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oil filling eyes were protected from rubeotic glaucoma induced by retina hypoxia
first reported by Smith (McLeod 1986; Smith 1981). The author attributed this
observation to decreased movements of vasoproliferative factors from ischaemic
retina to the anterior segment, thereby reducing anterior segment exposure. The
conclusions from both studies are that silicone oil is capable of reducing transport
of significantly.
Kathawate and Achaya have developed a 3D mathematical model of human eye
to simulate flow distribution and transport processes in silicone oil and results were
compared to water (Kathawate and Acharya
2008). A Navier Stokes model was
adopted where velocity, pressure and concentration fields were mathematically
calculated by solving the conservation equations for mass, momentum and drug
concentrations. The simulation data revealed that fluid velocity in silicone oil was
significantly lower than water when silicone oil was modelled as a highly viscous
fluid with a viscosity of 1.067 kg/ms, 1,000 folds higher than water (0.001 kg/ms).
The slower fluid motion in silicone oil may explain the decrease in oxygen and
vasoproliferative factors transport seen in the clinical and experimental studies
aforementioned. In addition, the lower velocities in the silicone oil resulted in
the slower transport of small (D = 6e−10 m2/s) molecules across the retinal layer.
A similar observation was demonstrated when very large (1e−11 m2/s) molecules
were modelled, suggesting that retinal-directed convective forces play a weaker role
in this instance and a diffusion mechanism is more important.
Consistent with the simulation data, the vitreal clearance of ganciclovir released
from an implant was found to be lower in the silicone oil as compared to salinefilled eyes following intravitreal placement (Perkins et al. 2001), suggesting that
highly viscous silicone oil will behave as a slow-release drug reservoir. When silicone oil fills of 0.5 and 1.0 mL volumes were tested to represent cases of suboptimal
filling, no variations in concentrations were observed, suggesting drug clearance is
independent of the filling volume. Other therapeutic agents used in conjunction to
silicone oil tamponade include retinoic acid (Nakagawa et al. 1995; Araiz et al.
1993) and bevacizumab (Falavarjani et al. 2010; Singh and Stewart 2008) which
have demonstrated therapeutic efficacy as an adjunctive treatment option to proliferative vitreoretinopathy, iris neovascularisation and neovascular glaucoma with
considerable degree of ocular tolerance. High drug levels in the posterior ocular tissues for longer than 1 week were achieved with an optically clear formulation of
acetylsalicylic acid in silicone oil (Kralinger et al. 2001a). The safety of this drug
formulation in rabbit was confirmed by assessing the retina health by ERG and
histological studies (Kralinger et al. 2001b). A retrospective study has demonstrated
that methotrexate administered at doses range from 200 to 1,200 mg was tolerable in
silicone oil-filled eyes and patient best-corrected visual acuity was either stable or
improved from pre-treatment (Hardwig et al. 2008).
In view of the lack of knowledge describing drug solubilities in silicone oil,
Pastor et al. performed a series of solubility studies with commonly used antiinflammatory agents (Pastor et al. 2008). The drug molecules were first dissolved in
organic solvent at therapeutic doses, followed by injection into purified silicone oil
of viscosity 1,000 cP where drug solubility was assessed by the transparency of the
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6 Principles of Retinal Drug Delivery from Within the Vitreous
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drug-silicone oil solutions. The data obtained showed that with the exceptions of
nabumetone and phenylbutazone, the remaining compounds investigated: dexamethasone, triamcinolone acetonide and indomethacin demonstrated poor solubilities
in silicone oil. This led the authors to conclude that most anti-inflammatory agents
used clinically are not completely soluble at therapeutic concentrations and quantification of concentrations from the eye would be inaccurate. Additionally, direct
injection of high concentration of triamcinolone acetonide into the silicone oil-filled
eye resulted in extensive sedimentation below the oil bubble that may potentially
induce cytotoxicity in the retinal layers. In order to improve the solubility, investigators suggested predispersing triamcinolone acetonide in silicone oil to produce a
homogeneous suspension prior to injection (Spitzer et
Despite the encouraging data with silicone oil, maintaining a constant drug level
is difficult to achieve in this vehicle due to inconsistent release kinetics which can
either follow square root time square when diffusion through the oil is rate limiting
or first-order kinetics when partitioning out of the oil into the vitreous is rate limiting (Ashton 2006). The individual variation in the magnitude of retinal detachment,
thus the duration and degree of silicone oil filling further complicate the dosage
regimen, suggesting safety and efficacy need to be evaluated carefully.
al. 2009).
