particles that weresuspended in an aqueous solution (pH 4.5).The average size of

the particles was approximately 300 nm.The CAP particles co-agulated in the ocular cul-de-sac because of a pH shift from 4.5to 7.4 (the pH of tears), and pilocarpine was slowly releasedfrom the coagulated CAP mass.The other early system, Piloplex,was an aqueous polymeric dispersion of pilocarpine salt and theco-polymer of laurylmethacrylated-acrylic acid. Piloplex wastested in humans and demonstrated limited success in sustaineddrug release4. Neither CAP latex nor Piloplex entered furthercommercial development because of various development issues, such as non-biodegradability, local toxicity and difficultyin the large-scale manufacture of sterile preparations. Subsequentresearch on nanoparticles has focused on biodegradable and/orbioadhesive nanospheres and nanocapsules, which will be covered in the section detailing recent developments.

Inserts. Solid inserts were introduced to the ophthalmic mar-ket 50 years ago.The earliest official record of a solid insert wasdescribed in the 1948 British Pharmacopoeia. It was an atropine-containing gelatin wafer, Lamellae. The potential of solid insertsfor sustained or controlled drug release was subsequently rec-ognized, and, in the 1970s and 1980s, numerous systems weredeveloped using various polymers, and different drug releaseprinciples were applied.The various types of inserts are catego-rized according to physicochemical properties in Table 2 (seereferences 6 and 23–25 for review).Although the advantages ofinserts in sustained or controlled drug release have been clearlydemonstrated, there is not a high level of acceptance amongstpatients, particularly the elderly. The low level of patient

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Table 2. Various types of ophthalmic inserts

Type Description Marketed product

Erodible inserts6,25 The fabrication polymer is hydrophobic but biodegradable. Drug is Nonereleased through the erosion of the surface of the insert

Soluble inserts6,23,25 The fabrication polymer is hydrophilic and water soluble LacrisertDrug release characteristics: Soluble ophthalmic drug insertDiffusion control for soluble drugs (SODI)Dissolution control for less soluble drugs

Hydrophilic but water-insoluble The fabrication polymer is hydrophilic but water-insoluble Noneinserts6,25 Drug release characteristics:

Diffusion control for soluble drugsDissolution control for less soluble drugs

Inserts using osmotic A polymeric matrix in which the drug is dispersed as discrete Nonesystem6,24 small domains. Upon placement in the cul-de-sac, tears are

imbibed into the matrix because of an osmotic pressure gradientcreated by the drug, whereupon the drug is dissolved and released

Membrane-controlled The drug core is surrounded by a hydrophobic polymer membrane; Ocusertdiffusional inserts6,23 this controls the diffusion of the drug from the core to the outside

acceptance is due primarily to the following issues: difficultywith self insertion, foreign body sensation and inadvertent lossfrom the eye.To date, only two insert products are listed in thePhysicians’ Desk Reference for Ophthalmology (Ocusert and Lacrisert),and pharmaceutical manufacturers are not actively developinginserts for commercialization.

Recent developmentsAn important lesson learned from earlier efforts in ophthalmicdrug delivery is the necessity of balancing the technologies ofsustained drug release or bioavailability improvement with pa-tient comfort and ease of use. It is generally agreed that thepreferred topical ophthalmic drug delivery system would beadministered in eye-drop form, without causing blurred vision and irritation. The preferred system would also provide improved bioavailability, site-specific delivery, and/orcontinuous drug release2,4,22.

With this in mind, recent research efforts have focusedlargely on systems and technologies in which drugs can be ad-ministered as an eye drop. Significant advancements have beenmade in the following areas:

• in situ-forming gels;

• oil-in-water emulsions;

• colloidal drug delivery systems (liposomes and nano-particles);

• microparticulates.

One in situ-forming gel, Timoptic-XE®, has been commer-cially available since 1994, and a cyclosporine-containing oil-in-water ophthalmic emulsion is in late Phase III development.

The development of liposomes, nanoparticles and micropar-ticulates for topical ophthalmic applications has proven to beextremely challenging. Despite recent progress, major obsta-cles remain to be overcome before commercialization can berealized, and their potential as injectable products for posteriordrug delivery is under current investigation. Finally, three new areas of interest in ophthalmic drug delivery include protein/peptide delivery, intraocular drug delivery and non-aqueous vehicle.

