Mechanisms and facilitation of corneal drug penetration

Jou'rnal of Controlled Release, 11 (1990) 79-90 Elsevier Science Publishers B.V., Amsterdam - - Printed in The Netherlands

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M E C H A N I S M S A N D FACILITATION OF CORNEAL DRUG PENETRATION*

Vincent H.L. Lee University of Southern Ca/ifomia, Schoo/ of Pharmacy, 1985 Zona/ A venue, Los A nge/es, CA 90033 (U. S. A.)

Key words: ocular drug delivery; penetration enhancers; paracellular pathway; transcellular pathway; ion-pair formation; prodrugs

A major challenge in ocular drug delivery is improving thepoor bioavailability of topically applied ophthalmic drugs by overcoming the severe constraints imposed by the eye on drug absorption. One such constraint is the impermeability of the cornea, the major route by which topically applied drugs enter the eye. Three methods are being considered to improve corneal drug penetration: the use of penetration enhancers, ion pair formation, and prodrug derivatization. Of the three, prodrug derivatization is the best developed and probably holds the most promise from the standpoint of versatility and safety. The objective of this paper is to review the usefulness of all three in ocular drug delivery and to review the routes and mechanisms of ocular drug absorption that form the basis for these methods.

I. INTRODUCTION

A major challenge in ocular therapeutics is improving the poor bioavailability of topically applied ophthalmic drugs. Such poor bioavailability, amounting to at best 10% of the applied dose, is largely due to precorneal processes that rapidly remove drug from the absorption site and to the existence of a well designed corneal structure that restricts the passage of drug molecules [ 1 ]. During the past two decades, con- siderable effort has been devoted to prolonging precorneal drug retention through vehicle ma- nipulation in hopes of enhancing ocular drug bioavailability [2-9]. The methods that have been attempted range from simply increasing the viscosity of the instilled solution through the incorporation of water-soluble polymers to the technologically more complex methods, in-

*Paper presented at the Fourth International Symposium on Recent Advances in Drug Delivery systems, Salt Lake City, UT, U.S.A., February 21-24, 1989.

volving the incorporation of drug in polymeric inserts that may or may not degrade with time. Thus far, such methods have only resulted in moderate success.This is indicated by the modest improvement in ocular drug bioavailability as exemplified by viscous solutions and by the lack of patient acceptance as exemplified by inserts. Clearly, improving precorneal drug retention alone is inadequate in bringing about marked improvement in ocular drug bioavailability. Improving the ability of the drug to penetrate the ocular membranes must also be considered. To meet this objective, the routes as well as the mechanisms by which topically applied drugs are ocularly absorbed must be understood.

Thus, the objective of this paper is to de- scribe the routes and mechanisms of ocular drug absorption and the means by which this process may be improved. Such means include the use of penetration enhancers, ion pair formation, and prodrug derivatization.

0168-3659/90/$03.50 © 1990 Elsevier Science Publishers B.V.

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II. ROUTES A N D M E C H A N I S M S OF OCULAR DRUG ABSORPTION

The major route by which most ophthalmic drugs enter the eye is traditionally believed to be via the cornea. Recent evidence suggests that a minor route exists involving the conjunctiva and the sclera that are contiguous with the cornea, the so-called non-corneal route [10-13]. The non-corneal route appears to be favored by drugs that are poorly absorbed by the cornea. A case in point is inulin, a linear polymer of D- glucose and D-fructose with a molecular weight of about 5000 daltons. Although this compound penetrates the cornea at least 100 times less efficiently than low molecular weight drugs [ 14 ], as much as 40% of the absorbed amount in the eye is due to non-corneal penetration [12]. While some information exists on the physicochemical determinants of drug diffusion across the conjunctiva and the sclera [ 13 ], there is little information on the factors related to the drug, its vehicle, and the physiology of the eye which collectively control the relative contribution of the corneal and the non-corneal routes to ocular drug absorption. This is an area that deserves careful study in the future. The reason is that the non-corneal route may spare the in- ternal layers of the cornea from the possible ill effects of the drug and may provide drug direct access to the uveal tract.