6.7.4 Role of Ocular Movements in Disordered Vitreous
The faster rate of material distribution and clearance in the liquefied vitreous could
be attributed to the loss of vitreous diffusional barrier and enhanced convective
forces; other factors such as ocular movements should also be considered. Stocchino
and colleagues used a custom-made human eye model mounted on a computercontrolled motorised support which allowed manipulation of eye rotation along the
vertical diameter of the eyeball. Using this experimental apparatus, saccadic eye
rotations was simulated as sinusoidal torsional oscillation. The cavity was filled with
glycerol solutions to mimic the increased viscosity, with the assumption that the
vitreous behaves as a Newtonian fluid. During the experiments, fluid motions in the
vitreous were recorded as images, which were then processed to obtain the velocity
field. The author integrated the velocity field using algorithms to calculate particle
trajectories as a mean of analysing stirring properties. The results demonstrated vitreous stirring as a function of flow induced by ocular rotations; with more efficient
stirring at areas with higher fluid velocities and lower stirring action at areas where
velocities were lower. The application of this model was appropriate for vitrectomised and highly liquefied eyes, where collageneous components of the vitreous
were removed and substituted by homogeneous fluid such as aqueous humour, saline
or silicone oil. Additionally, the large Peclet number of flow calculated in this study
led to the suggestion that advection (bulk flow) is more important than diffusion in
inducing mass transport when the vitreous is liquefied (Stocchino et
Therefore, sinusoidal eye rotations that increase the advective forces within the vitreous cavity may have a greater impact on larger molecules when diffusion is limited.
al. 2010).
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The result of this study is consistent with the work by Lee et al. (2009), who have
shown that ocular movement has no significant influence on intravitreal distribution of
Gd-DTPA (MW ~ 590 Da), a small molecule, in post-mortem elderly eyes.
6.8 Concluding Remarks
The intravitreal route is, at the present time, the most likely method to succeed in
some measure of retinal delivery. It is however, not guaranteed to achieve uniform,
long-term delivery at the retina and significant technological hurdles still exist in
sustaining drug therapy. Modelling, using data derived from imaging shows the
influence of convective flows in the elderly eye. It is hoped that such information
will strongly influence thinking with regard to treatment of AMD, DME and glaucoma,
particularly with regard to the target population who are aged and have morphological
changes in the vitreous humour.
References
Acar N, Kapran Z, Unver YB et al (2008) Early postoperative hypotony after 25-gauge sutureless
vitrectomy with straight incisions. Retina 28(4):545–552
Ahmadieh H, Feghhi M, Tabatabaei H et al (2008) Triamcinolone acetonide in silicone-filled eyes
as adjunctive treatment for proliferative vitreoretinopathy. A randomized clinical trial.
Ophthalmology 115:1938–1943
Akiba J, Ueno N, Chakrabarti B (1994) Mechanisms of photo-induced vitreous liquefaction. Curr
Eye Res 13:505–512
Akiba J, Kakehashi A, Ueno N et
Clin Exp Ophthalmol 233:430–434
Antcliff RJ, Spalton DJ, Stanford MR et al (2001) Intravitreal triamcinolone for uveitic cystoid macular
edema: an optical coherence tomography study historical image. Ophthalmology 108(4):765–772
Araie M, Maurice DM (1991) The loss of fluorescein, fluorescein glucuronide and fluorescein
isothiocyanate dextran from the vitreous by the anterior and retinal pathways. Exp Eye Res
52(1):27–39
Araiz JJ, Refojo MF, Arroyo MH et
ous silicone oil in an animal model of proliferative vitreoretionopathy. Invest Ophthalmol Vis
Sci 34:522–530
Ashton P (2006) Retinal drug delivery. In: Jaffe GJ, Ashton P, Pearson PA (eds) Intraocular drug
delivery. Taylor and Francis, New York, p 17
Atluri H, Mitra AK (2003) Disposition of short-chain aliphatic alcohols in rabbit vitreous by ocu-
lar microdialysis. Exp Eye Res 76:315–320
Atluri H, Anand BS, Patel J et al (2003) Mechanism of a model dipeptide transport across blood
ocular barriers following systemic administration. Invest Phthalmol Vis Sci 44(5): Abstract 364
Atluri H, Talluri RS, Mitra AK et al (2008) Functional activity of a large neutral amino acid transporter
(LAT) in rabbit retina: a study involving the in vivo retinal uptake and vitreal pharmacokinetics of
l-phenyl alanine. Int J Pharm 34712:23–30
Aukunuru J, Sunkara G, Bandi N et al (2001) Expression of multidrug resistance-associated pro-
tein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel
aldose reductase inhibitor. Pharm Res 18:565–572
al (1995) Serum-induced collagen gel contraction. Graefes Arch
al (1993) Antiproliferative effect of retinoic acid in intravitre-
153
6 Principles of Retinal Drug Delivery from Within the Vitreous
https://t.me/med1917
Bakri SJ, Snyder MR, Reid JM et al (2007) Pharmacokinetics of intravitreal bevacizumab (avastin).