In situ-forming gelsMajor progress has been made recently in ophthalmic gel tech-nology.This progress has been in the form of improved levels ofpatient acceptance, and, more specifically, the development ofdroppable gels (in situ-forming gels). The droppable gels areliquid upon instillation, and they undergo a phase transition inthe ocular cul-de-sac to form a viscoelastic gel, and this providesa response to environmental changes. Parameters that can changeand trigger the phase transition of droppable gels include

pH, temperature and ionic strength. Examples of potentialophthalmic droppable gels reported in the literature include:

• gelling triggered by a change in pH – CAP latex2,22,26, cross-linked polyacrylic acid and derivatives such as carbomersand polycarbophil;

• gelling triggered by temperature change – poloxamers2,22,26,methyl cellulose and Smart Hydrogel™;

• gelling triggered by ionic strength change – Gelrite2,26–28

and alginate29.

In addition, a combination system has been reported30,31, inwhich a thermally induced gelling material (methyl cellulose)is physically combined with a pH-induced gelling material(carbomer).The resultant system was able to achieve the in situ-gelling property with less total polymer content.

Among all droppable gel systems, only Gelrite has been usedin the formulation of a prescription ophthalmic product thathas been approved by the US Food and Drug Administration(FDA). Timoptic-XE®, timolol in Gelrite, was developed as anextension of the Timoptic ophthalmic solution product line.Through formulation into a droppable gel, the dosing fre-quency of Timoptic was reduced from twice-a-day to once-a-day and without the loss of ease of instillation.

Other droppable gel systems under assessment for clinicalapplications are DuraSite® and Smart Hydrogel™. DuraSite®

uses polycarbophil, a cross-linked polyacrylic acid, to achievethe desired in situ-gelling property32. Marketed drugs, such as levobunolol, pilocarpine, and diclofenac, have been refor-mulated in DuraSite®, and these new formulations are beingevaluated in clinical studies. In addition, AquaSite, an over-the-counter tear product formulated in DuraSite®, has beenmade commercially available.

Smart Hydrogel™ is a graft co-polymer of polyacrylic acidand a poloxamer33.As with poloxamers, Smart Hydrogel™ hasthe property of reverse thermal gelation, but it requires only alow polymer concentration (1 to 3%) to gel at body tempera-ture. In addition, Smart Hydrogel™ is bioadhesive because ofits polyacrylic acid component.

As described, gel systems are limited in their ability to bothimprove bioavailability and facilitate sustained drug release.Once- or twice-a-day dosing is the typical expectation fromthese gel systems.

Oil-in-water emulsionsEmulsion technology has been applied to oral, parenteral anddermatological dosage forms for many years. However, it wasn’t until the 1980s that it was used in the development of ophthalmic formulations. This delay can be attributed to the following:

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• the difficulty in manufacturing sterile emulsions with acceptable sterility assurance and globule size control;

• the difficulty in achieving acceptable long-term stability;

• the difficulty in achieving a high comfort level.

Most of the early investigational ophthalmic emulsions mimicthe formulations of parenteral emulsions, and use phospholipidsand pluronics as emulsifiers. Because phospholipids are sensitiveto oxygen, antioxidants are incorporated into these emulsionformulations to improve their shelf-life. Even with antioxidants,however, the phospholipid-containing emulsions are still limitedin room temperature stability.

The in vivo data obtained from studies of these early formu-lations confirm that emulsions can be effective topical ophthalmicdrug delivery systems34,35, with a potential for sustained drug re-lease36,37. Naveh and co-workers noted that the intraocular-pressure-reducing effect of a single, topically administered doseof pilocarpine emulsion lasted for more than 29 h in albino rab-bits, whereas that of the generic pilocarpine solution lasted onlyfive hours36.

Oil-in-water emulsions are particularly useful in the deliveryof water-insoluble drugs. Previously, ointments and suspensionswere the only two available options, but the former suffered frompoor patient acceptance because of blurred vision and mattedeyelids, and the latter appeared to have problems with particle irritation, poor bioavailability, and changes in polymorphism andparticle size upon storage. The newly developed oil-in-wateremulsion offers a third option that has the advantages of an oint-ment without its drawbacks.