Unlike non-corneal drug absorption, corneal drug absorption is well studied with respect to the role played by the various layers of the cornea to drug penetration and to the mechanisms and pathways by which this process occurs. The cornea is a trilaminate structure consisting of a hydrophilic stromal layer sandwiched between a very lipophilic epithelial layer on the outside and a much less lipophilic endothelial layer on the inside. Depending on the lipophilicity of the drug, the contribution of the individual layers to the total corneal resistance to drug penetration varies. This has been determined for a series of beta blockers [15]. As seen in Fig. 1, the corneal epithelium contributes to over 90% of

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Log Distribution Coefficient

Fig.1. Contribution of the corneal epithelium ( [] ), corneal stroma ( • ), and corneal endothelium ( O ) as a percentage of the total corneal resistance to the in vitro penetration of fl blockers in the albino rabbit. From left to right: atenolol, sotalol, nadolol, acebutolol, metoprolol, timolol, oxpreno- lol, levobunolol, propranolol, bevantolol, bufuralol, and penbutolol. Adapted from Ref. [ 43 ].

the corneal resistance for hydrophilic compounds (log DC < 0.2, where DC is distribution coefficient), decreasing to about 50% for the moderately lipophilic (0.2 < log DC < 0.75 ) and to less than 10% for the lipophilic (log DC > 2). This is accompanied by an increase in the contribution due to the corneal endothelium from less than 5% for hydrophilic compounds through 30% for the moderately lipophilic and to 50% for the lipophilic. A similar trend is seen in the contribution from the corneal stroma.

Almost all of the ophthalmic drugs that have been studied appear to cross the cornea by sim- ple diffusion. None of them appear to do so by carrier-mediated transport and endocytosis. An aspect of corneal drug transport that deserves further study in the future is the role of the various drug receptors in corneal drug movement and retention. Although receptors for such drugs as beta blockers [16], glucocorticoids [17], and vitamin A [18] are known to exist at various levels in the cornea for some time, only recently has their role in corneal drug transport been appreciated. Lee and Carson [19] proposed that retinol-binding proteins in the cornea play some role in sustaining vitamin A con-

centration in the albino rabbit eye following topical instillation in peanut oil. Using immu- nohistochemical techniques, Rojanasaku and Robinson [ 20 ] detected a high concentration of steroid receptors in the apical layers of the rabbit corneal epithelium which they demon- strated to be partly involved in the binding of topically applied progesterone. Binding was re- versible and subject to competition by triamcinolone acetonide. The authors speculated that the steroid receptors were responsible for re- tarding the diffusion of progesterone and other steroids across the cornea on the one hand and for their accumulation in the cornea on the other [17,21]. Based on the above preliminary results, it is reasonable to conclude that drug receptors will play some role in corneal drug transport and accumulation.

There are two obvious pathways by which drug can diffuse across the corneal epithelium: paracellular and transcellular. The paracellular pathway is anatomically the intercellular space. The intercellular space in the basement membrane of this tissue is rather wide so that even a large molecule like horseradish peroxidase (M.W. 40,000 ), when injected into the anterior chamber, will diffuse anteriorly in the corneal epithelium, stopping within the top two to three layers [22]. There the intercellular space nar- rows as the cells undergo transformation from a columnar to a flattened arrangement.

The stratified corneal epithelial cell layer can be characterized as a "tight" ion transporting tissue [ 23 ]. This is so because of the high resistance exhibited by the paracellular pathway, 12- 16 k ~ cm 2 [24]. The tight junction which is responsible for giving rise to such a high resistance is comprised of the zonula occludens and its associated strands, the zonula adherens and its Ca2+-dependent adhesive, uvomorulin, and the desmosomes. It serves as a barrier not only to the paracellular diffusion of solutes but also to the lateral diffusion of lipid soluble solutes from the apical to the basolateral portion of the membrane [25 ]. Integrity of the tight junction depends on Ca 2+ [26,27] through its indirect

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effects on junctional elements other than the tight junction contact itself [28 ]. The elements affected include the zonula adherens [29,30], the desmosomes [31 ], and the Ca 2+-dependent adhesion molecule uvomorulin. The associa- tion of actin filaments inside the cell with the junctional complex also seems to be disrupted by low extracellular Ca 2 + [29,30]. Thus, drugs that disrupt actin filaments, such as cytochalasin B, may increase paracellular permeability [32].