Ophthalmology 114:855–859
Balazs EA, Denlinger JL (1982) Aging changes in the vitreous. In: Sekular R, Kline D, Dismukes
K (eds) Aging and human visual function. AR Liss, New York, pp 45–57
Balazs L (1960) Physiology of the vitreous body. In: Schepens CL (ed) Vitreous body in retina
surgery: special emphasis on reoperations. CV Mosby, St. Louis, pp 29–48
Balazs EA, Denlinger JL (1984) The vitreous. In: Daveson H (ed) The eye. Academic, New York,
pp 533–589
Barza M, Kane A, Baum J (1983) Pharmacokinetics of intravitreal carbenicillin, cefazolin and
gentamicin in rhesus monkeys. Invest Ophthalmol Vis Sci 24:1602–1606
Beer PM, Bakri SJ, Singh RJ et
al (2003) Intraocular concentration and pharmacokinetics of triam-
cinolone acetonide after a single intravitreal injection. Ophthalmology 110:681–686
Benz MS, Albini TA, Holz ER et
al (2006) Ophthalmology 113:1174–1178
Bettelheim FA, Samuel Zigler Jr J (2004) Regional mapping of molecular components of human
liquid vitreous by dynamic light scattering. Exp Eye Res 79:713–718
Bishop P (2000) Structural macromolecules and supramolecular organization of the vitreous gel.
Prog Retin Eye Res 19(3):323–344
Bito LZ (1977) The physiology and pathophysiology of intraocular fluids. Exp Eye Res 25(Suppl):
273–289
Bito LZ, Baroody RA (1987) Ocular trace metal kinetics and toxicology. I. The distribution of
intravitreally injected Cu
++
within intraocular compartments and its loss from the globe. Invest
Ophthalmol Vis Sci 28:101–105
Boon CJF, Klevering BJ, Kuijk FJ et al (2008) Reflux after intravitreal injection of bevacizumab.
Ophthalmology 115(7):1268–1269
Brasnjevic IH, Steinbusch WH, Schmitz C et al (2009) Delivery of peptide and protein drugs over
the blood-brain barrier. Prog Neurobiol 87(4):212–251
Brown DJ, Bishop P, Hamdi H, Kenney MC (1996) Cleavage of structural components of mam-
malian vitreous by endogeneous matrix metalloproteinase-2. Curr Eye Res 15(4):439–445
Chastain JE (2003) Chapter 3: general considerations in ocular drug delivery. In: Mitra AK (ed)
Ophthalmic drug delivery system, vol 130. Marcel Dekker, New York, pp 83–90
Ciferri A, Magnasco A (2007) The vitreous gel: a composite structured network engineered by
nature. Liq Cryst 34(2):219–227
Cobo LM, Forster RK (1981) The clearance of intravitreal gentamicin. Am J Ophthalmol 92:59–62
Constable PA, Lawrenson JG, Dolman DEM et
al (2006) P-Glycoprotein expression in human retinal
pigment epithelium cell lines. Exp Eye Res 83(1):24–30
Cunha-Vaz JG (1997) The blood-ocular barriers: past, present and future. Doc Ophthalmol
93:149–157
Cussler EL (2009) Diffusion: mass transfer in fluid systems. Cambridge University Press, Cambridge
Dalkara D, Kolstad KD, Caporale N et
al (2009) Inner limiting membrane barriers to AAV-
mediated retinal transduction from the vitreous. Mol Ther 17:2096–2102
De Juan E, Hardy M, Hatchell DL et al (1986) The effect of intraocular silicone oil on anterior
chamber oxygen pressure in cats. Arch Ophthalmol 104:1063–1064
Dhillon B, Kamal A, Leen C (1998) Intravitreal sustained-release ganciclovir implantation to control
cytomegalovirus retinitis in AIDS. Int J STD AIDS 9(4):227–230
Dias CS, Mitra AK (2000) Vitreal elimination kinetics of large molecular weight FITC-labeled
dextrans in albino rabbits using a novel microsampling technique. Pharm Sci 89:572–578
Duke-Elder WS (1930) The nature of the vitreous body, Monograph supplement IV. Br J
Ophthalmol. Monograph supplement V: 44
Dvorhik BH, Marquis JK (2000) Disposition and toxicity of a mixed backbone antisense oligo-
nucleotide, targeted against human cytomegalovirus, after intravitreal injection of escalating
single doses in the rabbit. Drug Metab Dispos 28:1255–1261
Falavarjani KG, Modarres M, Nazari H (2010) Therapeutic effect of bevacizumab injected into the
silicone oil in eyes with neovascular glaucoma after vitrectomy for advanced diabetic retinopathy.