In the oil-in-water emulsion, the water-insoluble drug is solu-bilized in the internal oil phase, thereby remaining in the pre-ferred solution state. By keeping the drug in solution, the issue ofpotential absorption because of slow dissolution of solid drugparticles is avoided. In addition, the blurred vision caused by oilsis minimized by the water in the external phase. Furthermore, theconcentration of the drug in the oil phase can be adjusted to max-imize thermodynamic activity, thus enhancing drug penetration.

As technologies have advanced, the obstacles preventing thedevelopment of ophthalmic emulsions have gradually been removed. The improvements in both machinery and asepticprocessing allow for the reproducible manufacture of a sterileproduct with greater assurance than was previously possible.Moreover, new types of emulsifiers that are safe, non-irritatingand chemically unique have become available. Some of theseemulsifiers have demonstrated a remarkable ability to stabilizeemulsions. Using novel polymeric emulsifiers, a newly formu-lated cyclosporine ophthalmic emulsion demonstrates excellentroom temperature stability and extremely low ocularirritation38,39. This emulsion is in Phase III clinical studies forthe treatment of dry eye disease.

LiposomesDuring the early stages of research into ophthalmic drug de-livery, it was widely observed that positively-charged lipo-somes have a greater affinity for ocular tissues than neutral ornegatively charged liposomes19,40. Recent studies have con-firmed that positively charged liposomes are superior in theirability to increase both precorneal drug retention and drugbioavailability. For example, through the use of g-scintigra-phy, the precorneal drainage rate of positively-charged lipo-somes was demonstrated to be slower than that of neutral ornegatively charged liposomes41. Similarly, the addition ofstearylamine to a liposomal preparation enhanced the cornealabsorption of dexamethasone valerate42, and the enhancementwas believed to be because of the positive charges conferredby stearylamine onto the liposomes. Finally, the mydriatic re-sponse in rabbits dosed with atropine containing positively-charged multilamellar vesicles (MLV) liposomes was pro-longed when compared to the response in animals dosed withatropine containing neutral or negatively charged MLV43.

The greater affinity of positively charged liposomes for ocular tissues has been attributed to the negatively chargedcorneal surface: the corneal epithelium is thinly coated withnegatively charged mucin to which the positive surface-charge of the liposomes may adsorb more strongly44.

The use of bioadhesive polymers to coat liposomes is astrategy designed to prolong the precorneal retention of lipo-somes45,46. Using Carbopol 1342 as the bioadhesive polymerat a pH of 5, coated pilocarpine-containing liposomes wereshown to produce both a larger area under the meiotic inten-sity curve and a longer duration of action, when comparedwith the non-coated liposomes45. In a similar study conductedby Davies et al.46, the Carbopol-coated liposomes were retainedin the precorneal area longer than the non-coated liposomes,but the mydriatic response of the entrapped drug, tropi-camide, was not enhanced or prolonged.

The potential of liposomes as a topical ophthalmic drug de-livery system is limited because of their limited drug loading ca-pacity and stability. In addition, large-scale manufacture of sterileliposomes is expensive and technically challenging. Recently,researchers have begun to explore the potential of liposometechnology in posterior drug delivery. By injecting liposomepreparations subconjunctivally or intravitreally, a sustaineddrug release effect has been demonstrated in some studies22,47.

NanoparticlesWhen appropriately formulated for ophthalmic drug delivery,nanoparticles may provide sustained drug release and pro-longed therapeutic activity. To achieve this, the particles mustbe retained in the ocular cul-de-sac after topical adminis-tration, and the entrapped drug must be released from the

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particles at an appropriate rate. If the drug leaks out of the par-ticles too fast, then there will be little sustained drug release.On the other hand, if the release is too slow, then the concen-tration of the drug in the tears may be too low to allow ade-quate drug penetration into ocular tissues.

To enhance particle retention in the ocular cul-de-sac, it ishighly desirable to fabricate the particles with bioadhesive ma-terials. Without bioadhesion, nanoparticles are eliminatedfrom the precorneal site almost as quickly as aqueous solu-tions. For example, in an ocular disposition study conductedby Wood et al.48, nanoparticles fabricated using poly-hexyl-2-cyanoacrylate were rapidly cleared from the precorneal siteafter topical administration, and only approximately 1% of theinstilled dose adhered to corneal and conjunctival surfaces.

