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Drug design strategies for ocular therapeutics
advanced
drug delivery ELSEVIER
Advanced Drug Delivery Reviews 14 (1994) 269-279
reviews
Drug design strategies for ocular therapeutics G.C. Visor Gilead Sciences, 353 Lakeside Drive, Foster City, CA 94404, USA
(Received April 16, 1992; Accepted September 1, 1992)
Contents Abstract ............................................................................................................................................. 269 1. Introduction .................................................................................................................................... 270 2. Chemical delivery systems ..................................................................................................................
271
3. The soft drug approach ..................................................................................................................... 3.1. Soft [3-blockers ........................................................................................................................ 3.2. Soft steroids ............................................................................................................................
273 273 273
4. The prodrug approach ......................................................................................................................
275
5. Conclusions..................................................................................................................................... 277 References .......................................................................................................................................... 277
Abstract
The goal of this work is to review the various approaches to the design of ophthalmic agents with improved therapeutic profiles. A critical focus of the discussion will include not only optimal structure/transport properties of lead molecules, but also the potential metabolic transformations of target tissues. The careful consideration of such metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and provides for the potential of site-specific bioactivation, thus enabling the realization of significant improvements in efficacy and minimization of side-effect profiles, locally and systemically. Key words. Chemical delivery systems; Soft drugs; Prodrugs; Ocular drug metabolism; Site-specific delivery; Bioactiva-
tion; Corneal transport
0169-409X/94/$27.00 © 1994 Elsevier Science B.V. All rights reserved SSD1 0 1 6 9 - 4 0 9 X ( 9 3 ) E 0 0 5 7 - L
270
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
1. Introduction The design of therapeutic agents for the eye is a unique task that is limited by the location of the organ itself as well as by the functional physiology of the component tissues. As a relatively isolated organ that has a number of avascular components (e.g. cornea, trabecular meshwork, lens), topical therapy is by far the most effective for a number of disease states and diagnostic procedures (glaucoma, inflammation, herpes keratitis, lens extraction, vitrectomy, etc). However, due to a number of protective systems (lacrimal apparatus, eyelids, cornea, sclera, conjunctiva) the majority of the dose applied will be delivered, not to the ocular tissues (typically < 5%), but to the general circulation via the nasolacrimal system and nasal/gastric mucosa [1]. Therein lies the largest problem with many of the therapeutic agents utilized for ophthalmic disease [2-4]. Many of these drugs are typically lead compounds that were originally developed for oral/parenteral therapy, and therefore can be expected to elicit a profound pharmacological response when absorbed systemically from a topically instilled dose. Thus a patient treated for primary glaucoma with an underlying cardiovascular/respiratory condition, may well be adversely affected by the non-(ocular) productive absorption of a [3-agonist like epinephrine or a [~-antagonist like timolol [5-7]. In addition to the potentially adverse effects of ophthalmic drugs that are absorbed systemically, there are also instances where the local effects of these agents themselves are severely limiting. This is certainly the case with local corticosteroid therapy where complications may involve the development of elevated intraocular pressure (IOP), glaucoma (open angle) and potentially cataracts [8]. Corticosteroid therapy has also been implicated in the increased incidence of herpes simplex keratitis (cornea), resulting from an enhanced destructive effect of collagenase on the collagen of the cornea. These adverse events as well as the extended duration of secondary cellular responses to even a single steroid dose suggest the need for molecules with a greater therapeutic index [9]. Thus, in order to maximize the therapeutic index of ophthalmic drugs it is necessary to design
compounds based not only on structure/transport considerations but also on intrinsic metabolic and physiologic processes of the eye [10]. It is these factors as well as the inherent activity of the compound itself that will ultimately determine efficacy/toxicity. Tl~e particular importance of metabolic considerations can be realized upon review of the ability of ocular tissues to transform a number of drugs and other exogenous agents [11-13]. The metabolic spectrum of activity includes not only the classical hydrolytic reactions in the cornea, aqueous humor and choroid tissues but also a number of other pathways that involve hydroxylation, oxidation and reduction of exogenous substances. Therefore, not only does the potential exists for controlling the metabolic deactivation of drugs through designed structural modifications, but there is also the very real possibility of controlled site-specific bioactivation. Both approaches provide the capability of maximizing the safety/efficacy of ophthalmic agents and will be the focus of this review.
2. Chemical delivery systems The incorporation of predictable metabolic activation into the design of therapeutics has been termed a "chemical delivery system" (CDS) [10]. Chemical delivery systems for site-specific therapy have been shown to be successful approaches for the brain as well as for the eye [14,15]. In this type of system, enzymatic processes associated exclusively or preferentially at the target tissue are utilized to convert the inactive CDS to the active drug. These systems may well require more than one (enzymatic) bioactivation step to produce the active agent, due to the multifunctional requirements needed for barrier transport and site-specific delivery [16]. Such a system has been developed for the site-specific delivery of adrenaline (epinephrine) to the anterior segment of the eye, via diester derivatives of adrenalone [17,18]. Adrenalone (Scheme I, 1) is the synthetic precursor of adrenaline (Scheme I, 2), which is devoid of any significant sympathomimetic activity of its own [19]. However, a series of ester derivatives (Scheme I, 3; e.g. R - (CH3)2CHCH2CO-) were
271
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269 279
0
RO
O
NHC.3 R,H f
erase
RO"
=
3
II O
NHCH3
~
1 1 1 1
.
