Ocular delivery using poly(ortho esters)

Advanced Drug Delivery Reviews 57 (2005) 2053 – 2062 www.elsevier.com/locate/addr

Ocular delivery using poly(ortho esters)B Jorge Heller * PO Box 3519, Ashland, OR 97520, USA Received 21 June 2005; accepted 13 September 2005 Available online 8 November 2005

Abstract Three families of poly(ortho esters) were investigated as a means of delivering 5-fluorouracil (5-FU), an antiproliferative agent used as an adjunct to glaucoma filtering surgery. Release of 5-FU from a crosslinked POE II occurred predominantly by diffusion with little weight loss, while release of 5-FU from a linear polymer occurred by an erosion-controlled process confined predominantly to the surface layers. No ocular biocompatibility studies were carried out. Rate of release of 5-FU from POE III, a viscous, injectable material, could be controlled by polymer molecular weight and polymer hydrophobicity. Excellent biocompatibility was demonstrated in subconjunctival, intravitreal and suprachoroidal injections. Polymer lifetime in the various sites investigated was between 1 and 3 weeks. The effect of sustained 5-FU release was investigated in rabbits that underwent a trabeculectomy and the effectiveness of maintaining low intraocular pressure for 1 month demonstrated. Release of 5-FU from POE IV was investigated using both solid and viscous, injectable materials. Good control over rate of 5-FU release by an erosion-controlled process was achieved from both types of formulations. Excellent biocompatibility was demonstrated in subconjunctival, intracameral, intravitreal and suprachoroidal injections. Lifetimes in the various sites ranged from 5 weeks for subconjunctival injections to 3 months for intravitreal injections to more than 6 months for intracameral and suprachoroidal injections. D 2005 Elsevier B.V. All rights reserved. Keywords: Poly(ortho ester); 5-fluorouracil delivery; Bioerodible polymer; Glaucoma; Biocompatibility; Ophthalmology; Injectable polymer

Contents 1. 2.

Introduction . . . . Poly(ortho esters) . 2.1. POE II . . . 2.2. POE III . .

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B This review is part of the Advanced Drug Delivery Reviews theme issue on bDrug Delivery Strategies to Treat Age-Related Macular DegenerationQ, Vol. 57/14, 2005. * Tel.: +1 541 552 0941; fax: +1 541 552 0941. E-mail address: [email protected].

0169-409X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2005.09.007

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2.2.1. Biocompatibility . . . . . . 2.2.2. Glaucoma filtering surgery 2.3. POE IV. . . . . . . . . . . . . . . 2.3.1. Biocompatibility . . . . . . 3. Conclusions . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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Treatment of ocular diseases by non-topical intraocular administration generally requires multiple injections. However, aside from considerable patient discomfort, serious side effects can occur. These undesirable side effects can be greatly diminished by developing bioerodible ocular implants that provide localized and sustained drug release over the desired time, thus eliminating the need for frequent injections. While other synthetic polymers have been used to provide such sustained release devices, this review will only cover poly(ortho esters). General reviews on the use of various bioerodible polymers for ocular drug delivery have been published [1,2]. Because of the importance of 5-fluorouracil in ocular therapy, the review will cover in vitro studies of release of 5-fluorouracil even though not all systems covered were used in in vivo applications.

O

O

O

O

O

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O

O-R

O

O

O

CH

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n POE III

(H) CH3 O O

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O-CH-(CH2)4

POE II

O

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C n

O

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O-CH 2

R

n POE I

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POE II is prepared as shown in Scheme 2. While ortho ester linkages are hydrolytically labile, the polymer is highly hydrophobic so that erosion in an aqueous environment is very slow [5]. For this reason, and in view of the acid-labile nature of ortho ester linkages, desired erosion rates can be achieved by the incorporation of acidic excipients into the polymer matrix. [6]. The effectiveness of the acidic excipient is governed by its pK a and the amount incorporated. Poly(ortho esters) can also be prepared as crosslinked materials by using a triol, either alone or as a mixture with diols, where the ratio of diol to triol controls crosslink density. The synthesis of a crosslinked polymer is shown in Scheme 3 [7]. POE II has been investigated as a matrix for the controlled release of 5-fluorouracil (5-FU) which is

Poly(ortho esters) have been extensively reviewed [3,4] and only a brief description of the various polymer families will be presented here. Poly(ortho esters) have been under development since the early 1970s and during that time, four O

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2.1. POE II

2. Poly(ortho esters)

O-R

. . . . . .

families of poly(ortho esters) have been described. These are shown in Scheme 1. POE I was not investigated in ocular applications and studies of POE II in ocular delivery were limited to in vitro release studies of 5-fluorouracil (5-FU). However, extensive studies dealing with biocompatibility and drug delivery have been carried out with POE III and POE IV.