The paracellular pathway is the primary route of passive ion permeation in the corneal epithelium [33]. This pathway has also been proposed to be one of the two by which topically applied methanol, ethanol, and butanol are absorbed into the rabbit eye [34], the other being through putative pores in the plasma membrane of the corneal epithelial cells. The limit- ing size of the paracellular pathway appears to be in the order of 60 ,~ or less, the molecular size of glycerol [ 35 ]. Evidence for the diffusion of such molecules in the aqueous space is indicated by the low values of the activation energy for transcorneal flux when compared with those for molecules using the transcellular pathway. Thus, the activation energy is 5.7 kcal m o l - ' for water, 6.5 kcal mol-1 for butanol, and 4.0 kcal mo1-1 for glycerol, when compared with values of 25.5 kcal mol- ~ for hydrocortisone and 25.1 kcal mo1-1 for triamcinolone acetonide [34].

Until recently little work has been devoted to characterizing the paracellular pathway in corneal drug transport. This recent interest in the paracellular pathway was prompted by the ob- servation that compounds of medium molecular weight such as inulin [14,40,41] as well as charged compounds such as sodium cromoglycate [36] and the ionized species ofpilocarpine [37,38] and sulfonamides [39] could cross the cornea. It was suspected that the paracellular pathway was involved. In the case of ionizable compounds the ionized species do not cross the cornea as efficiently as the unionized. A factor of 2-3 favoring the unionized species has been

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reported for pilocarpine based on in vitro corneal permeability measurements [37,38], and a factor of 4-7 has been reported for sulfonamide carbonic anhydrase inhibitors based on in vivo measurements [39 ].

Considering that the total surface area of the cornea exposed to the tear that is attributable to the paracellular pathway is rather small, most drugs would probably opt for the transcellular pathway in crossing the cornea. The principal drug properties governing drug absorption via the transcellular pathway are (a) the lipophilicity of the drug, as reflected by its n-octanol/ buffer partition coefficient, (b) its pKa, which determines the proportion of drug in its pref- erentially absorbed form at a given pH, and, (c) in selected cases, molecular size. Of the three drug properties, lipophilicity is the most well studied and perhaps the best understood.

The extent of corneal drug absorption appears to very parabolically with the drug's partition coefficient. Such correlations have been reported for steroids [42 ], beta blockers [43 ], aniline derivatives [44], and alkyl p-amino- benzoates [45], all within a rather narrow range of lipophilicity, pKa, and molecular size. The optimum partition coefficient for corneal drug absorption is reported to be in the range of 10 to 100. The correlation between the corneal permeability coefficient and the partition coefficient worsened, however, when the range of compounds was expanded. This is shown in Fig. 2 [46]. In this instance, including a molecular size term, thus accounting for an alternate pathway of corneal drug transport, improved the correlation [47 ].

For many years, lipophilicity was about the only physicochemical property deemed to be important in the selection and design of ophthalmic drugs. Only recently was the importance of aqueous solubility appreciated. This expansion in focus was motivated largely by the commitment to obtain a topically effective carbonic anhydrase inhibitor, in which balancing the aqueous against the lipid solubility seems to be crucial to its therapeutic efficacy. Indeed,

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Fig. 2. Effect of lipophilicity on drug concentration in the aqueous humor at 20 minutes post-instillation of aqueous solution. From left to right; glycerol, methanol, ethanol, butanol, pilocarpine, pyrilamine, prednisolone, hydrocortisone, propranolol, fluorometholone acetate, fluorometholone, and progesterone. From Ref. [46].

the lack of proper balance between these two physicochemical properties is probably responsible for the lack of consistent topical efficacy of the commercially available carbonic anhydrase inhibitors: acetazolamide, methazolam- ide, ethoxzolamide, and dichlorphenamide. These compounds are administered only orally and even then are used only as an adjunct in glaucoma therapy.