L O ~
cstcra:cstcrase
5"
HO HO
I
~
NHCH3
reductase reductase
OH RO RO
OH sterase=,R'HI O'-'-~ ""~" Vesteras¢ L0-~,,.,,,,~ 6
OH HO ~
~
2
NHCH3
HO
Scheme I found to produce a dramatic mydriatic response and decrease in IPO following topical administration of solutions equivalent to 0.05% of the parent compound adrenalone [20]. This is in sharp contrast to the minimal level of activity exhibited by adrenalone even at concentrations of 2%. The mechanism responsible for this observed activity was clearly not simply the enhanced flux of the diesters across the corneal barrier and facile hydrolytic cleavage of the esters to adrenalone. Instead, it was proposed and subsequently demonstrated that the adrenalone esters undergo a reduction-hydrolysis sequence to form epinephrine exclusively in the iris-ciliary body, whereas in the rest of the eye or systemic circulation, ester hydrolysis results only in the production of the inactive adrenalone. It was also observed that even when adrenalone was administered at a 40-fold higher concentration than the diesters, only adrenalone could be detected in the various tissue compartments. This indicates that the diester or monoester (Scheme I, 1, 3, 5) form of adrenalone not only is responsible for facilitating intraocular transport, but is also the preferential substrate for the ketone reductase. The site-specific bioactivation of the adrenalone diesters in the tissues of the uveal tract ap-
pears to be consistent with its role as a major site of drug metabolism within the eye. The metabolic reduction of the ketone functionality as in the diester derivatives of adrenalone also has been established to be a preferential pathway in mammals. This reduction process eliminates lipid-soluble carbonyls and transforms them into alcohols that are significantly more polar [21,22]. The tissue distribution of carbonyl reductases is also fairly widespread (liver, kidney, lung, heart, brain, spleen) and includes certain vascular tissues of the eye. Based on these observations, it appears that the biotransformation of adrenalone derivatives involves the following: either (a) direct or sequential hydrolysis by esterases of the esterified catechols to give the inactive adrenalone, or (b) reduction of the ketone to the alcohol (Scheme I, 6) followed by esterase cleavage of the esters leading to the active adrenaline. Although not clearly established in these studies, the stereospecificity of the reductase seems fairly obvious, based on the high level of activity exhibited by the ester derivatives as well as on the relatively low level of activity associated with the D-enantiomer of adrenalin. This approach, therefore, illustrates the concept of a site-specific chemical delivery system and clearly distinguishes it from a simple prodrug sys-
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269 279
272
NOH
II
7
o II O~CH2__C__CH2NHCH(CHa) 2
8
I
O--CH2~C--CH2NHCH(CH3) 2
9 Scheme II
tern. Prodrugs like dipivalyl or diisovaleryl epinephrine [23,20] deliver drug (non-specifically) to all compartments of the eye and potentially to the central compartment of the body due to instilled dose drainage. The chemical delivery system on the other hand is site-specific and therefore is much more efficient and conceivably better tolerated. The accumulation of data on the high level of metabolic activity observed in the tissues of the uveal tract (iris, ciliary body, choroid) as well as their functional role in a number of physiological processes (aqueous humor dynamics, intraocular pressure regulation, avascular tissue support, etc.) suggests that targeting this site for drug bioactivation would be most beneficial. This has been the case for the CDS prepared for a number of [3-antagonists [24, 25]. These compounds have proven to be very valuable in the treatment of glaucoma. However, as mentioned in the Introduction, they have been associated with adverse cardiovascular, respiratory, central and ocular effects. In an effort to minimize these adverse events a series of hydrolytically sensitive oxime functions (Scheme II, 7) were designed into a number of [3antagonists. These compounds like adrenaline/ adrenalone are [3-hydroxylamines and therefore, via an enzymatic hydrolysis-reduction sequence (Scheme II, 7-9), could result in site-specific bioactivation in the iris-ciliary body tissues. Details of the synthetic routes [24,25] and related studies can be found elsewhere; however, a review of the more significant findings is appropriate. In comparative studies with the [3-antagonist propranolol (Scheme II, 9) and its corresponding CDS (propanolone oxime) [26], it was found that
propranolol was able to reduce the IOP of rabbits for about 4 hours at a concentration of 1% (Fig. 1). At this dose, propranolol was found to be irritating as characterized by slight congestion, redness and swelling. The irritancy was found to be greatly enhanced at a concentration of 2.5% and apparently was the cause of the insignificant IOP effects. The propanolone oxime on the other hand (1%) produced a hypotensive ocular state that was both more intense and of significantly longer duration. In addition, the oxime derivative was devoid of any local irritation. Evaluation of the in-vivo tissue distribution of propranolone oxime (Table 1) revealed, as expected, the parent compound, propranolol, in
-22 I
i
TIME
|
•
•
•
(hours)
Fig. 1. Effect ofpropranolol hydrochloride (9) and propranolol oxime hydrochloride (7) on the ]OP pressure of rabbits. • propranolol hydrochloric (9) 1%; • - propranolo[ hydrochloride (9) 2.5%; O = propranolone oxime hydrochloride (7) 1%; [] = propranolone oxime hydrochloride (9) 2.5%; - - = saline solution (n=6-10).
G.C. Visor~AdvancedDrug Deliver)' Rev&ws 14 (1994) 269-279 Table 1 Tissue concentrations (g/g) of propranolol and propanolone oxime at various time intervals following topical administration of propanolone oxime HCI (1% solution) Tissue t y p e
P r o p r a n o l o l Propanolone Time oxime (min)
Cornea Iris/ciliary body Aqueous humor
1.68 ± 0.75 2.11 ± 0.29 0.04 _+ 0.02
23.75 _+ 4.91 7.79 ± 1.10 0.82 ± 0.09
30 30 30
Cornea Iris/ciliary body Aqueous humor
1.14 ± 0.29 1.79 _+ 0.20 0.71 ± 0.I1
16.40 ± 5.80 0.00 ± 0.00 0.80 _+ 0.06
60 60 60
Cornea Iris/ciliary body Aqueous humor
1.14 _+ 0.22 0.43 ± 0.11 0.00 ± 0.00
0.00 ___0.00 0.00 _+ 0.00 0.00 ± 0.00
120 120 120
measurable concentrations up to 2 hours after administration in the iris/ciliary body and cornea [26]. The formation of the parent compound propranolol was never detected in rats, rabbits or dogs following intravenous infusions. Finally, the stereospecificity of the enzymatic reduction was also established (as exclusively the S - ( - ) form) following chromatographic analysis of iris/ciliary body tissue treated with a chiral reagent [27]. This is consistent with the high level of activity exhibited on a molar basis by this enantiomer relative to that associated with the R-( + ) form. Thus, as previously hypothesized in the adrenalone CDS, the (enzymatic/reduction) biotransformation of propanololone oxime appears to be both site- and stereo-specific.
273
The functional moieties for metabolic transformation typically do not involve oxidation or conjugation pathways and should take place at a rapid rate following receptor interaction. By design, this should take place without the formation of reactive intermediates or allow for competitive routes of transformation to occur. The details of soft analog design have been presented elsewhere in several literature reviews and applications that include a number of therapeutic areas (e.g. mydriatics, anticholinergics, anti-inflammatory, antimicrobials) [28,29]. 3.1. Soft [J-blockers Utilizing what is termed the "inactive metabolite approach", a series of soft analogs were derived from the acidic metabolite of the 13-antagonist, metoprolol (Chart I, 10). Metaprolol has been shown to undergo multiple oxidative degradations among which the phenylacetic acid (Chart I, 11) derivative is a major product. As the phenylacetic acid metabolite is inactive, it can be used as the structural lead for soft synthetic preparation [30]. A series of lipophilic esters (Chart I, 12) were prepared based on this approach and found to provide significant reductions of IOP in rabbits for extended periods of time [31]. The adamantylethyl ester derivative (Chart l, 13) was found to be the most effective from the standpoint of reducing IOP (Fig. 2), el±citing minimal irritation and undergoing rapid hydrolysis in plasma [32]. Thus, it fits the desired profile of a soft analog in that it is both active and predictably metabolized, thereby minimizing the potential for systemic side-effects.
3. The soft drug approach 3.2. Soft steroids" Another metabolism-based approach to the design of ophthalmic agents is that associated with soft analogs. Soft analogs are a class of compounds that are close structural analogs (isosteric, isoelectronic) of known active drugs or endogenous substances [16]. These soft compounds are different from the lead compound in that they have a specific metabolic (preferentially hydrolytic) "handle" built into their structure that provides a one-step pathway for controllable detoxication.