1. Introduction

O

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C-O

n

R'

O

O

O

O

O

POE IV

Scheme 1. Poly(ortho ester) families.

O-R n

J. Heller / Advanced Drug Delivery Reviews 57 (2005) 2053–2062

used as an adjunct to glaucoma filtering surgery. Glaucoma is characterized by an increase in intraocular pressure (IOP). When topical treatment is not effective, a procedure known as trabeculectomy is performed. In this procedure, a fistula is created between the anterior chamber and the subconjunctival space in order to reduce the IOP. However, normal scarring leads to closure of the filtration site due to fibroblast proliferation so that antiproliferative agents such as 5-FU must be used. This requires daily injections for 2 weeks, which is not only traumatic for the patient, but can also lead to significant problems such as corneal epithelial erosion, hypotonia and endophthalmitis [8,9]. Initial studies used a crosslinked poly(ortho ester) containing varying amounts of copolymerized 9,10dihydroxystearic acid to modulate erosion rate [10]. As previously described, the crosslinked polymer was obtained by first preparing a ketene acetal-terminated prepolymer, incorporating 5-FU and then crosslinking with 1,2,6-hexanetriol [7]. Release of 5-FU is shown in Fig. 1. While, as expected, the amount of copolymerized 9,10-dihydroxystearic acid modulates release of 5-FU, as shown by the numbers in parentheses that denotes weight loss, there is very little polymer erosion. Since we are dealing with a crosslinked polymer, matrix hydrolysis does not necessarily lead to weight loss and chain scission will predominantly lead to a decrease in crosslink density. Thus, the dominant mode of 5-FU release is diffusion. However, the expected t 1/2 dependence is not observed due to an increasing permeation rate caused by the gradually decreasing crosslink density resulting from hydrolytic chain scission. To achieve an erosion-controlled release of 5-FU, a linear polymer was investigated next using a composition that will produce soft, pliable devices. Since it has been shown that the glass transition temperature of the polymer can be accurately controlled by proper choice of diol, or mixture of diols [11], 1,6-hexanediol was chosen. As already described [6], erosion rate of POE II is controlled by the incorporation of acidic excipients into the polymer matrix. Three acidic excipients, itaHO-R-OH

+

O

O

O

O

O

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O

O

+ HO-R-OH +

O

O

O

O

O

O

R

O

O

O

O

O

O

O

O

O

R(OH)3

CROSSLINKED POLYMER

Scheme 3. Generic synthesis of crosslinked POE II.

conic, adipic and suberic acids, were investigated, and based on results obtained, suberic acid was selected. Release of 5-FU from polymer discs containing varying amounts of suberic acid are shown in Fig. 2 [12]. The figure shows a reasonably linear release that is proportional to the amount of incorporated suberic acid. Further, as shown by the number in parentheses that denote weight loss of the polymer at the indicated point in time, erosion tracks drug release. This was further corroborated in a separate experiment, shown in Fig. 3, where weight loss and 5-FU release has been plotted. The concomitant 5-FU release and weight loss indicate a surface erosion mechanism. Unfortunately, a polymer containing only 1,6-hexanediol has a glass transition temperature only slightly above 20 8C and is not only very soft, but is also easily deformable and is thus not suitable for ocular applications. While the use of physical blends to improve mechanical properties was briefly investigated [12] and did show some promise, it was not further investigated. 2.2. POE III POE III is prepared as shown in Scheme 4 [13]. In this synthesis, the triol is 1,2,6-hexanetriol. Because R is (CH2)4, the polymer chains are very flexible and the polymer is a viscous, gel-like material at room temperature. The viscous nature of the mate-

O

O

O

O

O

O-R n

Scheme 2. Generic synthesis of linear POE II.