The early attempts in the search for topically effective carbonic anhydrase inhibitors were focused on modifying existing carbonic anhydrase inhibitors. This effort resulted in carbonic anhydrase inhibitors that were moderately effective in lowering the intraocular pressure in rabbits and monkeys. Examples of such compounds include trifluormethazolam- ide [48], analogs of ethoxzolamide such as 6-hydroxy-2-benzothiazolesulfonamide [49], aminozolamide [50 ], and (2-sulfamoyl-6-benzothiazolyl) -2,2-dimethylpropionate [51 ], and N-methylacetazolamide and other N-substi-

tuted sulfonamide carbonic anhydrase inhibitors [52]. However, none of the above compounds possesses aqueous solubility in the 1- 2% range; therefore, they can only be formulated as suspensions or gels, which are less well accepted by patients than are aqueous solutions.

The poor aqueous solubility problem has now been solved in the thienothiopyran-2-sulfonamides [53]. Depending on the structural fea- tures on the thienyl ring, such as presence and position of a hydroxyl group, the oxidation state of sulfur atom, and chirality of the hydroxyl substituent, analogs with aqueous solubility in the range of 0.03-1.5% can be obtained. This is at least 10-60-fold improvement over ethoxzolamide and (2-sulfamoyl-6-benzothiazolyl)-2,2- dimethylpropionate. One of these analogs, MK- 927 (d/-5,6-dihydro-4- (2-methylpropylam- ino )4H-thieno (2,3b) -thiopyran-2-sulfonamide-7,7-dioxide HC1), has been found to lower the intraocular pressure in monkeys and rabbits with experimentally induced ocular hyper- tension for 6-8 hours following the topical instillation of 2% solutions [54,55]. This is the most promising topical carbonic anhydrase inhibitor reported to date.

III. A P P R O A C H E S TO ENHANCE CORNEAL DRUG PERMEABIL ITY

There are basically two approaches that may be used to enhance corneal drug permeability: (a) modify integrity of the corneal epithelium transiently by using penetration enhancers, and (b) modify the lipophilicity of the drug through ion pair formation or prodrug derivatization.

a. Use of penetration enhancers

In principle, because of the prominent role played by the corneal epithelium in the penetration of hydrophilic and moderately lipophilic drugs, modifying the integrity of the corneal epithelium should enhance corneal drug absorption. This expectation is borne out in the

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extreme situation where the corneal epithelium is removed prior to drug administration. Under this condition, the amount of drug absorbed across the cornea is increased by a factor of 2- 15 [56,57].

Although no additives have been included in ophthalmic formulations to deliberately lower the barrier function of the corneal epithelium, there exist in the very same formulations additives which can inadvertently bring about the same result. Such additives are the preservatives and the chelating agents that are required to keep formulations sterile and chemically stable.

Many reports have been devoted to the effect of preservatives on corneal drug absorption. As an example, Camber and Edman [57] demon- strated that exposing the isolated porcine cornea to 0.01% benzalkonium chloride or 0.5% chlorobutanol for four hours almost doubled the transcorneal flux of pilocarpine, a magnitude of increase comparable to that obtained by de-ep- ithelizing the cornea [57]. Chlorhexidine dig- luconate (0.01%) and a mixture of 0.04% methyl paraben and 0.02 % propyl paraben were less effective. The same rank order of effectiveness was seen in the transcorneal flux of dexamethasone, although none of the preservatives afforded the same factor of increase as the de- epithelized cornea. By contrast, 0.01% benzalkonium chloride reduced rather than enhanced the corneal penetration of the isopropyl ester of prostaglandin PGF2~ [58]. This is probably due to a reduction in the lipophilic characteristics of the corneal epithelium caused by the pre- servative. Overall, the effect of preservatives on corneal drug absorption is consistent with the lipophilicity of the drugs affected and with the effect of the preservatives on the corneal epithelial ultrastructure [59 ].