The ability to manage the multitude of ocular inflammatory conditions (conjunctivitis, keratitis, uveitis, blepharitis, etc) is certainly limited by the side-effects associated with (topical/systemic) corticosteroids (elevated IOP, glaucoma, cataracts, secondary infections). However, without prompt treatment of some of these conditions, severe ocular damage may occur. Therefore, it is appropriate to review an application of the inactive metabolite
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
274
OH
OH
J
I
CHzCHCHzNHCH(CH3)z
O--CHzCHCHzNHCH(CH3) z
* 1=<005 eeP
,
E E
£
L Z
CH2CH2OCH3
W
CH2COOH
lO
(~ Z < -r U
ll OH
OI
*1"
L
-Z"
I
OH
I
O ~CH2CHCH2NHCH(CH3)2
I
-3
O ~CH2CHCH2NHCH(CH3)2
0 TIME,
hr
Fig. 2. Effect of the soft 13-blocker (10) on the IOP of rabbits following unilateral treatment with 0.1 ml of 0.25% solution. Solution was administered at 0 and 2 hours. [] - control eye; • = treated eye; *p<0.05, **p<0.005. CH2COOR
CH2COO'CH2CH2
(adamantyl¢thyl) 13 Chart I
approach in the design of a soft steroid for topical administration. In this example of designing compounds based on structural-metabolic relationships, an inactive
metabolite of prednisolone (Al-cortienic acid) was used as the lead and "reactivated" via structural modifications [33]. The resulting soft corticosteroid, loteprednol etabonate (LE) (Scheme III, 14; (chloromethyl 17ct-ethoxycarbonyloxy-1 l]3-hydroxy-3-oxoandrosta-l,4-diene 17[3-carboxylate), was approximately 4 times that of dexamethasone. This compound possesses a 17[3-chloromethyl ester functionality that is designed to be rapidly hydrolyzed in ocular tissues as shown in Scheme III to two inactive metabolites (15 and 16). The in vivo anti-inflammatory activity of this compound was found to be equivalent to or greater than beta-
Ok~ -'OCH2CI HO
14
Loteprexlnol Etabonate
'~
O~'k OH HO
15
A1 -Cortienic Acid Etabonate Scheme 111
I '~
0 HO
16
A1 -Cortienic Acid
' ~
OH
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
Table 2 Intraocular pressure after steroid administration1'2 Time
Vehicle control
.--.
6O
Dexamethasone Loteprednol
(h)
l
etabonate
Treated eye 0 3 7 24 31 48 55
15.62 15.37 14.50 15.62 16.04 15.81 15.23
± ± ± ± ± ± ±
1.42 1.41 1.31 1.43 1.44 1.41 1.38
15.85 16.21 19.38 18.13 20.23 18.63 17.04
± ± ± ± ± ± ±
0.44 0.50 0.59* 1.07 0.63* 0.97 0.76
15.88 15.65 16.90 14.92 14.90 15.44 15.65
± ± ± ± ± ± ±
1.47 1.39 1.44 1.35 1.33 1.44 1.40
Control eye 0 3 7 24 31 48 55
15.92 15.81 14.90 16.08 16.31 16.04 15.50
± 1.45 ± 1.49 ± 1.36 ± 1.46 ___ 1.45 ± 1.45 ± 1.46
15.62 16.00 19.63 18.48 20.29 17.96 16.44
± ± ± ± + ± ±
0.60 0.62 0.71" 1.08 0.76** 0.63 0.48
15.85 15.77 16.65 14.92 15.50 15.54 15.50
± ± ± ± ± ± +
1.51 1.43 1.44 1.35 1.41 1.46 1.40
~Twelve rabbits were evaluated via a cross-over method. Steroid or vehicle were administered 8 times per day for 2 days. 2Table entries are the mean + SE m m H g . *p<0.005 when compared to the control value. **p <0.05 when compared to the control value.
methasone and the systemic side-effects (thymolytic activity, adrenal suppression) to be significantly less than those typically associated with standard steroid therapies [33,34]. In a direct comparison of the IOP-elevating activity of LE and dexamethasone in rabbits, it was found that the soft steroid did not elicit a significant response (Table 2) [35]. The dexamethasone did show, as expected, a marked increase in IOP; as many as half of the animals ( n = 6 out of 12) had increases of 4~10 mmHg and two animals exhibited an increase of 10-15 mmHg. The results also suggested that the treatment regimen employed (8 x per day, 0.1%) could also induce significant increases of IOP in control eyes of rabbits treated with dexamethasone, presumably via systemic absorption. Studies of the ocular distribution of LE following topical administration determined that the compound was effectively transported into the anterior segment of the eye, with levels of the parent compound and metabolites in the cornea, aqu-
275
.~ 40 ~
I~11 i
I--q~t,,b~it~
I
2o
I1) O0
0
. . . . . . . .
0
2
4
6
8
time (hours) Fig. 3. Loteprednol etabonate and metabolites in the cornea. Average + SD (n = 4 except for t = 2 h where n - 3).
eous humor and iris/ciliary body [36]. The highest levels of LE and metabolites were found in the cornea and this is consistent with the cornea being the primary site of absorption as well as the largest barrier to anterior segment delivery (Fig. 3). The presence of the highest ratio of metabolites to parent drug in the corneal tissue also reflects its well-established role in drug metabolism and in particular esterase activity [37-40].
4. The prodrug approach The utilization of the prodrug approach has also been established to be quite valuable in the design and development of therapeutic agents for the eye [41-43]. The concept involves the derivitization of the active compound with transient transport moieties that will enhance the delivery characteristics and, hopefully, the therapeutic value of the drug. The pro-derivative is designed to be a transport/protective form of the drug that is transformed into the active drug by either enzymatic or chemical processes before reaching and/ or at the site of action [44]. A principal requirement for a prodrug, then, is that it be inactive and undergo biotransformation exclusively/preferentially to the parent compound. It is also impor-
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269 279
276
C--O--C
i
II
H
/
l
X
+
I
O
I
O
R
=
i'+ S
C--O--C
!
X-
\
o
17
C--O--C
\
N
19
18
i' +J ! \ N
/
H20 C--OH
= R
X-
19
+ R1
C~H
+ N
O
O
II
\
20
21
18
•
HX
Scheme IV
tant to note the differences between prodrugs, soft drugs and chemical delivery systems, as their utilizations are certainly not interchangeable [45]. Thus the selection of a particular strategy will ultimately be dictated by the therapeutic goal: i.e., modification of intrinsic drug toxicity, improved site, tissue or receptor selectivity, enhanced membrane transport, etc. In many of the ophthalmic applications employing the prodrug approach, the bioreversible systems are designed primarily to transverse the primary barrier to ocular absorption, which is the cornea. As the cornea is a tissue that is biphasic in structure (epithelium, stroma, epithelium) most pro-derivatives will need to have some degree of biphasic solubility in order to be effective. These pro-derivatives should, however, have no other pharmacodynamic impact than that provided by the parent compound itself. Although there are several functionalities (hydroxyl, carboxyl, amino, etc.) that are adaptable to the pro-drug approach and thus capable of forming labile ester transport forms, a particularly useful strategy for compounds containing tertiary amines has been developed and is appropriate for review. This bioreversible system is based on the concept of "soft quaternary salts" [4~48] and has been found to be effective with these types of molecules due to their highly pHdependent delivery across biological membranes. Preparation of prodrugs of tertiary amines in this
manner, therefore, involves quaternization of the amine, via a reaction with an ~-haloester as depicted in Scheme IV. The resulting product is characterized by its facile enzymatic or chemical hydrolysis, thereby eliminating the quaternary center (19), regeneration of the starting tertiary amine, and production of an acid and an aldehyde (Scheme IV, 18, 20 and 21, respectively). Control of the physicochemical properties, stability and bioconversion rates can be affected by the appropriate selection of functionalities for R and Rt. An illustration of this type of prodrug system with the parasympathomimetic agent, pilocarpine (Chart II, 22), demonstrates the flexibility and value of the approach. As with most ophthalmic agents, an enhancement of lipophilicity often leads to improved transport across the cornea
N
oZ
I
CH3
22 Chart I1
G.C. Visor~AdvancedDrug Delivery Reviews 14 (1994) 269-279
have utility in the design o f other therapeutic agents like anticholinergics and antibacterials, via the "soft a n a l o g " a p p r o a c h [49,50].