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Fig. 1. Cumulative release of 5-fluorouracil from a crosslinked poly(ortho ester) prepared from a 15:85 mole ratio of triethylene glycol and 3-methyl-1,5-pentanediol in the prepolymer crosslinked with 1,2,6-hexanetriol and containing varying amounts of copolymerized 9,10-dihydroxystearic acid (DHSA). Disks, 1.2  6.4 mm in a pH 7.4 buffer at 37 8C. Numbers indicate weight loss. Device contains 10 wt.% (5 mg) 5-fluorouracil (E) 0.005 mol DHSA, (5) 0.001 mol DHSA, (n) 0.01 mol DHSA (from [Ref. 10]).

rial allows incorporation of therapeutic agents by mixing at room temperature without the need to use solvents. This is clearly advantageous when thermally labile, or solvent-sensitive materials need to be incorporated. The rate of release of agents physically incorporated into POE III can be controlled by variations in the molecular weight of the polymer as shown in Fig. 4. In these in vitro experiments, 5-FU was released between 1 day for a polymer having a 3500-Da molecular weight to about 1 week for a 33,300-Da molecular weight [14]. When 5-FU release and polymer weight loss shown as T 50% is plotted as a function of polymer molecular weight, results shown in Fig. 5 are obtained [14]. The plot shows excellent linearity (r = 0.9999 for 5-FU release and 0.9981 for weight loss). The results can be rationalized in terms of 5-FU release occurring by a combination of diffusion and erosion. For a 3500-Da polymer, erosion is relatively fast and very little diffusion takes place. However, for a 15,200-Da polymer, erosion is slower so that drug diffusion becomes more important. Rate of drug release can also be controlled by modifying the hydrophobicity of the polymer. This can be accomplished by changing the triol from 1,2,6-

Fig. 2. Cumulative release of 5-FU from a polymer prepared from a 35:65 mole ratio of trans-cyclohexanedimethanol and 1,6-hexanediol containing varying amounts of itaconic acid (IA). Disks 0.25  6.4 mm in a pH 7.4 phosphate buffer at 37 8C. Numbers in parentheses indicate percent weight loss. Device contains 10 wt.% 5-FU; ( ) 0.31% IA, (o) 0.08% IA, (5) 0.02% IA and (n) 0% IA (from Ref. [12]).

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hexanetriol to 1,2,10-decanetriol [15]. In this particular case, R in Scheme 4 is (CH2)8. Fig. 6 compares release of 5-FU from a polymer based on 1,2,6-hexanetriol (open symbols) with the more hydrophobic polymer based on 1,2,10-decanetriol (closed symbols). It will be noted that release from a 3.1-kDa

Fig. 3. Cumulative weight loss (5) and cumulative release of 5-FU (n) from a polymer prepared with 1,6-hexanediol and incorporating 0.15% suberic acid. Disks, 0.25  6.4 mm in a pH 7.4 phosphate buffer at 37 8C. Device contains 10 wt.% 5-FU (from Ref. [12].

J. Heller / Advanced Drug Delivery Reviews 57 (2005) 2053–2062 OCH2CH3 CH2 -CH-R-OH

+

OH OH

R' C

CH2 - CH-R-OH

OCH2CH3

O

OCH2CH3

+

CH3 CH2OH

OCH2CH3

O-CH 2

R' +

O C

R'

CH3 CH2OH

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C O

O-CH-R n

Scheme 4. Generic synthesis of POE III.

2.2.1. Biocompatibility POE III has been extensively investigated in ocular applications, and its biocompatibility in various parts of the eye investigated. The various sites are shown in Fig. 7 [16]. ARVO (Association for Research in Vision and Ophthalmology) statement on the use of animals in ophthalmic and vision research were observed during the experiments.

fabrication thus avoiding g-sterilization that has been shown to produce acidic species [19]. Biocompatibility could also be improved by using various basic excipients such as sodium acetate, calcium carbonate, hydroxyapatite and magnesium hydroxide to neutralize acidic species generated during sterilization and hydrolysis [20]. Addition of 5-fluorouracil did not significantly alter biocompatibility [21]. However, addition of dexamethasone markedly improved biocompatibility by reducing conjunctival hyperemia and completely suppressing conjunctival chemosis. It also prolonged ocular residence [21].