Eye 24:717–719
154
C.G. Wilson et al.
https://t.me/med1917
Falkner CI, Binder S, Kruger A (2001) Outcome after silicone oil removal. Br J Ophthalmol
85:1324–1327
Fatt I (1975) Flow and diffusion in the vitreous body of the eye. Bull Math Biol 37:85–90
Fatt I (1977) Hydraulic flow conductivity of the vitreous. Invest Ophthalmol Vis Sci 16:565–568
Ficker L, Meredith TA, Gardner S et
Ophthalmol Vis Sci 31(3):502–505
Foulds WS, Allan D, Moseley H et al (1985) Effect of intravitreal hyaluronidase on the clearance
of tritiated water from the vitreous to the choroid. Br J Ophthalmol 69:529–532
Fowlkes WL (1963) Meridonal flow from the corona ciliaris through the pararetinal zone in the
rabbit vitreous. Invest Ophthalmol Vis Sci 2(1):63–71
Friedrich S, Cheng Y, Saville B (1997a) Drug distribution in the vitreous humour of the human
eye: the effects of intravitreal injection position and volume. Curr Eye Res 16:663–669
Friedrich S, Cheng Y, Saville B (1997b) Finite element modelling of drug distribution in the vitre-
ous humor of the rabbit eye. Ann Biomed Eng 25:303–314
Gardner TW, Antonetti DA, Barber AJ et
inner blood-retinal barrier. Doc Ophthalmol 97:229–237
Gauthier R, Joly S, Pernet V et al (2005) Brain-derived neurotrophic factor gene delivery to muel-
ler glia preserves structure and function of light-damaged photoreceptors. Invest Ophthalmol
Vis Sci 46:3383–3392
Giordano GG, Refojo MF (1998) Silicone oils as vitreous substitutes. Prog Polym Sci
23:509–532
Gisladottir S, Loftsson T, Stefansson E (2009) Diffusion characteristics of vitreous humour and
saline solution follow the Stokes Einstein equation. Graefes Arch Clin Exp Ophthalmol
247:1677–1684
Guembel HOC, Krieglsteiner S, Rosenkranz C et
intraocular devices in patients with cytomegalovirus retinitis. Graefes Arch Clin Exp
Ophthalmol 237:824–829
Halfter W (1998) Disruption of the retinal basal lamina during early embryonic development leads
to a retraction of vitreal endfeet, and increased number of ganglion cells, and aberrant axon
outgrowth. J Comp Neurol 397:89–104
Halfter W, Dong S, Schurer B et
and vitreous body. Invest Ophthalmol Vis Sci 46:2202–2209
Han Y, Sweet DH, Hu D et al (2001) Characterization of a novel cationic drug transporter in human
retinal pigment epithelial cells. J Pharmacol Exp Ther 296:450–457
Hardwig PW, Pulido JS, Bakri SJ (2008) The safety of intraocular methotrexate in silicone-filled
eyes. Retina 28:1082–1086
Heiduschka P, Fietz PH, Hofmeister S et
after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci 48:2814–2823
Hennessy M, Spiers JP (2007) A primer on the mechanics of P-glycoprotein the multidrug trans-
porter. Pharmacol Res 55(1):1–15
Hertz L, Dienel GA (2004) Lactate transport and transporters: general principles and functional
roles in brain cells. J Neurosci Res 79(1–2):11–18
Holekamp NM (2010) The vitreous gel: more than meets the eye. Am J Ophthalmol 149:32–36
Hornan D, Edmeades N, Krishnan R et al (2010) Use of pegaptanib for recurrent and non-clearing
vitreous haemorrhage in proliferative diabetic retinopathy. Eye (Lond). doi:10.1038/eye. 2010.14
Hosoya K, Kondo T, Tomi M et
blood-retinal barrier: a possible route for delivery of monocarboxylic acid drugs to the retina.