O +
CH2Hs CH2J/~
•
C H ~ O ~ C ~ R 2
5. C o n c l u s i o n s
C1-
RI=H, CH3 23
R2=(CH2)nCH3 n= 10-16
Chart Ill
and into the anterior segment o f the eye. Therefore, a series o f lipophilic pro-derivatives o f pilocarpine (Chart III, 23, Rl = H ; n = 14) were prepared and evaluated for miosis. It was determined that a solution o f c o m p o u n d 23 equivalent to 0.2% pilocarpine was significantly more potent and longer-lasting than a solution containing 2% pilocarpine (Fig. 4). To demonstrate that the proderivative itself did not contribute to the activity exhibited, the corresponding N-hexadecyl " h a r d " salt was also synthesized, tested and found to be inactive, thereby establishing that the "soft quaternary" salts of pilocarpine were indeed true prodrugs. This system has also been demonstrated to
3.0z ,,~
2.5-
-~
2D-
A
PILOCARPINE
HYDROCHLORIDE
O
PILOCARPINE
HE XA DECANOYLOXYMETHYLCHLORIDE
Q
0 0
~ 1.5~ 1.0" J 0..5" ..I i =E O
i I0
,
, 30
,
, 50
,
, 70
,
i 90
i
i IlO
277
,
I i 130
v I50
J
i i I'K)
i
•
190
TIME (MINUTES)
Fig. 4. The relative miosis caused by a 2.0% pilocarpine hydrochloride solution (A) vs. a 0.2% solution of pilocarpine hexadecanoyloxymethyl chloride (C)).
As the incidence o f ocular disease rises dramatically with age, so do the complications associated with its therapeutic management. This is the result o f the local and systemic side-effects of the powerful agents used and their impact on patients' underlying disease states. The approaches outlined in this review--chemical delivery systems and soft d r u g s - provide the means for enhancing the overall safety and efficacy o f ophthalmic drugs. This is accomplished by not only careful analysis o f the various factors affecting drug-receptor interactions, but also by the metabolic pathways that will ultimately control a comp o u n d ' s disposition. Therefore, it is expected that appropriate structural optimization in this m a n n e r will lead to drugs with maximal separation o f therapeutic benefit from toxicity.
References
[1] Cumming, J.S. (1980) Relevant anatomy and physiology of the eye. In: J.R. Robinson (Ed.), Ophthalmic Drug Delivery Systems, American Pharmaceutical Association, p. 1. [2] Everitt, D.E. and Avorn, A. (1990) Systemic effects of medications used to treat glaucoma, Ann. Intern. Med. 112, 12~125. [3] Fraunfelder, F.T. and Meyer, S.M. (1989) Adverse reactions to glaucoma medications, Int. Opthalmol. Clin. 29, 143 146. [4] Lynch, M.G., Whitson, J.T., Brown, R.H. Nguyen, H. and Drake, M.M. (1988) Topical beta-blocker therapy and central nervous system side-effects. A preliminary study comparing betaxolol and timolol, Arch. Ophthamol. 106, 908.-911. [5] Polansky, J.R. (1990) Beta-adrenergic therapy for glaucoma, Int. Ophthalmol. Clin. 30, 219 229. [6] Physicians" Desk Reference for Ophthalmology (1992), p. 218. [7] Chiou, G.C. (1990) Development of o-timolol for the treatment of glaucoma and ocular hypertension, J. Ocul. Pharmacol. 6, 67 74. [8] Vaughan, D. and Asbury, T. (1986) General Ophthalmolgy, 1lth edn., Lange Medical Publications, Los Altos, CA, p. 62.
278
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269-279
[9] Polansky, J.R. and Wenreb, R.N., (1984) Anti-Inflammatory agents: Steroids as anti-inflammatory agents. In: Pharmacology of the Eye M.L. Sears (Ed.), SpringerVerlag, Berlin, p. 490. [10] Bodor, N. (1988) Designing safer ophthalmic drugs. In: H. van der Goot, G. Domany, L. Pallos and H. Timmerman (Eds.), Trends in Medicinal Chemistry '88, Elsevier Science Publishers, Amsterdam, p. 145. [11] Shichi, H. and Nebert, D.W., (1980) Drug metabolism in ocular tissues. In: T.E. Gram (Ed.), Extrahepatic Metabolism of Drugs and other Foreign Compounds, SP Medical & Scientific Books, New York, p. 333. [12] Das, N.D. and Shichi, H. (198 l) Enzymes of mercapturate synthesis and other drug-metabolising reactions-specific localization in the eye, Exp. Eye Res. 33, 525 533. [13] Ellis, P., Littlejohn, K. and Deitrich, R. (1972) Enzymatic hydrolysis of pilocarpine, Invest. Ophthalmol. 11, 747 751. [14] Bodor, N. and Brewster, B.E. (1983) Problems of delivery of drugs to the brain, Pharm. Ther. 19, 332389. [15] Bodor, N. (1987) Redox drug delivery systems for targeting drugs to the brain. In: R.L. Juliano (Ed.), Biological Approaches to Controlled Drug Delivery of Drugs, The New York Academy of Sciences, New York, p. 289. [16] Bodor, N. (1984) Novel approaches to the design of safer drugs: soft drugs and site-specific chemical delivery systems. In: B. Testa (Ed.), Advances in Drug Research, Vol. 13, Academic Press, London, p. 255. [17] Bodor, N. and Visor, G. (1984) A site-specific chemical delivery system as a short acting mydriatic agent, Pharm. Res. 4, 168-173. [18] Bodor, N. and Visor, G. (1984) Formation of adrenaline in the iris/ciliary body from adrenalone diesters, Exp. Eye Res. 38, 621 626. [19] Weekers, R., Delmarcell, Y. and Gustin, J. (1955) Treatment of ocular hypertension by adrenalin and diverse sympathomimetic amines, Am. J. Ophthalmol. 40, 666 672. [20] Bodor, N., Kaminski, J.J. and Roller, R.G. (1978) Improved delivery through biological membranes. VI. Potent sympathomimetic adrenalone derivatives, Int. J. Pharm. 1, 189 196. [21] Felsted, R.L. and Bachur, N.R. (1980) Mammalian carbonyl reductases, Drug Metab. Rev. 11, 1-60. [22] Ahmed, N.K., Felsted, R.L. and Bachur, N.R. (1979) Comparison and characterization of mammalian xeniobiotic ketone reductases, J. Pharmacol. Exp. Ther. 209, 12 19. [23] Hussain, A. and Truelove, J.E. (1976) Prodrug approaches to enhancement of physicochemical properties of drugs. IV. Novel epinephrine prodrug, J. Pharm. Sci. 65, 15101512. [24] Bodor, N., Elkoussi, A., Kano, M. and Nakamura, T. (1987) Improved delivery through biological membranes. 26. Design, synthesis, and pharmacological activity of a novel chemical delivery system for L3-adrenergic blocking
agents, J. Med. Chem. 31, 100-106. [25] Bodor, N. and Elkoussi, A. (1991) Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime a new potential antiglaucoma agent, Pharm. Res. 8, 1389-1395. [26] Elkoussi, A.A. and Bodor, N. (1989) Formation of propranolol in the irisciliary body from its propanolol ketoxime precusor~a potential antiglaucoma drug, Int. J. Pharm. 53, 189-194. [27] Bodor, N. and Prokai, L. (1990) Site- and stereospecific ocular drug delivery by sequential enzymatic bioactivation, Pharm. Res. 7, 723-725. [28] Hammer, R.H., Wu., W., Sastry, J.S. and Bodor., N. (1991) Short acting mydriatics, Curr. Eye Res. 10, 565 570. [29] Hammer, R.H., Amin, K., Gunes, Z.E., Brouillette, G. and Bodor, N. (1988) Novel 'soft' anticholinergic agents, Drug Design Delivery 2, 207-219. [30] Bodor, N., Oshiro, Y., Loftsson, T., Katovich, M. and Caldwell, W. (1984) Soft drugs. VI. The application of the inactive metabolite approach for the design of soft !3blockers, Pharm. Res. 3, 120-125. [31] Bodor, N., EI-Koussi, A.A., Kano, M. and Khalifa, M.M. (1988) Soft drugs. 7. Soft 13-blockers for systemic and ophthalmic use, J. Med. Chem. 31, 1651-1656. [32] Bodor, N. and E1Koussi, A. (1988) Novel 'soft' B-blockers as potential safe antiglaucoma agents, Curt. Eye Res. 7, 369 374. [33] Bodor, N. (1988) The application of soft drug approaches to the design of safer corticosteroids. In: C.E. Kligman, A.M. Schopf and R.B. Stoughton (Eds.), Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs, Raven Press Ltd, New York, p. 13. [34] Druzgala, P., Hochhaus, G. and Bodor, N. (1991) Soft drug. 1(). Blanching activity and receptor binding activity of a new type of glucocorticoid: loteprednol etabonate, J. Steroid Biochem. Mol. Biol. 38, 149--154. [35] Bodor, N., Bodor, N. and Wu, W-M. (1992) A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits, Curr. Eye Res. 11, 525 530. [36] Druzgala, P. and Wu, W.-M. (1991) Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes, Curr. Eye Res. 10, 933-937. [37] Southern, A.L. Altman, K., Vittek, J., Boniuk, V. and Gordon, G.G. (1976) Steroid metabolism in ocular tissues of the rabbit, Invest. Ophthalmol. 15, 222 228. [38] Garzon, P., Delgado-Partida, P. and Gallegos, A.J. (1976) Progesterone metabolism by human cornea, J. Steroid Biochem. 7, 377-379. [39] Galleros, A.J., Delgado-Partida, P. and Garzon, P. (1976) The presence of 613-steroid hydroxylase in human cornea. J. Steroid Biochem. 7, 135 137. [40] Lee, V.H. (1983) Esterase activities in adult rabbit eyes, J. Pharm. Sci. 72, 239 244. [41] Lee, V.H. and Li, V.H. (1989) Prodrugs for improved ocular drug delivery, Adv. Drug Delivery Rev. 3, 1 38.