2.2.1.1. Subconjunctival injections. Subconjunctival biocompatibility was investigated using New Zealand albino white rabbits [17,18]. After injection of 200 Al, an acute inflammation developed, but was rapidly resolved. Biocompatibility could be substantially improved by careful polymer purification and aseptic

2.2.1.2. Intravitreal injections. This was evaluated in pigmented rabbit eyes using 100 Al of POE alone, POE with incorporated magnesium hydroxide or a combination of 5-FU and dexamethasone [22]. After injection, the polymer appeared as a round bulk moving concomitantly with eye movement. POE

Fig. 4. Cumulative 5-FU release from an acetate polymer, mean F S.D. (n = 6), in phosphate buffer, pH 7.4 at 37 8C. (o) POE 3500 Da; ( ) POE 5800 Da; (5) POE 10100 Da; (n) POE 15,200 Da; (D) POE 33,300 Da (from Ref. [14]).

Fig. 5. Comparison between 5-FU release and POE weight loss vs. POE molecular weight using T50% for both parameters (from Ref. [14]).

C10 polymer is similar to the release from a 11.9-kDa C6 polymer and the release from a 22.3-kDa C10 polymer is similar to the release from a 33.3-kDa C6 polymer.

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Fig. 6. Cumulative release of 5-FU (1% w/w) from different molecular weight POEC6 (open symbols) and from POEC10 (closed symbols) in phosphate buffer, pH 7.4 at 37 8C. (o) 11.9 kDa; (5) 33.3 kDa; (n) 3.0 kDa; ( ) 15.3 kDa and (E) 22.3 kDa (n = 3, sdm) (from Ref. [15]).

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alone, or containing 5-FU has markedly degraded by day 5, but in the presence of the basic magnesium hydroxide, or dexamethasone, lifetime was about 2 weeks. The injections were well tolerated and no inflammatory reactions could be observed clinically. In some eyes, a discrete cellular infiltration in the vitreous adjacent to the inner limiting membrane and the optic nerve head was observed. The incorporation of magnesium hydroxide or dexamethasone significantly reduced the inflammatory cell infiltration. 2.2.1.3. Suprachoroidal injections. Administration by this novel route was achieved by creating a scleral incision followed by careful tunelization in the suprachoroidal space followed by the injecting 100 Al of polymer very posteriorly between the sclera and the choroids [23]. No adverse effects were detected. The polymer appeared unchanged for about 1 week and then disappeared over 2–3 weeks. 2.2.2. Glaucoma filtering surgery In view of its excellent biocompatibility, the effect of sustained release 5-FU on preventing failure of trabeculectomy was carried out. In this study, rabbits underwent a trabeculectomy and were divided into three groups. One group of rabbits had a trabeculectomy alone, one group was administered 200 Al of POE III alone, and one group was administered 200 Al of POE III with 1 wt.% 5-FU. HPLC studies have

shown that 5-FU was gradually released over a 2week period. Recently, studies were conducted where the IOP of rabbits with trabeculectomy only, rabbits with trabeculectomy and polymer only and rabbits with trabeculectomy and polymer containing 1 wt.% 5-FU were compared [24]. It was shown that only polymer with 5-FU was able to maintain a lowered IOP for up to 1 month, the time span of the experiment. Furthermore, the polymer with 5-FU was able to achieve the lowered IOP with a significantly reduced 5-FU toxicity. 2.3. POE IV Work with POE III has convincingly demonstrated that poly(ortho esters) have excellent potential for ocular drug delivery. However, POE III has two inherent limitations. It can only be prepared as a semi-solid, gel-like material, and it is prepared by a synthetic procedure that involves long reaction times, is very difficult to scale up in an industrial setting and control of molecular weight, essential for reproducible release kinetics, is virtually impossible. Thus, despite excellent results, no further work with POE III was carried out and emphasis has shifted to POE IV. POE IV is prepared as shown in Scheme 5. POE IV differs from POE II in that it contains a latent acid in the polymer backbone incorporated to control erosion rate. The latent acid is usually based on glycolic acid, but lactic acid has also been used. Thus, unlike POE II that required the addition of acidic excipients, erosion rate of POE IV is controlled by the concentration of the latent acid in the polymer

Fig. 7. Schematic of an eye showing different sites of polymer injection (from Ref. [16]).