Grass and Robinson [34] were among the first to emphasize the positive effect of chelating agents on corneal drug absorption. They found that 0.5% EDTA doubled the ocular absorption of topically applied glycerol and crom-

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olyn sodium. The underlying mechanism was though to be the chelation of the Ca 2+ ion which regulated the permeability of the paracellular pathway. It is therefore not surprising that progesterone, a lipophilic drug that crosses the corneal epithelium via the transcellular pathway,was unaffected by EDTA in its absorption.

The above findings support the feasibility of using penetration enhancers to promote corneal drug penetration. The use of penetration enhancers to modify the integrity of the ab- sorptive membranes thereby enhancing drug absorption is an active area of research in peptide and protein drug delivery [60]. Such an approach is virtually untested in ophthalmology, however, despite the striking similarity in bioavailability between ophthalmic drugs and peptide and protein drugs. To date, only two reports have hinted to the use of penetration enhancers to promote the ocular absorption of topically applied drugs [61,62]. But the results were m i x e d - - azone was found not to affect the ocular bioavailability of topically applied levobunolol [61] while promoting the ocular absorption of topically applied cyclosporine [62 ].

In any event, before penetration enhancers can be used on a routine basis in ophthalmology, it must be established unambiguously that the changes in membrane integrity are indeed transient and predictable, and therefore, would not compromise the defense mechanisms of the eye so severely as to cause harm. There is evidence that penetration enhancers themselves can penetrate the eye and may therefore lead to unknown toxicological complications. For instance, benzalkonium chloride was found to ac- cumulate in the cornea for days [63]. EDTA was found to reach the iris-ciliary body in concentrations high enough to alter the permeability of the blood vessels in the uveal tract indi- rectly accelerating drug removal from the aqueous humor [46]. Moreover, repeated application of 0.5 % EDTA was observed to signif- icantly alter the corneal epithelial architecture, even though a single application was well tolerated [35 ].

b. Alterations in lipophilicity

1. Ion pair formation Ion pair formation is another approach that

may be considered for facilitating corneal drug transport. In 1981, Wilson et al. reported that ion pair formation between cromolyn sodium, an organic anion, and benzalkonium chloride, an organic cation, modestly improved the absorption of both compounds in the albino rabbit eye, but that neither was transported without the other [65 ]. Approximately 0.07% of the administered dose of cromolyn sodium and 0.7% of benzalkonium chloride were found in the aqueous humor at 30 minutes.

The use of ion pair formation to promote corneal drug absorption was revisited in a series of recent papers by Kato et al. [66-68]. These in- vestigators found that the extent of drug ioni- zation, hence the pH of the medium and the pKa of the drug, and the chain length of the ion pairing agent were both important factors deter- mining the extent of improvement in ocular drug penetration due to ion pair formation. Thus, ion pair formation with caprylic acid enhanced the corneal penetration of bunazosin (pKa 7.7) more than that of pilocarpine (pK~ 6.67) [66]. In addition, the enhancement in corneal penetration of bunazosin by caprylic acid was more pronounced at pH 6.5 than at pH 8. This is indicated by the ratio of increase of 9.32 at the lower pH as compared with that of 2.28 at the higher pH. In a homologous series of saturated straight-chain fatty acids, the higher homologs were more effective in enhancing the corneal absorption of bunazosin. The specific rank order was capriate (C10)>caprylate (C8)>caproate (C6) [66]. Two lines of evidence implicate ion pair formation as the principal mechanism underlying the enhancement in corneal absorption by long-chain fatty acids: first, the good correlation between the increase in corneal absorption of bunazosin and the increase in its partition coefficient by long-chain fatty acids [66] and, second, the lack of direct

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effect of the long-chain fatty acids on corneal epithelial integrity [68 ].