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269-279 [42] McClure, D.A. (1975) The effect of a pro-drug of epinephrine (dipivalyl epinephrine) in glaucoma--general pharmacology, toxicology, and clinical experience. In: T. Higuchi and V. Stella (Eds.), Pro-drugs as Novel Drug Delivery Systems, American Chemical Society, Washington, DC, p. 224. [43] Maudgal, P.C., Clercq, K.D., Descamps, J. and Missotten, L. (1984) Topical treatment of experimental herpes simplex keratouveitis with 2'-O-glylacyclovir, Arch. Ophthalmol. 102, 140-142. [44] Bodor, N. (1981) Novel approaches in prodrug design, Drugs of the Future V1, 165-182. [45] Bodor, N. (1985) Prodrugs versus soft drugs. In: H. Bundgaard. (Ed.), Design of Prodrugs, Elsevier Science Publishers, Amsterdam, p. 333.
279
[46] Bodor, N. (1977) Novel approaches for the design of membrane transport properties of drugs. In: E.B. Roche (Ed.), Design of Biopharmaceutical Properties through Prodrugs and Analogs, Academy of Pharamceutical Sciences, Washington, DC, p. 98. [47] Bodor, N. (1979) U.S. Patent 4,160,099, July 3, 1979. [48] Bodor, N. (1977) U.S. Patent 4,046,899, September 6, 1977. [49] Bodor, N., Woods, R. Raper, C., Kearney, P. and Kaminski, J.J. (1980) Soft drugs. 3. A new class of anticholinergic agents, J. Med. Chem. 23, 474-480. [50] Bodor, N. (1980) Soft drugs. 1. Labile quaternary ammonium salts as soft antimicrobials, J. Med. Chem. 2L 469-474.
drug delivery ELSEVIER
Advanced Drug Delivery Reviews 14 (1994) 269-279
reviews
Drug design strategies for ocular therapeutics G.C. Visor Gilead Sciences, 353 Lakeside Drive, Foster City, CA 94404, USA
(Received April 16, 1992; Accepted September 1, 1992)
Contents Abstract ............................................................................................................................................. 269 1. Introduction .................................................................................................................................... 270 2. Chemical delivery systems ..................................................................................................................
271
3. The soft drug approach ..................................................................................................................... 3.1. Soft [3-blockers ........................................................................................................................ 3.2. Soft steroids ............................................................................................................................
273 273 273
4. The prodrug approach ......................................................................................................................
275
5. Conclusions..................................................................................................................................... 277 References .......................................................................................................................................... 277
Abstract
The goal of this work is to review the various approaches to the design of ophthalmic agents with improved therapeutic profiles. A critical focus of the discussion will include not only optimal structure/transport properties of lead molecules, but also the potential metabolic transformations of target tissues. The careful consideration of such metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and provides for the potential of site-specific bioactivation, thus enabling the realization of significant improvements in efficacy and minimization of side-effect profiles, locally and systemically. Key words. Chemical delivery systems; Soft drugs; Prodrugs; Ocular drug metabolism; Site-specific delivery; Bioactiva-
tion; Corneal transport
0169-409X/94/$27.00 © 1994 Elsevier Science B.V. All rights reserved SSD1 0 1 6 9 - 4 0 9 X ( 9 3 ) E 0 0 5 7 - L
270
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
1. Introduction The design of therapeutic agents for the eye is a unique task that is limited by the location of the organ itself as well as by the functional physiology of the component tissues. As a relatively isolated organ that has a number of avascular components (e.g. cornea, trabecular meshwork, lens), topical therapy is by far the most effective for a number of disease states and diagnostic procedures (glaucoma, inflammation, herpes keratitis, lens extraction, vitrectomy, etc). However, due to a number of protective systems (lacrimal apparatus, eyelids, cornea, sclera, conjunctiva) the majority of the dose applied will be delivered, not to the ocular tissues (typically < 5%), but to the general circulation via the nasolacrimal system and nasal/gastric mucosa [1]. Therein lies the largest problem with many of the therapeutic agents utilized for ophthalmic disease [2-4]. Many of these drugs are typically lead compounds that were originally developed for oral/parenteral therapy, and therefore can be expected to elicit a profound pharmacological response when absorbed systemically from a topically instilled dose. Thus a patient treated for primary glaucoma with an underlying cardiovascular/respiratory condition, may well be adversely affected by the non-(ocular) productive absorption of a [3-agonist like epinephrine or a [~-antagonist like timolol [5-7]. In addition to the potentially adverse effects of ophthalmic drugs that are absorbed systemically, there are also instances where the local effects of these agents themselves are severely limiting. This is certainly the case with local corticosteroid therapy where complications may involve the development of elevated intraocular pressure (IOP), glaucoma (open angle) and potentially cataracts [8]. Corticosteroid therapy has also been implicated in the increased incidence of herpes simplex keratitis (cornea), resulting from an enhanced destructive effect of collagenase on the collagen of the cornea. These adverse events as well as the extended duration of secondary cellular responses to even a single steroid dose suggest the need for molecules with a greater therapeutic index [9]. Thus, in order to maximize the therapeutic index of ophthalmic drugs it is necessary to design
compounds based not only on structure/transport considerations but also on intrinsic metabolic and physiologic processes of the eye [10]. It is these factors as well as the inherent activity of the compound itself that will ultimately determine efficacy/toxicity. Tl~e particular importance of metabolic considerations can be realized upon review of the ability of ocular tissues to transform a number of drugs and other exogenous agents [11-13]. The metabolic spectrum of activity includes not only the classical hydrolytic reactions in the cornea, aqueous humor and choroid tissues but also a number of other pathways that involve hydroxylation, oxidation and reduction of exogenous substances. Therefore, not only does the potential exists for controlling the metabolic deactivation of drugs through designed structural modifications, but there is also the very real possibility of controlled site-specific bioactivation. Both approaches provide the capability of maximizing the safety/efficacy of ophthalmic agents and will be the focus of this review.