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O HO

CH2 -C-O-R-O

H n

+

HO-R'-OH DIOL

LATENT ACID O

O

O

O

DIKETENE ACETAL

O R'-O

O

O

O

O

O

CH2 -C-O-R-O

n

O

O

O

O

O m

POE IV

Scheme 5. Generic synthesis of POE IV.

backbone. When the polymer is exposed to an aqueous environment, the latent acid will hydrolyze and the liberated glycolic or lactic acid will then catalyze hydrolysis [25]. Synthesis of POE IV by the addition of diols to the diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane, abbreviated by the acronym DETOSU, occurs readily and has been scaled up to kilogram quantities. By variations in the nature of the diol(s), solid materials, or soft, gel-like materials can be obtained. Solid POE IV has been investigated as a matrix for 5-FU delivery. Fig. 8 shows the effect of latent acid on rate of release of 5-FU from compression-molded disks containing 10 wt.% 5-FU [26]. As seen, 5-FU release is proportional to the amount of latent acid and release is linear with only a minimal burst. Furthermore, visually drug depletion coincided with complete polymer erosion. Fig. 9 shows release rate of 5-FU from solid disks of polymer incorporating 20 wt.% 5-FU [27]. The plot also shows weight loss of the device. While material balance for the weight loss determinations at high erosion values is poor, the data convincingly show a concomitant 5-FU release and weight loss, indicating an erosion-controlled process. Further, these data are best interpreted by invoking a process where erosion is confined predominantly to the surface layers. One characteristic of surface erosion is a proportionality between rate of drug release and drug load-

ing. Theoretically, when drug loading is doubled, rate of drug release should also double. The effect of varying drug loadings on rate of 5-FU release is shown in Fig. 10 [28]. The observed rate of drug release is 0.58 mg/day, 1.04 mg/day and 1.79 mg/ day. The calculated release rates based on increased loading should be 1.22 mg/day and 2.49 mg/day. While these values are higher than those actually observed, there is little doubt that there is a correspondence between loading and rate of release so that

Fig. 8. 5-Fluorouracil (5-FU) release from a polymer prepared from 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane, trans-cyclohexanedimethanol glycolide (tCDM/Gly) and trans-cyclohexanedimethanol (tCDM) as a function of diol ratios. (5) 75/25 tCDMCDM/Gly, (n) 80/20 tCDM-CDM/Gly, ( ) 90/10 tCDM-CDM/ Gly. 0.05 M phosphate buffer, pH 7.4, 37 8C. Drug loading 10 wt.% (from Ref. [26]).

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Fig. 9. Polymer weight loss ( ) and 5-FU release (n) from a polymer prepared from 3,9-diethylidene-2,4,8,10-tetraoxaspiro [5.5]undecane and 1,3-propanediol/triethylene glycol glycolide (90:10). Drug loading 20 wt.%. 0.05 M phosphate buffer, pH 7.4, 37 8C (from Ref. [27]).

data in Fig. 10 are consistent with a predominantly surface erosion process. 2.3.1. Biocompatibility The biocompatibility of POE IV was investigated in subconjunctival, intracameral, intravitreal and suprachoroidal injections [29]. The POE IV used was 6 kDa molecular weight POE70LA30 prepared as previously described [30]. All studies were carried out using pigmented Fauve de Bourgogne rabbits at the Hotel Dieu Hospital in Paris. ARVO (Association for Research in Vision and Opthalmology) statement on the use of animals in ophthalmic and vision research were observed during the experiments. 2.3.1.1. Subconjunctival Injections. Subconjunctival injections of 200 Al polymer were performed superonasally with a 20 G needle, under local anesthesia. Slit-lamp examinations were performed daily for 6 months after injection (n = 6). During the first few days, the polymer triggered a grade 1.0 F 0.3 hyperemia, but no chemosis or lachrimation. The mild inflammatory reaction significantly decreased by day 8. Polymer lifetime under the conjunctiva was about 5 weeks, significantly longer than POE III that under similar conditions had a lifetime of about 1 to 2 weeks. Histopathological examination confirmed good biocompatibility.