Pharm Res 18:1670–1676
Hosoya K, Ohshima Y, Katayama K et al (2003) Use of microdialysis to evaluate efflux transport
of organic anions across the blood-retinal barrier. AAPS PharmSci 5(S1):583
Hosoya K, Makihara A, Tsujikawa Y et al (2009a) Roles of inner blood-retina barrier organic
anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid,
benzylpenicillin and 6-mercaptopurine. J Pharm Exp Ther 329:87–93
al (1990) Cefazolin levels after intravitreal injection. Invest
al (2000) The molecular structure and function of the
al (1999) Complications after implantation of
al (2005) Embryonic synthesis of the inner limiting membrane
al (2007) Penetration of bevacizumab through the retina
al (2001) MCT1-mediated transport of L-lactic acid at the inner
155
6 Principles of Retinal Drug Delivery from Within the Vitreous
https://t.me/med1917
Hosoya K, Tachikawa M et al (2009b) Inner blood-retinal barrier transporters: role of retinal drug
delivery. Pharm Res 26:2055–2065
Itakura H, Kishi S, Kotajima N et al (2009) Decreased vitreal hyaluronan levels with aging.
Ophthalmologica 223:32–35
Jongebloed WL, Worst JFG (1987) The cisternal anatomy of the vitreous body. Doc Ophthalmol
67:183–196
Jonas JB, Halyer JK, Panda-Jonas S (2000) Intravitreal injection of crystalline cortisone as adjunc-
tive treatment of proliferative vitreoretinopathy. Br J Ophthalmol 84:1064–1067
Kakeshi A, Ueno N, Chakrabarti B (1994) Molecular mechanisms of photochemically induced
posterior vitreous detachment. Ophthalmic Res 26:51–59
Kathawate J, Acharya S (2008) Computational modeling of intravitreal drug delivery in the
vitreous chamber with different vitreous substitutes. Int J Heat Mass Transfer 51(23–24):
5598–5609
Kagemann L, Wollstein G, Ishikawa H et al (2006) Persistence of Cloquet’s Canal in normal
healthy eyes. Am J Ophthalmol 142:862–864
Kim H, Lizak MJ, Tansey G et al (2005) Study of ocular transport of drugs released from an intra-
vitreal implant using magnetic resonance imaging. Ann Biomed Eng 33(2):150–164
Kim H, Csaky KG, Chan C et al (2006) The pharmacokinetics of rituximab following an intravit-
real injection. Exp Eye Res 82(5):760–766
Kitano S, Nagataki S (1986) Transport of fluorescein monoglucuronide out of the vitreous. Invest
Ophthalmol Vis Sci 27:998–1001
Koeberle MJ, Hughes PM, Skellern GG et
of type of melanin and characteristics. Pharm Res 20(10):1702–1709
Kolancy D, Pars-Vanginderdueren R, Van Lommel A, Stalmans P (2005) Vitrectomy with peeling
of the inner limiting membrane for treating diabetic macular edema. Bull Soc Belge Ophthalmol
296:15–23
Konstantinidis L, Mameletzi E, Mantel I et
treatment of retina angiomatous proliferation (RAP). Graefes Arch Clin Ophthalmol
247(9):1165–1171
Kralinger MR, Kieselbach GF, Voigt M et al (2001a) Slow release of acetylsalicylic acid by intra-
vitreal silicone oil. Retina 21:513–520
Kralinger MT, Hamasaki D, Kieselbach GF et al (2001b) Intravitreal acetylsalicylic acid in sili-
cone oil: pharmacokinetics and evaluation of its safety by ERG and histology. Graefes Arch
Clin Exp Ophthalmol 239:208–216
Krohne TU, Eter N, Holz FG et al (2008) Intraocular pharmacokinetics of bevacizumab after a
single intravitreal injection in humans. Am J Ophthalmol 146(4):508–512
Kunimoto DY, Kaiser RS, Wills Eye Retina Service (2007) Incidence of endophthalmitis after
20-and 25-gauge vitrectomy. Ophthalmology 114:2133–2137
Kusuhara H, Sugiyama Y (2004) Efflux transport systems for organic anions and cations at the
blood-CSF barrier. Adv Drug Deliv Rev 56(12):1741–1763
Lai MM, Ruby AJ, Sarrafizadeh R et al (2008) Repair of primary rhegmatogeneous retinal detach-
ment using 25-gauge transconjunctival sutureless vitrectomy. Retina 28(5):729–734
Laude A, Tan LE, Wilson CG et al (2010) Intravitreal therapy for neovascular age-related macular
degeneration and inter-individual variations in vitreous pharmacokinetics. Prog Retin Eye Res
29(6):466–475
Lee SS, Harutyunyan I, D’Argenio DZ et al (2009) The effect of vitreous syneresis on drug
transport. In: Proceedings: ARVO summer eye research conference, NIH, Bethesda. Abstract
no 8, p 17
Mannermaa E, Vellonen K-S, Urtti A et al (2006) Drug transport in corneal epithelium and blood-
retina barrier: Emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev
58(11):1136–1163
Maurice DM (1957) The exchange of sodium between the vitreous body and the blood and aqueous
humor. J Physiol 137:110–125
al (2003) Binding of memantine to melanin: influence
al (2009) Intravitreal ranibizumab (Lucentis) in the
156
C.G. Wilson et al.