2. Chemical delivery systems The incorporation of predictable metabolic activation into the design of therapeutics has been termed a "chemical delivery system" (CDS) [10]. Chemical delivery systems for site-specific therapy have been shown to be successful approaches for the brain as well as for the eye [14,15]. In this type of system, enzymatic processes associated exclusively or preferentially at the target tissue are utilized to convert the inactive CDS to the active drug. These systems may well require more than one (enzymatic) bioactivation step to produce the active agent, due to the multifunctional requirements needed for barrier transport and site-specific delivery [16]. Such a system has been developed for the site-specific delivery of adrenaline (epinephrine) to the anterior segment of the eye, via diester derivatives of adrenalone [17,18]. Adrenalone (Scheme I, 1) is the synthetic precursor of adrenaline (Scheme I, 2), which is devoid of any significant sympathomimetic activity of its own [19]. However, a series of ester derivatives (Scheme I, 3; e.g. R - (CH3)2CHCH2CO-) were
271
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269 279
0
RO
O
NHC.3 R,H f
erase
RO"
=
3
II O
NHCH3
~
1 1 1 1
.
L O ~
cstcra:cstcrase
5"
HO HO
I
~
NHCH3
reductase reductase
OH RO RO
OH sterase=,R'HI O'-'-~ ""~" Vesteras¢ L0-~,,.,,,,~ 6
OH HO ~
~
2
NHCH3
HO
Scheme I found to produce a dramatic mydriatic response and decrease in IPO following topical administration of solutions equivalent to 0.05% of the parent compound adrenalone [20]. This is in sharp contrast to the minimal level of activity exhibited by adrenalone even at concentrations of 2%. The mechanism responsible for this observed activity was clearly not simply the enhanced flux of the diesters across the corneal barrier and facile hydrolytic cleavage of the esters to adrenalone. Instead, it was proposed and subsequently demonstrated that the adrenalone esters undergo a reduction-hydrolysis sequence to form epinephrine exclusively in the iris-ciliary body, whereas in the rest of the eye or systemic circulation, ester hydrolysis results only in the production of the inactive adrenalone. It was also observed that even when adrenalone was administered at a 40-fold higher concentration than the diesters, only adrenalone could be detected in the various tissue compartments. This indicates that the diester or monoester (Scheme I, 1, 3, 5) form of adrenalone not only is responsible for facilitating intraocular transport, but is also the preferential substrate for the ketone reductase. The site-specific bioactivation of the adrenalone diesters in the tissues of the uveal tract ap-
pears to be consistent with its role as a major site of drug metabolism within the eye. The metabolic reduction of the ketone functionality as in the diester derivatives of adrenalone also has been established to be a preferential pathway in mammals. This reduction process eliminates lipid-soluble carbonyls and transforms them into alcohols that are significantly more polar [21,22]. The tissue distribution of carbonyl reductases is also fairly widespread (liver, kidney, lung, heart, brain, spleen) and includes certain vascular tissues of the eye. Based on these observations, it appears that the biotransformation of adrenalone derivatives involves the following: either (a) direct or sequential hydrolysis by esterases of the esterified catechols to give the inactive adrenalone, or (b) reduction of the ketone to the alcohol (Scheme I, 6) followed by esterase cleavage of the esters leading to the active adrenaline. Although not clearly established in these studies, the stereospecificity of the reductase seems fairly obvious, based on the high level of activity exhibited by the ester derivatives as well as on the relatively low level of activity associated with the D-enantiomer of adrenalin. This approach, therefore, illustrates the concept of a site-specific chemical delivery system and clearly distinguishes it from a simple prodrug sys-
G.C. Visor/Advanced Drug Delivery Reviews 14 (1994) 269 279
272
NOH
II
7
o II O~CH2__C__CH2NHCH(CHa) 2
8
I
O--CH2~C--CH2NHCH(CH3) 2
9 Scheme II
tern. Prodrugs like dipivalyl or diisovaleryl epinephrine [23,20] deliver drug (non-specifically) to all compartments of the eye and potentially to the central compartment of the body due to instilled dose drainage. The chemical delivery system on the other hand is site-specific and therefore is much more efficient and conceivably better tolerated. The accumulation of data on the high level of metabolic activity observed in the tissues of the uveal tract (iris, ciliary body, choroid) as well as their functional role in a number of physiological processes (aqueous humor dynamics, intraocular pressure regulation, avascular tissue support, etc.) suggests that targeting this site for drug bioactivation would be most beneficial. This has been the case for the CDS prepared for a number of [3-antagonists [24, 25]. These compounds have proven to be very valuable in the treatment of glaucoma. However, as mentioned in the Introduction, they have been associated with adverse cardiovascular, respiratory, central and ocular effects. In an effort to minimize these adverse events a series of hydrolytically sensitive oxime functions (Scheme II, 7) were designed into a number of [3antagonists. These compounds like adrenaline/ adrenalone are [3-hydroxylamines and therefore, via an enzymatic hydrolysis-reduction sequence (Scheme II, 7-9), could result in site-specific bioactivation in the iris-ciliary body tissues. Details of the synthetic routes [24,25] and related studies can be found elsewhere; however, a review of the more significant findings is appropriate. In comparative studies with the [3-antagonist propranolol (Scheme II, 9) and its corresponding CDS (propanolone oxime) [26], it was found that
propranolol was able to reduce the IOP of rabbits for about 4 hours at a concentration of 1% (Fig. 1). At this dose, propranolol was found to be irritating as characterized by slight congestion, redness and swelling. The irritancy was found to be greatly enhanced at a concentration of 2.5% and apparently was the cause of the insignificant IOP effects. The propanolone oxime on the other hand (1%) produced a hypotensive ocular state that was both more intense and of significantly longer duration. In addition, the oxime derivative was devoid of any local irritation. Evaluation of the in-vivo tissue distribution of propranolone oxime (Table 1) revealed, as expected, the parent compound, propranolol, in
-22 I
i
TIME
|
•
•
•
(hours)
Fig. 1. Effect ofpropranolol hydrochloride (9) and propranolol oxime hydrochloride (7) on the ]OP pressure of rabbits. • propranolol hydrochloric (9) 1%; • - propranolo[ hydrochloride (9) 2.5%; O = propranolone oxime hydrochloride (7) 1%; [] = propranolone oxime hydrochloride (9) 2.5%; - - = saline solution (n=6-10).