2.3.1.2. Intracameral injections. A tunelized corneal incision was made in the superotemporal part of the peripheral cornea. A needle was then inserted in the anterior chamber and 50 Al of polymer injected. Slitlamp examinations were performed daily for 6 months after injection (n = 6). The injected polymer appeared as a mobile transparent bubble in the anterior chamber. The polymer degraded very slowly without inducing any clinical inflammation, or elevating IOP. In some eyes, the bubble was still visible after 6 months. Histopathological examination of eyes nucleated 7 days after injection confirmed good biocompatibility. 2.3.1.3. Intravitreal injections. Intravitreal injections were performed in the superotemporal quadrant of the eye within 3 mm of the limbus under a surgical microscope. 100 Al of the polymer was slowly injected in the vitreous cavity through a 0.9-mmdiameter needle under direct visualization. Slit-lamp examinations were regularly performed for 4 months after injection. (n = 6). After injection, the polymer appeared as a round bulk floating in the vitreous cavity, moving concomitantly with eye movement. No change in bubble size was apparent for 9 days, but at later time points, the

Fig. 10. Effect of loading on rate of 5-FU release from a poly(ortho ester) prepared from 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane, trans-cyclohexanedimethanol, 1,6-hexanediol, triethylene glycol and triethylene glycol glycolide (15/40/40/5). (n) 5.5 wt.% 5-FU (14 mg), (5) 11.6 wt.% 5-FU (28 mg), ( ) 23.6 wt.% 5-FU (56 mg). 0.05 M phosphate buffer, pH 7.4, 37 8C (from Ref. [28]).

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bubble size very slowly decreased. Polymer lifetime was about 3 months. No inflammatory reaction was observed and IOP remained normal. Histopathological examination confirmed good biocompatibility. 2.3.1.4. Suprachoroidal injections. The superotemporal quadrant conjunctiva and Tenon’s capsule were dissected as appropriate for the extent of the procedure. A small, limbus-parallel, full thickness scleral incision was performed 4–5 mm from the limbus. A 5–6-mm-long gentle dissection of the virtual suprachoroidal space separating the sclera and choroids was performed with blunt tip microsurgical scissors. A curved cannula with an olivary tip was introduced into the suprachoroidal space and advanced toward the posterior pole, with the tip apposed to the inner wall of the sclera to avoid trauma to the choroid. 100 Al of polymer (n = 6) was then injected. The polymer did not flow back after injection. Conjunctiva were replaced and topical antibiotic ointment applied to minimize risk of postoperative infection. The whole procedure was performed under direct visualization with the use of the operating microscope and indirect ophthalmoscopy. Rabbits were examined for 6 months postoperatively with a slit lamp and the fundus observed by indirect ophthalmoscopy. Immediately after injection, the polymer appeared to spread in a limited area of the suprachoroidal space at the extremity of the created tunnel, triggering a visible elevation of the retina and choroids. After day 1, the polymer spread to a larger and thinner area in the suprachoroidal space. The injection did not cause subretinal, or choroidal hemorrhage. There was no evidence of inflammation or change in IOP and histopathological studies indicated good biocompatibility. Polymer was still present in the suprachroidal space after 6 months.

3. Conclusions These studies conclusively show that both POE III and POE IV have excellent potential as a delivery system in ocular applications. While POE III has exhibited excellent biocompatibility, its application is hindered by its difficult synthesis that would make commercialization very difficult. Further, for most applications, its lifetime is

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too short. Although lifetime can be extended by the incorporation of basic excipients, this is an added complication and would make regulatory approval more difficult. On the other hand, POE IV has none of these difficulties since it can be readily prepared by a well-developed synthesis that has been scaled up under GMP and has very long residence times in various eye compartments. While this review emphasized 5-FU, many other therapeutic agents including peptides and proteins have been delivered from POE IV. Thus, this polymer has excellent potential for treating various eye disorders, either as a viscous, injectable material, or as a solid, implantable matrix.

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[12] [13]

[14]

[15]

[16]

[17]

[18]

[19]

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