https://t.me/med1917
Maurice DM (1987) Flow of water between aqueous and vitreous compartments in the rabbit eye.
Am J Physiol 252:F104–F108
Maurice DM (1997) The regurgitation of large vitreous injections. J Ocul Pharmacol Ther
13(5):461–463
McLeod D (1986) Silicone-oil injection during closed microsurgery for diabetic retinal detachment.
Graefes Arch Clin Exp Ophthalmol 224:55–59
Missel P (2002) Hydraulic flow and vascular clearance influences on intravitreal drug delivery.
Pharm Res 19(11):1636–1647
Missel P, Homer M, Muralikrishnan R (2010) Simulating dissolution of intravitreal triamcinolone
acetonide suspensions in an anatomically accurate rabbit eye model. Pharm Res
27:1530–1546
Modarres M, Nazari H, Falavarjani KG et al (2009) Intravitreal injection of bevacizumab before
vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol 19(5):848–852
Moldow B, Sander B, Larsen M et al (1998) The effect of acetazolamide passive and active trans-
port of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular
oedema. Graefes Arch Clin Exp Ophthalmol 236:881–889
Mortlet N, Young SH (1993) Prevention of intraocular pressure rise following intravitreal injec-
tion. Br J Ophthalmol 77:572–573
Moseley H (1981) Mathematical model of diffusion in the vitreous humour of the eye. Clin Phys
Physiol Meas 2(3):175–181
Moseley H, Foulds WS, Allan D et
rabbit vitreous. Br J Ophthalmol 68:145–151
Mura M, Tan SH, Smet MD (2009) Use of 25-gauge vitrectomy in the management of primary
rhegmatogeneous retinal detachment. Retina 29:1299–1304
Nakagawa M, Refojo MF, Marin JF et
cone copolymer oils in a rabbit model of proliferative vitreoretionopathy. Invest Ophthalmol
Vis Sci 36:2388–2395
Nakin KN, Lavin MJ, Leaver PK (1992) Primary vitrectomy for rhegmatogeneous retinal detach-
ment. Graefes Arch Clin Exp Ophthalmol 231:344–346
Okamoto F, Okamoto Y, Fukada S et
after vitrectomy for various vitreoretinal disorders. Invest Opthalmol 51:744–751
Park J, Bungay PM, Lutz RJ et
drugs administered by intravitreal injection and controlled release implant. J Control Release
105(3):279–295
Park KH, Woo SJ, Hwang JM et al (2010) Short-term outcome of bimanual 23-gauge transcon-
junctival sutureless vitrectomy for patients with complicated vitreoretinopathies. Ophthalmic
Surg Lasers Imaging 41(2):207–214
Parravano M, Oddone F, Tedeschi M et al (2010) Retinal functional changes measured by micro-
perimetry in neovascular age-related macular degeneration treated with ranibizumab: 24-month
results. Retina 30(7):1017–1024
Pastor JC, Nozal MJD, Zamarron E et
other anti-inflammatory drugs in silicone oil. Implications for therapeutic efficacy. Retina
28:1247–1250
Peeters L, Sanders N, Braeckmans K et al (2005) Vitreous: a barrier to nonviral ocular gene
therapy. Invest Ophthalmol Vis Sci 46:3553–3561
Perkins SL, Yang CH, Ashton P et al (2001) Pharmacokinetics of the ganciclovir implant in the
silicone-filled eye. Retina 21:10–14
Pitkänen L, Ruponen M, Nieminen J (2003) Vitreous is a barrier in nonviral gene transfer by cat-
ionic lipids and polymers. Pharm Res 20(4):576–583
Pitkänen L, Ranta V, Moilanen H et al (2005) Permeability of retinal pigment epithelium: effects
of permeant molecular weight and lipophilicity. Invest Ophthalmol Vis Sci 46:641–646
Poliner LS, Schoch LH (1987) Intraocular pressure assessment in gas-filled eyes following vitrec-
tomy. Arch Ophthalmol 105(2):200–202
al (1984) Routes of clearance of radioactive water from the
al (1995) Retinoic acid in silicone and silicone-fluorosili-
al (2010) Vision-related quality of life and visual function
al (2005) Evaluation of coupled convective-diffusive transport of