Biodegradation is also a highly desirable property for thefabrication materials of nanoparticles. This is primarily due tosafety concerns.

In recent studies of nanoparticles, the most commonly usedpolymers are various poly(alkylcyanoacrylates), poly-e-capro-lactone and polylactic-co-glycolic acid, all of which arebiodegradable polymers that undergo hydrolysis in tears. Inone study conducted by Marchal-Heussler et al.49, the efficiencyof betaxolol delivery was compared among nanoparticlesmade of these three types of polymers.The results showed thatpoly-e-caprolactone nanoparticles yielded the highest pharma-cological activity, and the agglomeration of these nanoparticlesin the conjunctival sac was thought to be responsible for thegood level of performance. Using poly-e-caprolactone as thefabrication polymer and carteolol as the entrapped drug,Marchal-Heussler and coworkers further demonstrated thatnanocapsules outperformed nanospheres in the reduction ofintraocular pressure50. This improvement was attributed to thefact that carteolol remained in solution in the oil-core of thenanocapsules, and therefore was more readily available forpenetration into ocular tissues.

Physicochemical properties of nanoparticles also have an effect on their efficiency in drug delivery. Among the param-eters studied, both the surface charge and the binding of thedrug to the particles were found to be more important thanthe drug-loading percentage51.

Coating nanoparticles with positively charged bioadhesivepolymers is a recent strategy designed to further enhance theinteraction between nanoparticles and the negatively chargedcorneal surface. The positively charged coating, however, maynot necessarily improve the performance of the nanoparticles.A recent publication reported that chitosan-coated nanocap-sules doubled the ocular bioavailability of indomethacin whencompared with the non-coated preparation, whereas poly-L-lysine-coating failed to improve bioavailability52.The authorssuggested that the positive surface charge was not critical

because both chitosan and poly-L-lysine conferred positivecharges onto the particles. It was suggested instead that thespecific nature of chitosan was responsible for the bioavailabil-ity improvement.

The efficiency of drug delivery upon co-administration ofnanoparticles with viscous or bioadhesive polymers was alsoexplored through the use of pilocarpine-loaded albuminnanoparticles53. The results showed that most of the polymersstudied had a minimal impact on delivery efficiency. The co-administration of mucin, however, resulted in a significant improvement in drug bioavailability.

The potential use of nanoparticles as an ophthalmic drugdelivery system has been demonstrated in numerous studiesfor either hydrophobic or hydrophilic drugs (see Refs 21 and22 for review). Despite the promising in vivo results, many is-sues must be resolved before an ophthalmic product can be developed using this technology. The major developmentissues for nanoparticles include formulation stability, controlof particle size, control of the rate of drug release, and large-scale manufacture of sterile preparations. Similar to the researchdirection taken for liposomes, research has begun to focus on the use of this technology in posterior drug delivery.

MicroparticulatesMicroparticulates are drug-containing, micron-sized poly-meric particles suspended in a liquid medium. Drugs can bephysically dispersed in the polymer matrix or covalently boundto the polymer backbone54. Upon topical instillation, the parti-cles reside in the ocular cul-de-sac, and the drug is releasedfrom the particles through diffusion, chemical reaction,and/or polymer degradation. Microparticulates are larger thannanoparticles, which may make them better suited for sus-tained or controlled drug release, but the larger size may makethem less tolerable.

Biodegradation, bioadhesion and biocompatibility are thedesired properties for the fabrication polymers of ophthalmicmicroparticulates. The following are examples of publishedbiodegradable microparticulates, in which the in vivo efficacyperformance is reportedly superior to that of the correspond-ing conventional dosage forms:

• microspheres of methylprednisolone chemically linked tohyaluronate esters55;

• pilocarpine-loaded albumin or gelatin microspheres56;

• acyclovir-loaded chitosan microspheres57.

An interesting system that uses collagen pieces or particles hasrecently been developed.The Collasomes system was developedto replace the collagen shield, a type of soluble ophthalmic insert that offered sustained drug release, but caused blurred

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vision and was difficult to insert22. Collasomes efficiently deliver hydrophilic molecules, and are well-tolerated by patients58. Technically they are not microparticulates becausetheir size is in the millimeter range, but they can reportedly beinstilled as an eye drop.

