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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5394_Библиотеки_им_академика_М_И_Перельмана
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373
15 Ocular Iontophoresis
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Fig. 15.1 Schematic representation of the potential routes of drug penetration in the ocular globe
using an annular transscleral probe. The drug penetrates through the pars plana and migrates along
the sclera and the suprachoroidal space. Direct penetration in the vitreous or in the aqueous humor
does not seem to occur using low current densities (<10 mA/cm
2
)
Fig. 15.2 Representation of the different iontophoretic prototypes developed at the Bascom
Palmer Eye Institute (J.M. Parel and F. Behar-Cohen and the team)
MRI studies showed that both anodal and cathodal iontophoresis provided significant enhancement in ocular delivery compared to passive transport in the in vitro
and in vivo studies. Transscleral iontophoretic delivery was related to the position
and duration of the iontophoresis application in vivo. Permeants were observed to
be delivered primarily into the anterior segment of the eye when the pars plana
was the application site. Extending the duration of iontophoresis at this site
allowed the permeants to be delivered into the vitreous more deeply and to a greater
extent than when the application site was at the back of the eye near the fornix.
374
F.F. Behar-Cohen et al.
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Fig. 15.3 First Optis transscleral probe used for a clinical trial. (a) Schematic representation of the
probe with a tungsten electrode on the bottom and a drug reservoir of 0.5 cm
2
. (b) The whole system with a syringe to introduce the drug into the reservoir and another tube to extract the fluid in
order to create a constant flux during the procedure. The probe and the forehead return electrodes
are connected to a generator. (c) Procedure preformed on a patient with topical anesthesia
Fig. 15.4 OcuPhor transscleral probe, developed by Iomed®. (a) Representation of the scleral
probe, and (b) placement in the cul de sac of a patient
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This demonstrated that electrode placement was an important factor in transscleral
iontophoresis, and the ciliary body (pars plana) was determined to be the pathway of
least resistance for iontophoretic transport (Molokhia et al. 2007). Experiments involving
constant current transscleral iontophoresis of 2 mA (current density 10 mA/cm2)
and subconjunctival injection were conducted with rabbits in vivo and postmortem and
with excised sclera in side-by-side diffusion cells in vitro. The postmortem and in vitro
experiments were expected to be helpful in clarifying the importance of vascular
clearance and other transport barriers in transscleral iontophoresis. Manganese ion
2+
(Mn
) and manganese ethylenediaminetetraacetic acid complex (MnEDTA2−) were
the model permeants. The results show that pretreatment of the eye with an electric
field by iontophoresis enhanced subconjunctival delivery of the permeants to the
anterior segment of the eye in vivo. This suggests that electric field induced barrier
alterations can be an important absorption enhancing mechanism of ocular iontophoresis. Penetration enhancement was magnified in the postmortem experiments with
larger amounts of the permeants delivered into the eye and to the back of the eye.
The different results observed in the in vivo and postmortem studies can be attributed
to ocular clearance in ocular delivery and suggest that pharmacokinetic studies performed
ex vivo cannot be extrapolated to clinical situations (Molokhia et al. 2008).
15.4.1 Transscleral Iontophoresis of Antibiotics
Table 15.3 summarizes the principal studies on transscleral delivery of antibiotics.
Barza et al. (1986) used a very small probe (1 mm in diameter) placed over the pars
plana to deliver gentamycin, ticarcillin and cephazolin to the rabbit vitreous. High
concentrations of those drugs were measured in the vitreous after iontophoresis of
uninfected rabbits. However because of the high current densities used, burns were
commonly observed at the site of iontophoresis. Therefore, the penetration of the
drug directly to the vitreous could result, at least in part from direct penetration
through disrupted tissues. Transscleral iontophoresis of gentamycin was found to be
a useful supplement to intravitreal injection in an experimental endophthalmitis
model caused by P. aeruginosa in the rabbit. Higher rates of sterilization were
observed in eyes that received both transscleral iontophoresis of gentamycin and
intravitreal injections of gentamycin compared to intravitreal injections alone (Barza
et al. 1987a, b). In the monkey, therapeutic levels were obtained in the vitreous
following transscleral iontophoresis of gentamycin. Electroretinograms were
normal in all eyes after iontophoresis but indirect ophthalmoscopy showed localized
area of retinal burns in the area of pars plana where the electrode had been placed
(Barza et al. 1987a, b). Other studies reported lower antibiotic concentrations in
the vitreous but used much lower current densities (Burstein et al. 1985). However,
in this study tissue concentrations were not measured. It has been suggested
that high and long-lasting concentrations of gentamycin could be obtained in the
vitreous without any retinal lesion, by using 2% agar in the 10% gentamycin
solution, and performing a transscleral iontophoresis with a 2 mm in diameter probe
376
F.F. Behar-Cohen et al.