Thus, there is preliminary evidence that ion pair formation may be useful in promoting corneal drug penetration under certain conditions. Nevertheless, it has yet to be resolved whether the enhancement results from an increase in the availability of the drug at the corneal surface or from shielding of the charge on the drug by the ion pairing agent, thus allowing it to diffuse across the lipid environment of the corneal epithelium. As is the case of penetration enhancers, however, the ultimate usefulness of such an approach must await careful study to verify the long-term effects of the ion pairing agents, frequently surfactants in nature, on corneal health.

degree of enhancement in corneal drug absorption [76,77] or by increasing the lipophilicity of the prodrugs, thereby impeding their absorption into the systemic absorption without neg- atively affecting their ocular absorption [85]. The basis for the second method is the differential lipophilic characteristics of the membranes responsible for ocular absorption (cornea) and systemic absorption (conjunctival and nasal mucosae) [86 ]. Both methods have been found to be feasible in the case of timolol.

Thus, as seen in Fig. 3, the O-butyryl prodrug of timolol improved the ocular absorption of timolol 5.5 times without affecting systemic absorption. When a four-fold lower concentration of the prodrug was used, the extent of ocular

2. Prodrug derivatization Thus far, the prodrug approach to enhance

corneal drug absorption is the only approach that has met commercial realization. Prodrugs were formally introduced to ophthalmology about a decade ago with the testing of dipivalyl epinephrine as a means to improve the corneal penetration of epinephrine [69]. Since then, this concept has been extended to several other ophthalmic drugs with the aim to achieve one of the following outcomes through enhanced corneal penetration: (a) enhanced ocular potency, as exemplified by the prodrugs of some carbonic anhydrase inhibitors [51,52,70], steroids [71], antivirals [72], and beta blockers [73,74], (b) a lower incidence of systemic side effects through reduction of the instilled dose, as exemplified by the prodrugs of timolol [75- 78 ], phenylephrine [ 79 ], and terbutaline [80 ], and/or (c) altered duration of action, as exemplified by the prodrugs of timolol [81 ], pilocarpine [82 ], and adrenalone [83 ]. Such appli- cations have recently been reviewed by Lee and Li [82].

The use of prodrugs to reduce the systemic absorption of topically applied drugs is a recent development. This aim is achieved by either re- ducing the instilled dose in proportion to the

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absorption obtained was the same as that obtained from the higher dose of timolol. Signifi- cantly, systemic absorption was reduced ten times. As a result, the therapeutic index as assessed by the ratio of aqueous humor to plasma concentrations seemed to improve fifteenfold [77].

Table 1 shows the effect of prodrug derivatization on the ocular and systemic absorption of timolol. Except of the neopentanoyl ester, all the prodrugs used in this study improved the ocular absorption of timolol to some extent. Moreover, five of them hindered the systemic absorption of timolol. Such prodrugs were O- pivaloyl, neopentanoyl, hexanoyl, cyclopropanoyl, and benzoyl timolol. The net effect was that the therapeutic index, as defined by the ra- tion of ocular to systemic absorption, was improved 2-8 times. It is therefore possible to design prodrugs that are poorly absorbed into the bloodstream and yet are well absorbed into the eye.

Although prodrugs hold great promise in improving ocular drug delivery, they have yet to be considered routinely for improving the physicochemical characteristics of drugs originally developed for systemic use with respect to ocu-

TABLE1

Areas under the concentration-time curves (AUC) in the aqueous humor and plasma, and th ratio of these areas (AH/plasma) , following the topical instillation of 25 pl of various concentrations of timolol and its prodrugs in the pigmented rabbit (from Ref. [85] )

Compound Log AUC (#M min) AH/ PC plasma

Aqueous Plasma humor

Timolol - 0.019 441 O-Acetyl timolol 1.12 1607 O-Propionyl timolol 1.62 1951 O-Butyryl timolol 2.08 1939 O-Isobutyryl timolol 2.19 1770 O-Valeryl timolol 2.67 713 O-Pivaloyl timolol 2.68 747 O-Neopentanoyl timolol 3.11 137 O-Hexanoyl timolol 3.35 1480 O-Cyclopropanoyl timolol 1.74 1298 O-Benzoyl timolol 2.55 629