Of all the available ocular drug delivery approaches,microparticulates and solid inserts are the only two technolo-gies that have the potential to achieve truly controlled and sus-tained drug release. Microparticulate technology has the ad-vantage of superior patient acceptability because the particlesare suspended in a medium that can be topically administeredas an eye drop, or intraocularly administered as an injection.However, the manufacture and control of large-scale manufac-turing of sterile microparticulates is very challenging and ex-pensive.Therefore the economic value of microparticulates forcommercialization is significantly reduced.

To date, only one microparticulate ophthalmic prescriptionproduct, Betoptic® S, is on the US market. By binding betaxololto ion-exchange resin particles, Betoptic® S retards drug releasein the tear and enhances drug bioavailability. Betoptic® S 0.25%is bioequivalent to Betoptic Solution 0.5% in lowering intra-ocular pressure. By reducing the drug strength by half, andslowing down the drug-release rate in tears, Betoptic® S signifi-cantly improves the ocular comfort of Betoptic Solution59.

Posterior drug deliveryIntravitreal drug injection is the current therapy for posteriorsegment disorders.The procedure is associated with a high riskof complications, particularly when frequent, repeated injec-tions are required. Thus, sustained-release technologies arebeing proposed3,60, and the possible benefits of using lipo-somes, nanoparticles or microparticulates in intravitreal injec-tions are under current investigation for posterior drug deliv-ery. Initial results indicate that these technologies do retarddrug release after injection, but they introduce other problems,such as intravitreal toxicity of the drug carriers, interferencewith vision and difficulties in the large-scale manufacture ofsterile preparations3,60.

Alternative routes of administration include subconjunctivalinjection of sustained-release drug carriers, and the use of im-plants; that is, osmotic minipumps3,61, biodegradable scleralplugs62, and biodegradable poly-(caprolactone) matrices63. In1996, Vitrasert61, an intravitreal implant of ganciclovir, re-ceived FDA approval for the treatment of cytomegalovirus retinitis. See Ref. 3 for a comprehensive review of intraoculardelivery systems.

Delivery of proteins and peptidesAlthough small peptides (molecular weight less than 5000)can be absorbed via the topical, ocular route into ocular tissues

or the circulatory system, larger peptides and proteins cannotbe absorbed without the aid of penetration enhancers64,65,which have not been well-accepted because of local toxicity.Recently, less irritating ocular penetration enhancers have beenfound for insulin. They can reportedly improve the absorptionof insulin via the topical, ocular route and achieve a biologi-cally effective systemic level of insulin63. Cytochalasin B, a cytoskeletal modulator, is another potential enhancer of ocular penetration with low toxicity64.

Non-aqueous vehicleA non-aqueous, comfortable vehicle is desired for topicalophthalmic drug delivery because of drug degradation trig-gered by water or the premature leakage of the drug from thedelivery system in the presence of water. Typically, lipophilicvehicles (that is, mineral oils and vegetable oils) have beenused, but they are poorly accepted by patients due to blurredvision and matted eyelids. Reconstitution with water prior touse is unacceptable because of cost and patient compliance issues.

Perfluorocarbons, or fluorinated silicone liquids, have re-cently been suggested as good non-aqueous vehicles for topi-cal ophthalmic drug delivery66,67.They are chemically and bio-logically inert, and have a low surface tension, excellentspreading characteristics and close-to-water refractive indices.Perfluorocarbons have been studied for years as a blood substi-tute68; minimal systemic toxicity is expected via the topicalroute.

Future directionsA few new products have been commercialized as a result ofthe research into ophthalmic drug delivery. The performanceof these new products, however, is still far from being perfect.An ideal system should be able to achieve an effective drugconcentration at the target tissue for an extended period oftime, while minimizing systemic exposure. In addition, thesystem should be both comfortable and easy to use. Patient acceptance will continue to be emphasized in the design of future ophthalmic drug delivery systems.

Major improvements are required in each of the technol-ogies discussed in this review. Some approaches are relativelyeasy to manufacture, but are limited in their ability to providesustained drug release. Other approaches are promising withregard to sustained drug release, but are difficult to manufac-ture. Stability is a major issue with particulates and liposomes.