References
Probe diameter
(mm) Drug Animal
Current density
(mA/cm
2
)
Duration
(min) Tissue Time (h)
Concentration
(mg/mL)
Burstein et al. (1985) 2.5 Gentamycin sulfate
(100 mg/mL)
Rabbit 10.7 3 V 24 8.9
Barza et al. (1986) 1 Gentamycin sulfate
(25–50 mg/mL)
Rabbit 3.33 10 V 3 <2
Barza et al. (1987a, b) 0.5 Gentamycin sulfate
(25–50 mg/mL)
Monkey 200 1 V 24 28
2 V 24 11–44 (burn)
Barza et al. (1986) 1 Cefazolin sodium Rabbit 27 10 V 3 35
67 10 V 3 119 (burn)
Barza et al. (1986) 1 Ticarcillin Rabbit 27 10 V 3 34
67 10 V 3 94 (burn)
Grossman and Lee
(1989)
3 Ketoconazole Rabbit 14.8 15 V 1 10.2 < MIC
Choi and Lee (1988) 3 Vancomycin Rabbit 12 10 V 2 13.4
16 3
Vollmer et
al. (2002) Amikacin (200 mg/mL) Rabbit 3.7 20 V 0.5 1
AH 5.3
5.5 V 0.5 3.9
AH 22.9
7.4 V 0.5 5.4
AH 39.7
Retina 92.3
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Table 15.3 Transscleral iontophoresis of antibiotics
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15 Ocular Iontophoresis
CCI 2mA, 4min, 25% Imipeneme, anodal iontophoresis
0,5
,01
,1
1
10
100
2624
AH
V
1g IV (human)
Time (hours)
Imipeneme [mg/ml]
enterococcus
klebsiella
proteus
staphaureus
haemophylus
pneumo
https://t.me/med1917
Fig. 15.5 Vitreous and aqueous humor pharmacokinetics of imipeneme after transscleral ionto-
phoresis in the rabbit in relation to more frequent bacterial sensitivity. Coulomb controlled anodal
iontophoresis (CCI) was performed on pigmented rabbits (N
peneme, 2 mA for 4 min. Concentrations of Imipeneme (mg/mL) in the aqueous humor (AH) and
in the vitreous (V) were measured at 0.5, 2, 6 and 24 h after application. Sensitivity of different
bacteria is represented on the graph
= 8 per time points) using 25% imi-
(2 mA for 10 min) treatment (Grossman et al. 1990). Vancomycin, a high molecular
weight glycopeptide, was iontophoresed from a 5% drug solution in contact with
25–30 mm2 of the temporal sclera overlaying the pars plana using a 3.5 mA current
intensity for 10 min. Bactericidal effective concentrations in the vitreous were
observed for about 12 h after a single treatment. This was the first demonstration
that a high molecular weight agent could be delivered in the posterior segment of
the eye by means of transscleral iontophoresis (Grossman and Lee 1989).
In an extended study, Vollmer et al. (2002) evaluated the amikacin levels in ocular
tissues and media 30 min after transscleral iontophoresis using an applicator placed
in the superior cul de sac of the rabbit eye. He found that intraocular amikacin levels
depend on the current densities but interestingly found that whilst 92.3 mg/mL amikacin was achieved in the retina, the vitreous remained quite low at 5.4 mg/mL
30 min after iontophoresis at 7.4 mA/cm2. This demonstrates that using transscleral
delivery, sampling the vitreous may not reflect posterior tissue levels. In this experiment amikacin levels were above the MCI with the highest current density.
We have evaluated the effect of the CCI system shown in Fig. 15.3 to deliver
imipeneme and cefatzidime in the pigmented rabbit eye. CCI iontophoresis was
performed at 2 mA for 4 min with 25% imipeneme or ceftazidime. Figures 15.5
and 15.6 show the antibiotic concentrations in the aqueous humor, vitreous and
378
F.F. Behar-Cohen et al.