3.9 113 4.5 357 3.9 500 3.5 554 3.5 506 3.3 216 1.5 498 1.6 86 1.8 822 1.6 811 2.3 273

lar absorption. Such a scenario may soon improve due to a recently proposed concept in ocular drug delivery. The key to this new concept is the ability of prodrugs to enhance the ocular potency of a drug candidate originally designed for systemic use but which was deliberately chosen because of its lack of systemic potency. This is, in effect, an attempt to achieve relative oculoselectivity, i.e., selective drug action in the eye without the risk of systemic complications. Therefore, the salient feature of this approach is to select a less potent drug candidate so as to minimize the incidence of systemic side effects and then to offset this loss in potency by enhancing its ocular absorption using prodrugs. Such an approach is the subject of a recent report by Sugrue et al. [87]. These in- vestigators reported that L-653,328, an acetate ester of the fl-blocker L-652,698, was as potent as timolol in lowering the intraocular pressure in the ~-chymotrypsinized albino rabbit. Yet compared with timolol - - the leading glaucoma drug whose therapeutic utility has somewhat been limited by its cardiovascular and pulmo- nary side effects, L-653,328 was at least 100 times less potent against the heart. This lack of systemic potency was consistent with the modest affinity of L-652,698, the active moiety of L-653,328, for the extraocular fl-receptors.

IV. CONCLUSION

Drug development for ocular diseases has traditionally relied on drugs originally developed for systemic use. Unfortunately, few of them are optimal for ocular absorption. This is because they possess few of the physicochemical properties that are required to overcome the constraints imposed by eye on drug absorption, which are far more severe than those imposed by the gastrointestinal tract. Such constraints include a short residence time, a narrow pH range that can be tolerated, a highly imperme-

able cornea , a smal l surface a rea for cornea l absorp t ion , a n d a m u c h larger sur face a rea for sys temic d rug loss. P a s t a t t e m p t s to i m p r o v e ocular d rug b ioava i l ab i l i ty have focused pr i - mar i ly on i m p r o v i n g p r eco rnea l d rug re ten t ion . O v e r c o m i n g the p o o r p e r m e a b i l i t y of the cornea has been cons ide red only recent ly . Resu l t s to da te indica te t h a t th i s object ive m a y be m e t by p e r t u r b i n g the p e r m e a b i l i t y of the co rnea with p e n e t r a t i o n enhancers , or by improv ing the l ipophi l ic i ty of the d rug t h r o u g h ion pa i r for- m a t i o n or p r o d r u g der iva t iza t ion . Of these two approaches , the p r o d r u g a p p r o a c h is the bes t deve loped a n d p r o b a b l y holds the m o s t p r o m i s e f rom the s t a n d p o i n t o f ve r sa t i l i t y a n d safety. F u t u r e r e sea rch in i m p r o v i n g ocular d rug delivery m u s t be devo ted to e luc ida t ing the re la t ion- ship b e t w e e n cell sur face cha rac t e r i s t i c s of the con junc t iva and the co rnea as re la ted to depo- s i t ion a n d r e t e n t i o n of d rug vehic les in the con- j unc t iva l sac. In th is a u t h o r ' s opinion, the de- v e l o p m e n t of m e t h o d s ba sed on the un ique b iochemica l a n d physiological charac te r i s t ics of the eye will be the n e x t f ron t i e r in ocular d rug delivery.

ACKNOWLEDGEMENT

T h i s work was s u p p o r t e d by g r an t s EY-3816 and EY-7389 f r o m the N a t i o n a l I n s t i t u t e s of Hea l th , Be thesda , M a r y l a n d , U.S.A., T h e au- t ho r is a holder of the G a v i n S. H e r b e r t P ro fessorsh ip .

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Mechanisms and facilitation of corneal drug penetration

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