al (2008) Solubility of triamcinolone acetonide and
157
6 Principles of Retinal Drug Delivery from Within the Vitreous
https://t.me/med1917
Rajan PD, Kekuda R, Chancy CD et al (2000) Expression of the extraneuronal monoamine trans-
porter in RPE and neural retina. Curr Eye Res 20:195–204
Richards AJ, Baguley DM, Yates JRW et al (2000) Variation in the vitreous phenotype of stickler
syndrome can be caused by different amino acid substitutions in the X position of the type ii
collagen gly-X-Y triple helix. Am J Hum Genet 67:1083–1094
Ruby AJ, Grand MG, William D et
ular pressure rise after pars plana vitrectomy with fluid-gas exchange. Retina 19(3):185–187
Sakurai E, Ozeki H, Kunou N et al (2001) Effect of particle size of polymeric nanospheres on
intravitreal kinetics. Ophthalmic Res 33:31–36
Scholes GN, O’Brien WJ, Abrams G et al (1985) Clearance of triamcinolone from vitreous. Arch
Ophthalmol 103:1567–1569
Sebag J (1987) Age-related changes in human vitreous structure. Graefes Arch Clin Exp
Ophthalmol 225:89–93
Sebag J (1989) The vitreous. Springer, New York
Sebag J (1998) Macromolecular structure of the corpus vitreous. Prog Polym Sci 23:415–446
Sebag J (2005) Molecular biology of pharmacology vitreolysis. Trans Am Opthalmol Soc
103:473–494
Sebag J, Balazs EA (1989) Morphology and ultrastructure of human vitreous fibers. Invest
Ophthalmol Vis Sci 30:1867–1871
Shen J, Cross ST, Tang-Liu D et
line as an in vitro model for drug transport studies across the blood-retinal-barrier. Pharm Res
20:1357–1363
Shimada H, Nakashizuka H, Hattori T et al (2008) Incidence of endophthalmitis after 20- and
25-gauge vitrectomy. Causes and prevention. Ophthalmology 115:2215–2220
Shimada H, Hattori T, Nakashizuka H et al (2009) Highly viscous fluid in macular holes. Case
report. Int Ophthalmol. doi:10.007/s10792-009-9321-z
Singh A, Stewart JM (2008) Intraocular bevacizumab for iris neovascularization in a silicone
oil-filled eye. Retinal Cases Brief Reports 2:253–255
Smith RJH (1981) Rubeotic glaucoma. Br J Ophthalmol 65:606–609
Spielberg L, Leys A (2009) Intravitreal bevacizumab for hyopic choroidal neovascularization:
short-term and 1-year results. Bull Soc Belge Ophthalmol 312:17–27
Spitzer MS, Kaczmarek RT, Yoeruek E et
patibility of triamcinolone injected and dispersed in silicone oil. Invest Ophthalmol Vis Sci
50:2337–2343
Stay MS, Xu J, Randolph TW et al (2003) Computer simulation of convective and diffusive trans-
port of controlled release drugs in the vitreous humor. Pharm Res 20:96–102
Stefánsson E (2009) Physiology of vitreous surgery. Graefes Arch Clin Exp Ophthalmol 247:147–163
Stepanova LV, Marchenko IY, Sychev GM (2005) Direction of fluid transport in the lens [Translated
from Byulleten’ Eksperimental’noi Biologii i Meditsiny]. Bull Exp Biol Med 139(1):57–58
Steuer H, Jaworski A, Elger B et
blood-retinal barrier. Invest Ophthalmol Vis Sci 46:1047–1053
Stocchino A, Repetto R, Siggers JH (2010) Mixing processes in the vitreous chamber induced by
eye rotations. Phys Med Biol 55:453–467
Takahashi J, Hikichi T, Mori F et al (2004) Effect of nucleotide P2Y2 receptor agonists on outward
active transport of fluorescein across normal blood-retina barrier in rabbit. Exp Eye Res
78(1):103–108
Tan LE, Orilla W, Tsai S et al (2011) Effects of vitreous liquefaction on the intravitreal distribution
of sodium fluorescein, fluorescein dextran and fluorescent microparticles. Invest Opthalmol Vis
Sci 52(2):1111–1118
Thompson JT, Glaser BM (1984) Effect of lensectomy on the movement of tracers from vitreous
to aqueous. Arch Ophthalmol 102:1077–1078
Thomas AV, Gilbert SJ, Duance VC (2000) Elevated levels of proteolytic enzymes in the aging