CCI 2mA, 4min, 25% Ceftazidime, cathodal iontophoresis
0,5
,01
,1
1
10
100
2624
AH
V
50mg/kg IV
(rabbit)
pseudomonas
haemophylus
proteus
E. Coli
klebsiella
Strepto
Time (hours)
Ceftazidime [mg/ml]
https://t.me/med1917
Fig. 15.6 Vitreous and aqueous humor pharmacokinetics of ceftazidime after transscleral
iontophoresis in the rabbit in relation to more frequent bacterial sensitivity. Coulomb controlled
cathodal iontophoresis (CCI) was performed on pigmented rabbits (N = 8 per time points) using
25% ceftazidime, 2
(AH) and in the vitreous (V) were measured at 0.5, 2, 6 and 24 h after application. Sensitivity of
different bacteria is represented on the graph
mA for 4 min. Concentrations of ceftazidime (mg/mL) in the aqueous humor
MCI of the two antibiotics for different bacterial agents. Comparison with IV
administration of the two antibiotics was shown only at selected time points.
Interestingly, CCI was more efficient that IV administration and allowed MCI levels
above therapeutic concentrations for at least 6
15.4.2 Transscleral Iontophoresis of Antiviral Drugs
Antiviral drugs effective against cytomegalovirus (CMV), such as ganciclovir and
foscarnet have been administered by iontophoresis as an alternative to intravitreal
injections. A 20% ganciclovir solution was used for a transscleral iontophoresis
with a 263 mA/cm2 current density for 15 min. Therapeutic levels were obtained
until 24 h after a single iontophoresis of ganciclovir in the rabbit (Lam et al. 1994).
However, the pH of such a solution is greater than 11, raising serious difficulties for
application on a human eye. Foscarnet was administered by a 0.19 mm
probe and the iontophoresis was performed with a current intensity of 1 mA for
10 min. Under these conditions, efficient vitreal concentrations were measured up
to 60 h after a single transscleral iontophoresis of foscarnet (Sarraf et al. 1995).
h (Figs. 15.5 and 15.6).
2
diameter
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15 Ocular Iontophoresis
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Unsurprisingly, with a calculated current density of 526 mA/cm2 for 10 min, small
burns were observed in the retina and the choroid adjacent to the application of the
probe. No electroretinographic changes and no histological (light and electron
microscopy) lesions were observed elsewhere than at the application site. After 21
consecutive days of the same treatment, the site of burn was not increased compared
to a single iontophoresis procedure (Yoshizumi et al. 1997). Iontophoresis could
thus be an interesting alternative to repeated intravitreal injections.
15.4.3 Transscleral Iontophoresis of Anti-Inflammatory Drugs
15.4.3.1 Aspirin
CCI of aspirin (10 mg/mL) was performed in rabbits using 5 mA/cm2 and 10 min
treatment. It was compared to topical and IV administration of aspirin. Levels of
aspirin at 30 min after treatment were 1,614 mg/mg in the anterior uvea, 495.9 mg/mL
in the aqueous humor, 443 mg/mg in the retina, 1,276 mg/mg in the choroid and
9.1 mg/mL in the vitreous. At 8 h, ocular aspirin concentrations were in the same
range for CCI and IV administration. IV injection resulted in blood plasma levels up
to 28 times higher than CCI and remained significantly elevated until 8 h after the
treatments (Voigt et al. 2002a–c; Kralinger et al. 2003).
15.4.3.2
Glucocorticoids
Glucocorticoids are widely used in treating posterior ocular inflammation. In 1965,
Lachaud demonstrated in a non-controlled trial that iontophoresis of hydrocortisone
acetate was beneficial for uveitic patients. More than 20 years later, Lam et al.
showed that transscleral iontophoresis of 30% dexamethasone, with a current
2
density of 421 mA/cm
and a 25 min treatment induce a peak concentration in the
vitreous of 140 mg/mL compared to 0.2 mg/mL after sub-conjunctival injection.
Chorioretinal and vitreal concentrations of dexamethasone were higher and lasted
longer than either sub-conjunctival and retrobulbar injections (Lam et al. 1989).