A reasonable strategy to circumvent the drawbacks of indi-vidual technologies is to combine technologies. Reported ex-amples include liposomes and nanoparticles in droppable gelsand liposomes and nanoparticles coated with bioadhesivepolymers.

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Much remains to be learned regarding the delivery charac-teristics of emulsions and perfluorocarbons. Combining thesetwo new technologies with earlier delivery approaches may beanother interesting area for exploration.

AcknowledgementThe author wishes to thank Orest Olejnik for his support andcritical review of this manuscript.

References01 Lang, J.C. (1995) Adv. Drug Deliv. Rev. 16, 39–43

02 Desai, S.D. and Blanchard, J. (1995) in Encyclopedia of Pharmaceutical

Technology (Swarbrick, J. and Boylan, J.C., eds), pp. 43–75, Marcel

Dekker, New York, NY, USA

03 Peyman, G.A. and Ganiban, G.J. (1995) Adv. Drug Deliv. Rev. 16, 107–123

04 Lee,V.H.L. and Robinson, J.R. (1986) J. Ocul. Pharmacol. Ther. 2, 67–108

05 Mezei, M. and Meisner, D. (1993) in Biopharmaceutics of Ocular Drug Delivery

(Edman, P., ed.), pp. 91–104, CRC Press, Boca Raton, FL, USA

06 Shell, J.W. (1985) Drug Dev. Res. 6, 245–261

07 Urtti, A. and Salminen, L. (1993) Surv. Ophthalmol. 37, 435–456

08 Chang, S-C. and Lee,V.H.L. (1987) J. Ocul. Pharmacol. Ther. 3, 159–169

09 McMahon, C.D. et al. (1979) Am. J. Ophthalmol. 88, 736–738

10 Chrai, S.S. et al. (1973) J. Pharm. Sci. 62, 1112–1121

11 Adler, C.A., Maurice, D.M. and Paterson, M.E. (1971) Exp. Eye Res. 11,

34–42

12 Patton,T.F. and Robinson, J.R. (1975) J. Pharm. Sci. 64, 1312–1315

13 Zignani, M.,Tabatabay, C. and Gurny, R. (1995) Adv. Drug Deliv. Rev. 16,

51–60

14 Liaw, J. and Robinson, J.R. (1993) in Ophthalmic Drug Delivery Systems

(Mitra, A.K., ed.), pp. 369–381, Marcel Dekker, New York, NY, USA

15 Smolin, G. et al. (1981) Am. J. Ophthalmol. 91, 220–225

16 Singh, K. and Mezei, M. (1983) Int. J. Pharm. 16, 339–344

17 Stratford, R.E. et al. (1983) Int. J. Pharm. 13, 263

18 Benita, S. et al. (1984) J. Microencapsulation 1, 203–206

19 Singh, K. and Mezei, M. (1984) Int. J. Pharm. 19, 263–269

20 Lee,V.H.L.,Takemoto, K.A. and Iimoto, D.S. (1984) Curr. Eye Res. 3,

585–591

21 Zimmer, A. and Kreuter, J. (1995) Adv. Drug Deliv. Rev. 16, 61–73

22 Le Bourlais, C. et al. (1998) Prog. Retinal Eye Res. 17, 33–58

23 Saettone, M.F. and Salminen, L. (1995) Adv. Drug Deliv. Rev. 16, 95–106

24 Saettone, M.F. (1993) in Biopharmaceutics of Ocular Drug Delivery (Edman, P.,

ed.), pp. 61–79, CRC Press, Boca Raton, FL, USA

25 Bawa, R. (1993) in Ophthalmic Drug Delivery Systems (Mitra, A.K., ed.),

pp. 223–259, Marcel Dekker, New York, NY, USA

26 Gurny, R. et al. (1987) in Ophthalmic Drug Delivery. Biopharmaceutical,

Technological and Clinical Aspects (Vol. 11) (Saettone, M.S., Bucci, G. and

Speiser, P., eds), pp. 27–36, Fidia Research Series, Liviana Press, Padova,