G.C. Visor~AdvancedDrug Deliver)' Rev&ws 14 (1994) 269-279 Table 1 Tissue concentrations (g/g) of propranolol and propanolone oxime at various time intervals following topical administration of propanolone oxime HCI (1% solution) Tissue t y p e
P r o p r a n o l o l Propanolone Time oxime (min)
Cornea Iris/ciliary body Aqueous humor
1.68 ± 0.75 2.11 ± 0.29 0.04 _+ 0.02
23.75 _+ 4.91 7.79 ± 1.10 0.82 ± 0.09
30 30 30
Cornea Iris/ciliary body Aqueous humor
1.14 ± 0.29 1.79 _+ 0.20 0.71 ± 0.I1
16.40 ± 5.80 0.00 ± 0.00 0.80 _+ 0.06
60 60 60
Cornea Iris/ciliary body Aqueous humor
1.14 _+ 0.22 0.43 ± 0.11 0.00 ± 0.00
0.00 ___0.00 0.00 _+ 0.00 0.00 ± 0.00
120 120 120
measurable concentrations up to 2 hours after administration in the iris/ciliary body and cornea [26]. The formation of the parent compound propranolol was never detected in rats, rabbits or dogs following intravenous infusions. Finally, the stereospecificity of the enzymatic reduction was also established (as exclusively the S - ( - ) form) following chromatographic analysis of iris/ciliary body tissue treated with a chiral reagent [27]. This is consistent with the high level of activity exhibited on a molar basis by this enantiomer relative to that associated with the R-( + ) form. Thus, as previously hypothesized in the adrenalone CDS, the (enzymatic/reduction) biotransformation of propanololone oxime appears to be both site- and stereo-specific.
273
The functional moieties for metabolic transformation typically do not involve oxidation or conjugation pathways and should take place at a rapid rate following receptor interaction. By design, this should take place without the formation of reactive intermediates or allow for competitive routes of transformation to occur. The details of soft analog design have been presented elsewhere in several literature reviews and applications that include a number of therapeutic areas (e.g. mydriatics, anticholinergics, anti-inflammatory, antimicrobials) [28,29]. 3.1. Soft [J-blockers Utilizing what is termed the "inactive metabolite approach", a series of soft analogs were derived from the acidic metabolite of the 13-antagonist, metoprolol (Chart I, 10). Metaprolol has been shown to undergo multiple oxidative degradations among which the phenylacetic acid (Chart I, 11) derivative is a major product. As the phenylacetic acid metabolite is inactive, it can be used as the structural lead for soft synthetic preparation [30]. A series of lipophilic esters (Chart I, 12) were prepared based on this approach and found to provide significant reductions of IOP in rabbits for extended periods of time [31]. The adamantylethyl ester derivative (Chart l, 13) was found to be the most effective from the standpoint of reducing IOP (Fig. 2), el±citing minimal irritation and undergoing rapid hydrolysis in plasma [32]. Thus, it fits the desired profile of a soft analog in that it is both active and predictably metabolized, thereby minimizing the potential for systemic side-effects.
3. The soft drug approach 3.2. Soft steroids" Another metabolism-based approach to the design of ophthalmic agents is that associated with soft analogs. Soft analogs are a class of compounds that are close structural analogs (isosteric, isoelectronic) of known active drugs or endogenous substances [16]. These soft compounds are different from the lead compound in that they have a specific metabolic (preferentially hydrolytic) "handle" built into their structure that provides a one-step pathway for controllable detoxication.
The ability to manage the multitude of ocular inflammatory conditions (conjunctivitis, keratitis, uveitis, blepharitis, etc) is certainly limited by the side-effects associated with (topical/systemic) corticosteroids (elevated IOP, glaucoma, cataracts, secondary infections). However, without prompt treatment of some of these conditions, severe ocular damage may occur. Therefore, it is appropriate to review an application of the inactive metabolite
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
274
OH
OH
J
I
CHzCHCHzNHCH(CH3)z
O--CHzCHCHzNHCH(CH3) z
* 1=<005 eeP
,
E E
£
L Z
CH2CH2OCH3
W
CH2COOH
lO
(~ Z < -r U
ll OH
OI
*1"
L
-Z"
I
OH
I
O ~CH2CHCH2NHCH(CH3)2
I
-3
O ~CH2CHCH2NHCH(CH3)2
0 TIME,
hr
Fig. 2. Effect of the soft 13-blocker (10) on the IOP of rabbits following unilateral treatment with 0.1 ml of 0.25% solution. Solution was administered at 0 and 2 hours. [] - control eye; • = treated eye; *p<0.05, **p<0.005. CH2COOR
CH2COO'CH2CH2
(adamantyl¢thyl) 13 Chart I
approach in the design of a soft steroid for topical administration. In this example of designing compounds based on structural-metabolic relationships, an inactive
metabolite of prednisolone (Al-cortienic acid) was used as the lead and "reactivated" via structural modifications [33]. The resulting soft corticosteroid, loteprednol etabonate (LE) (Scheme III, 14; (chloromethyl 17ct-ethoxycarbonyloxy-1 l]3-hydroxy-3-oxoandrosta-l,4-diene 17[3-carboxylate), was approximately 4 times that of dexamethasone. This compound possesses a 17[3-chloromethyl ester functionality that is designed to be rapidly hydrolyzed in ocular tissues as shown in Scheme III to two inactive metabolites (15 and 16). The in vivo anti-inflammatory activity of this compound was found to be equivalent to or greater than beta-
Ok~ -'OCH2CI HO
14
Loteprexlnol Etabonate
'~
O~'k OH HO
15
A1 -Cortienic Acid Etabonate Scheme 111
I '~
0 HO
16
A1 -Cortienic Acid
' ~
OH
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269-279
Table 2 Intraocular pressure after steroid administration1'2 Time
Vehicle control
.--.