Efficiency of the iontophoresis of dexamethasone was compared to systemic administration in an ocular model of pan uveitis in the rat. Using a 2.6 mA/cm2 current
density, a 400 mA current intensity for 4 min, iontophoresis was as efficient as intraperitoneal administration of dexamethasone in treating both the anterior and the
posterior segment of the eye. There were no observed effects on the systemic production of cytokines. Iontophoresis of dexamethasone resulted in a reduced systemic effect of the corticotherapy, yet retained a strong ocular effect (Behar-Cohen
et al. 1997).
In order to avoid pulsetherapy of methylprednisolone, such as in severe intraocular
inflammation or the treatment of corneal graft rejection, we proposed to evaluate the
effect of CCI on methylprednisolone (62.5 and 150 mg/mL) in the pigmented rabbits.
380
F.F. Behar-Cohen et al.
Pulse IV (10mg/kg)
MP(ng/mg dry tissue)
CCI 2mA, 4min,MPSS 62.5mg/ml
100
10
1
2624
1000
100
10
1
1000
cornea
iris/ciliary body
sclera
choroïd
retina
Time (hours)
2624
Time (hours)
https://t.me/med1917
Fig. 15.7 Comparison of medrol concentrations (ng/mg dry tissue) at different time points after
pulsetherapy of methylprednisolone sodium succinate (MPSS) (10 mg/kg) and CCI 2 mA, 4 min,
62.5 mg/mL MPSS. Experiments were performed on pigmented rabbits
We found that the concentrations of methylprednisolone increased in all ocular
tissues and fluids in relation to the intensities of current used (0.4, 1.0 and
2.0 mA/0.5 cm2) and duration (4 and 10 min). Sustained and highest levels of MP
were achieved in the choroid and the retina of rabbit eyes treated with the highest
current and 10 min duration of CCI. No clinical toxicity or histological lesions were
observed following CCI. Negligible amounts of MP were found in ocular tissues in
the CCI control group without the application of current. Compared to IV administration, CCI achieved higher and more sustained tissue concentrations with negligible systemic absorption (Behar-Cohen et al. 2002) (Fig. 15.7).
A hydrogel iontophoresis system was used to deliver dexamethasone phosphate
into the nonpigmented rabbits. The cylindrical drug-loaded hydrogel (5 × 5 mm)
was mounted on the end of the electrode of the device. Hydroxyethyl methacrylate
(HEMA), ethyleneglycol dimethacrylate (EDGMA) and deionized water (2.0, 0.04
and 6.5 mL, respectively) were polymerized with 2% sodium persulfate Na
2S2O8
(0.05 mL), 2% sodium metabisulfite Na2S2O5 (0.05 mL) and 2% ammonium ferrous
sulfate Fe(NH4)2(SO4)2 (0.025 mL). Cylinders of 5 mm height and 5 mm diameter
were dehydrated to form spongy cylinders, immersed in 10% (w/v in water) dexamethasone phosphate solution. Cathodal iontophoresis was performed using 5.1 mA/cm2
for 1–4 min. The probe was either placed directly on the conjunctiva or on the sclera
after conjunctival removal. How the placement of the probe was controlled during
the procedure was not mentioned, which may lead to high variability since
intraocular drug levels after iontophoresis were shown to be exceedingly dependent
on the electrode placement. Using either direct transscleral or conjunctival iontophoresis, the levels were similar with the highest levels found in the retina at 4 h
around 350 ng/mg (extrapolated from graphs) and below10 mg/mL in the vitreous
(Eljarrat-Binstock et al. 2005).
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15.4.3.3 Transscleral Iontophoresis of Carboplatin
Pharmacological distribution of carboplatin was examined in New Zealand White
Rabbits following a single intravenous infusion of carboplatin (18.7 mg/kg of body
weight), single subconjunctival carboplatin injection (5.0 mg/400 mL) or single
application of carboplatin delivered by Coulomb-controlled iontophoresis (CCI;
14 mg/mL carboplatin, 5.0 mA/cm2, 20 min). Significantly higher levels were
achieved than those with intravenous administration. Carboplatin concentrations in
the blood plasma were found to be significantly higher after intravenous delivery
than after focal delivery by subconjunctival injection or CCI. No evidence of ocular
toxicity was detected after focally delivered carboplatin (Hayden et al. 2004). On a
mice model of retinoblastoma, mice received six serial iontophoretic treatments
administered two times a week using a current density of 2.57 mA/cm2 for 5 min.