human vitreous. Invest Ophthalmol Vis Sci 41(11):3299–3304
al (1999) Intraoperative acetazolamide in the prevention of intraoc-
al (2003) Evaluation of an immortalized retinal endothelial cell
al (2009) The distribution, release kinetics and biocom-
al (2005) Functional characterization and comparison of the outer
158 C.G. Wilson et al.
https://t.me/med1917
Tiedel KG, Gabel VP, Neubaer L et
treatment of 415 consecutive patients. Graefes Arch Clin Exp Ophthalmol 228:19–23
Tognetto D, Minutola D, Sanguinetti G et al (2005) Anatomical and functional outcomes after
heavy silicone oil tamponade in vitreoretinal surgery for complicated retinal detachment.
A pilot study. Ophthalmology 112:1574–1578
Tojo K, Nakagawa K, Morita Y et
ganciclovir. Eur J Pharm Biopharm 47(2):99–104
Tsuji A (2005) Influx transporters and drug targeting: application of peptide and cation transport-
ers. Int Congress Series 1277:75–84
Ueno N, Sebag J, Hirokawa H et
in the presence of a photosensitizer. Exp Eye Res 44:863–870
Urtti A (2006) Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug
Del Rev 58:1131–1135
Wolter JR (1964) Pores in the inner limiting membrane of the human retina. Acta Ophthalmol
42:971–974
Worst JGF, Los LI (1995) Chapter 3: functional anatomy of the vitreous. In: Cisternal anatomy of
the vitreous. Kugler Publications, Amsterdam, Netherlands, pp 33–48
Xu J, Heys JJ, Barocas VH et
tions for drug delivery. Pharm Res 17:664–669
Yoganathan P, Deramo VA, Lai JC et al (2006) Visual improvement following intravitreal bevaci-
zumab (avastin) in exudative age-related macular degeneration. Retina 26:994–998
Yoneyama D, Shinozaki Y, Lu WL et al (2010) Involvement of system A in the retina-to-blood
transport of l-proline across the inner blood-retinal barrier. Exp Eye Res 90(4):507–513
Young S, Larkin G, Branley M et al (2001) Safety and efficacy of intravitreal triamcinolone for
cystoid macular oedema in uveitis. Clin Exp Ophthalmol 29(1):2–6
al (1990) Intravitreal silicone oil injection: complications and
al (1999) A pharmacokinetic model of intravitreal delivery of
al (1987) Effects of visible-light irradiation on vitreous structure
al (2000) Permeability and diffusion in the vitreous humor: implica-
Chapter 7
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Transscleral Drug Delivery
Dayle H. Geroski and Henry F. Edelhauser
Abstract The treatment of diseases of the posterior segment of the eye remains
limited by the ability to deliver effective doses of drugs to target tissues in the posterior eye. Topical delivery as drops and systemic delivery require large doses and
remain limited in delivering effective doses to the back of the eye. Intravitreal injection and implantation of intravitreal sustained-release delivery devices are effective
but invasive, and both modes of delivery share potential risks of retinal detachment,
endophtalmitis, hemorrhage, and cataract. Numerous studies have demonstrated
that drugs and solutes can diffuse across the sclera in vitro and in situ when delivered
by a periocular approach. Transscleral delivery could provide an effective alternative approach for delivering therapeutic agents to the posterior tissues of the eye.
7.1 Introduction
Approximately 1.7 million Americans over the age of 65 suffer from age-related
macular degeneration (AMD) and as the nation ages, this number will grow by an
estimated 200,000 new cases per year. Severe vision loss from AMD and other diseases affecting the posterior segment, including diabetic retinopathy, glaucoma, and
retinitis pigmentosa accounts for most cases of irreversible blindness worldwide.
As exciting new treatment modalities are being explored and developed for retinal
degenerations and posterior segment disease, effective modes of drug delivery to the
back of the eye are limited. Successful treatment of these visually devastating
diseases will most likely require delivering effective doses of pharmacologic agents
to the posterior segment, possibly in conjunction with surgical (including cell
transplant) or genetic intervention.
H.F. Edelhauser (*)
Emory University Eye Center, Emory University, 1365 Clifton Road NE,
Atlanta, GA 30332, USA
e-mail: ophthfe@emory.edu
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_7,
© American Association of Pharmaceutical Scientists, 2011
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