Italy

27 Rozier, A. et al. (1989) Int. J. Pharm. 57, 163–168

28 Sanzgiri,Y.D. et al. (1993) J. Control. Release 26, 195–201

29 Cohen, S. et al. (1997) J. Control. Release 44, 201–208

30 Joshi, A., Ding, S. and Himmelstein, K. (1993) US Patent 5,252,318,

12 October

31 Kumar, S., Haglund, B.O. and Himmelstein, K. (1994) J. Ocul. Pharmacol.

Ther. 10, 47–56

32 Patel, R. et al. (1994) US Patent 5,340,572, 23 August

33 Ron, E.S. et al. (1996) Proc. Int. Symp. Control. Release Bioact. Mat. 23

34 Garty, N. et al. (1994) Invest. Ophthalmol.Vis. Sci. 35, 2175

35 Muchtar, S. et al. (1992) Ophthalmic Res. 24, 142–149

36 Naveh, N., Muchtar, S. and Benita, S. (1994) J. Ocul. Pharmacol. Ther. 10,

509–520

37 Bar-Ilan, A. et al. (1994) Reg. Immunol. (USA) 6, 166–168

38 Ding, S.,Tien, W. and Olejnik, O. (1995) US Patent 5,474,979,

12 December

39 Ding, S. and Olejnik, O. (1997) Pharm. Res. 14, S41, Abstract 1127

40 Schaeffer, H.E. and Krohn, D.K. (1982) Invest. Ophthalmol.Vis. Sci. 22,

220–227

41 Fitzgerald, P. et al. (1987) Int. J. Pharm. 40, 81–84

42 Taniguchi, K. et al. (1988) J. Pharmacobiodyn. 11, 607–611

43 Meisner, D., Pringle, J. and Mezei, M. (1989) Int. J. Pharm. 55,

105–113

44 Shek, P.N. and Barber, R.F. (1987) Biochim. Biophys.Acta 902, 229–236

45 Durrani, A.M. et al. (1992) Int. J. Pharm. 88, 409–415

46 Davies, N.M. et al. (1992) Pharm. Res. 9, 1137–1144

47 Meisner, D. and Mezei, M. (1995) Adv. Drug Deliv. Rev. 16, 75–93

48 Wood, R.W. et al. (1985) Int. J. Pharm. 23, 175–183

49 Marchal-Heussler, L. et al. (1992) STP Pharm. Sci. 2, 98–104

50 Marchal-Heussler, L. et al. (1993) Pharm. Res. 10, 386–390

51 Marchal-Heussler, L. et al. (1990) Int. J. Pharm. 58, 115–122

52 Calvo, P.,Vila-Jato, L. and Alonso, M.J. (1997) Int. J. Pharm. 153,

41–50

53 Zimmer, A.K. et al. (1995) J. Control. Release 33, 31–46

54 Joshi, A. (1994) J. Ocul. Pharmacol.Ther. 10, 29–45

55 Kyyronen, K. et al. (1992) Int. J. Pharm. 80, 161–169

56 Leucuta, S.E. (1989) Int. J. Pharm. 54, 71–78

57 Genta, I. et al. (1997) J. Pharm. Pharmacol. 49, 737–742

58 Kaufman, H.E. et al. (1994) J. Ocul. Pharmacol.Ther. 10, 17–27

59 Jani, R. et al. (1994) J. Ocul. Pharmacol.Ther. 10, 57–67

60 Metrikin, D.C. and Anand, R. (1994) Curr. Opin. Ophthalmol. 5, 21–29

61 Ashton, P. et al. (1994) J. Ocul. Pharmacol.Ther. 10, 691–701

62 Hashizoe, M. et al. (1994) Arch. Ophthalmol. 112, 1380–1384

63 Borhani, H., Rahimy, M.H. and Peyman, G.A. (1993) Invest. Ophthalmol.

Vis. Sci. 34(Suppl.), 1488

64 Harris, D., Liaw, J-H. and Robinson, J.R. (1992) Adv. Drug Deliv. Rev. 8,

331–339

65 Chiou, G.C.Y. (1994) J. Ocul. Pharmacol.Ther. 10, 93–99

66 Meadows, D.L. (1992) US Patent 5,173,298, 22 December

67 Meadows, D.L. (1996) US Patent 5,518,731, 21 May

68 Riess, J.G. and Krafft, M.P. (1997) Artif. Cells Blood Substitutes and

Immobilization Biotechnol. 25, 43–52

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