A dose-dependent inhibition of intraocular tumor was observed after repetitive iontophoretic treatment. At carboplatin concentrations of 7 mg/mL, 50% of the treated
eyes (4/8) exhibited tumor control. No corneal toxicity was observed in the eyes
treated at carboplatin concentrations under 10 mg/mL (Hayden et al. 2006).
Using hydrogel iontophoresis, no effect of current was observed for carboplatin
delivery in non-pigmented rabbits (Eljarrat-Binstock et al. 2008).
Because systemic carboplatin is associated with severe side effects in young children and because intravitreous injections are not recommended in retinoblastoma
children for carcinologic reasons, iontophoresis of carboplatin could be an intriguing alternative. However, whether conjunctival and other loco-regional side effects
could occur remains to be evaluated before clinical application.
15.4.3.4 Is Transscleral Iontophoresis Safe?
Table 15.4 summarizes reports of lesions observed after transscleral iontophoresis.
Lesions that were observed were well circumscribed over the site of the direct
current application. Furthermore, the size of the lesion was correlated to the time of
treatment (Lam et
not increase the size and the importance of focal retinal and choroidal burns
(Yoshizumi et al. 1997).
The mechanisms of injury for these lesions could be related to direct effect of
high current density (capable of inducing cell membrane damage), heat insult,
chemical burn due to hydrolysis or modification of the pH at the surface of the eye.
However, it seems that efficient tissue concentrations of drugs were achieved without any induced lesions when the current density is controlled, and remains less than
100
mA/cm
2
for 5 min (Hughes and Maurice 1984). When focal lesions are induced
by iontophoretic application, the permeant drug may directly penetrate into the
vitreous through disorganized tissues, following the kinetic of an intravitreal injection.
In the case of iontophoresis without any observable lesion, the drug penetration
should follow other mechanisms which could be better understood by systematic
pharmacokinetic studies in all ocular tissues.
al. 1991). According to Yoshizumi et al., repeated treatment did
382
F.F. Behar-Cohen et al.
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Table 15.4 Lesions induced by transscleral iontophoresis
References Drug
Barza et
1986)
(
Barza et
1987a, b)
(
Lam et al.
(1991)
Sarraf et
(1995)
Yoshizumi
et al.
(1997)
Gentamycin 255 5 Rabbit Retinal and choroid
al.
Gentamycin 764 10 Monkey Retinal necrosis
al.
0.01 PBS 350 Lesion if time
0.01NaCl
al.
Foscarnet 530 10 Rabbit Retinal necrosis
0.09%
Current density
(mA/cm2) Duration (min) Animal Lesions observed
535
531 Up to 25 Retinal necrosis
>1 min
21 consecutive
days of
treatment
necrosis
Rabbit Choriocapillaris
occlusions, cells
infiltrate, necrosis
of RPE and retinal
cells
Localized area of
choroid, RPE and
retina over current
application
Same lesions
15.4.3.5 Transscleral Iontophoresis for High Molecular Weight
Compounds and Proteins
One study was performed on excised human and porcine sclera to show that iontophoresis could significantly enhance the transscleral flow of dextran up to 120 kDa
(Nicoli et al. 2009). However, these experiments cannot be extrapolated to in vivo
situations. In our case, in vivo iontophoresis was not efficient for the delivery of
proteins in ocular tissues at therapeutic concentrations. Enhanced formulations and/
or combinations of techniques may help achieve this purpose.
15.4.3.6 Clinical Application of Transscleral Iontophoresis
While a large number of pre-clinical studies not only in normal rabbits but also in
some animal models of ocular diseases have shown that iontophoresis was efficient
to deliver mostly antibacterial and corticosteroids into ocular tissues very limited
clinical studies have been undertaken to evaluate the tolerance and potential of this
drug delivery technique in humans.
In 2003, Iomed reported the ocular tolerance of a small surface applicator placed
on the scleral surface in the cul de sac, with specific limitations in duration and
intensity of the current to allow tolerance in patients (Parkinson et al. 2003a, b). In
order to avoid irritation, not only the current and duration but also the probe placement and the pH of the drug during iontophoresis must be controlled. Moreover,
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