6O
Dexamethasone Loteprednol
(h)
l
etabonate
Treated eye 0 3 7 24 31 48 55
15.62 15.37 14.50 15.62 16.04 15.81 15.23
± ± ± ± ± ± ±
1.42 1.41 1.31 1.43 1.44 1.41 1.38
15.85 16.21 19.38 18.13 20.23 18.63 17.04
± ± ± ± ± ± ±
0.44 0.50 0.59* 1.07 0.63* 0.97 0.76
15.88 15.65 16.90 14.92 14.90 15.44 15.65
± ± ± ± ± ± ±
1.47 1.39 1.44 1.35 1.33 1.44 1.40
Control eye 0 3 7 24 31 48 55
15.92 15.81 14.90 16.08 16.31 16.04 15.50
± 1.45 ± 1.49 ± 1.36 ± 1.46 ___ 1.45 ± 1.45 ± 1.46
15.62 16.00 19.63 18.48 20.29 17.96 16.44
± ± ± ± + ± ±
0.60 0.62 0.71" 1.08 0.76** 0.63 0.48
15.85 15.77 16.65 14.92 15.50 15.54 15.50
± ± ± ± ± ± +
1.51 1.43 1.44 1.35 1.41 1.46 1.40
~Twelve rabbits were evaluated via a cross-over method. Steroid or vehicle were administered 8 times per day for 2 days. 2Table entries are the mean + SE m m H g . *p<0.005 when compared to the control value. **p <0.05 when compared to the control value.
methasone and the systemic side-effects (thymolytic activity, adrenal suppression) to be significantly less than those typically associated with standard steroid therapies [33,34]. In a direct comparison of the IOP-elevating activity of LE and dexamethasone in rabbits, it was found that the soft steroid did not elicit a significant response (Table 2) [35]. The dexamethasone did show, as expected, a marked increase in IOP; as many as half of the animals ( n = 6 out of 12) had increases of 4~10 mmHg and two animals exhibited an increase of 10-15 mmHg. The results also suggested that the treatment regimen employed (8 x per day, 0.1%) could also induce significant increases of IOP in control eyes of rabbits treated with dexamethasone, presumably via systemic absorption. Studies of the ocular distribution of LE following topical administration determined that the compound was effectively transported into the anterior segment of the eye, with levels of the parent compound and metabolites in the cornea, aqu-
275
.~ 40 ~
I~11 i
I--q~t,,b~it~
I
2o
I1) O0
0
. . . . . . . .
0
2
4
6
8
time (hours) Fig. 3. Loteprednol etabonate and metabolites in the cornea. Average + SD (n = 4 except for t = 2 h where n - 3).
eous humor and iris/ciliary body [36]. The highest levels of LE and metabolites were found in the cornea and this is consistent with the cornea being the primary site of absorption as well as the largest barrier to anterior segment delivery (Fig. 3). The presence of the highest ratio of metabolites to parent drug in the corneal tissue also reflects its well-established role in drug metabolism and in particular esterase activity [37-40].
4. The prodrug approach The utilization of the prodrug approach has also been established to be quite valuable in the design and development of therapeutic agents for the eye [41-43]. The concept involves the derivitization of the active compound with transient transport moieties that will enhance the delivery characteristics and, hopefully, the therapeutic value of the drug. The pro-derivative is designed to be a transport/protective form of the drug that is transformed into the active drug by either enzymatic or chemical processes before reaching and/ or at the site of action [44]. A principal requirement for a prodrug, then, is that it be inactive and undergo biotransformation exclusively/preferentially to the parent compound. It is also impor-
G.C. Visor~Advanced Drug Delivery Reviews 14 (1994) 269 279
276
C--O--C
i
II
H
/
l
X
+
I
O
I
O
R
=
i'+ S
C--O--C
!
X-
\
o
17
C--O--C
\
N
19
18
i' +J ! \ N
/
H20 C--OH
= R
X-
19
+ R1
C~H
+ N
O
O
II
\
20
21
18
•
HX
Scheme IV
tant to note the differences between prodrugs, soft drugs and chemical delivery systems, as their utilizations are certainly not interchangeable [45]. Thus the selection of a particular strategy will ultimately be dictated by the therapeutic goal: i.e., modification of intrinsic drug toxicity, improved site, tissue or receptor selectivity, enhanced membrane transport, etc. In many of the ophthalmic applications employing the prodrug approach, the bioreversible systems are designed primarily to transverse the primary barrier to ocular absorption, which is the cornea. As the cornea is a tissue that is biphasic in structure (epithelium, stroma, epithelium) most pro-derivatives will need to have some degree of biphasic solubility in order to be effective. These pro-derivatives should, however, have no other pharmacodynamic impact than that provided by the parent compound itself. Although there are several functionalities (hydroxyl, carboxyl, amino, etc.) that are adaptable to the pro-drug approach and thus capable of forming labile ester transport forms, a particularly useful strategy for compounds containing tertiary amines has been developed and is appropriate for review. This bioreversible system is based on the concept of "soft quaternary salts" [4~48] and has been found to be effective with these types of molecules due to their highly pHdependent delivery across biological membranes. Preparation of prodrugs of tertiary amines in this
manner, therefore, involves quaternization of the amine, via a reaction with an ~-haloester as depicted in Scheme IV. The resulting product is characterized by its facile enzymatic or chemical hydrolysis, thereby eliminating the quaternary center (19), regeneration of the starting tertiary amine, and production of an acid and an aldehyde (Scheme IV, 18, 20 and 21, respectively). Control of the physicochemical properties, stability and bioconversion rates can be affected by the appropriate selection of functionalities for R and Rt. An illustration of this type of prodrug system with the parasympathomimetic agent, pilocarpine (Chart II, 22), demonstrates the flexibility and value of the approach. As with most ophthalmic agents, an enhancement of lipophilicity often leads to improved transport across the cornea
N
oZ
I
CH3
22 Chart I1
G.C. Visor~AdvancedDrug Delivery Reviews 14 (1994) 269-279
have utility in the design o f other therapeutic agents like anticholinergics and antibacterials, via the "soft a n a l o g " a p p r o a c h [49,50].
O +
CH2Hs CH2J/~
•
C H ~ O ~ C ~ R 2
5. C o n c l u s i o n s
C1-
RI=H, CH3 23
R2=(CH2)nCH3 n= 10-16
Chart Ill
and into the anterior segment o f the eye. Therefore, a series o f lipophilic pro-derivatives o f pilocarpine (Chart III, 23, Rl = H ; n = 14) were prepared and evaluated for miosis. It was determined that a solution o f c o m p o u n d 23 equivalent to 0.2% pilocarpine was significantly more potent and longer-lasting than a solution containing 2% pilocarpine (Fig. 4). To demonstrate that the proderivative itself did not contribute to the activity exhibited, the corresponding N-hexadecyl " h a r d " salt was also synthesized, tested and found to be inactive, thereby establishing that the "soft quaternary" salts of pilocarpine were indeed true prodrugs. This system has also been demonstrated to
3.0z ,,~
2.5-
-~
2D-
A
PILOCARPINE
HYDROCHLORIDE
O
PILOCARPINE
HE XA DECANOYLOXYMETHYLCHLORIDE
Q
0 0
~ 1.5~ 1.0" J 0..5" ..I i =E O
i I0
,
, 30
,
, 50
,
, 70
,
i 90
i
i IlO
277
,
I i 130
v I50
J
i i I'K)
i
•
190
TIME (MINUTES)
Fig. 4. The relative miosis caused by a 2.0% pilocarpine hydrochloride solution (A) vs. a 0.2% solution of pilocarpine hexadecanoyloxymethyl chloride (C)).
As the incidence o f ocular disease rises dramatically with age, so do the complications associated with its therapeutic management. This is the result o f the local and systemic side-effects of the powerful agents used and their impact on patients' underlying disease states. The approaches outlined in this review--chemical delivery systems and soft d r u g s - provide the means for enhancing the overall safety and efficacy o f ophthalmic drugs. This is accomplished by not only careful analysis o f the various factors affecting drug-receptor interactions, but also by the metabolic pathways that will ultimately control a comp o u n d ' s disposition. Therefore, it is expected that appropriate structural optimization in this m a n n e r will lead to drugs with maximal separation o f therapeutic benefit from toxicity.
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