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10 Microparticles as Drug Delivery Systems for the Back of the Eye
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In the in vivo studies, the authors reported a faster clearance of the drug and the
microspheres in vitrectomized and pathologic eyes compared with healthy animals.
Authors observed that microspheres disappear from the vitreous cavity in 48 ± 5.2
days for normal eyes and 14 ± 2.4 days in animals that underwent vitrectomy before
the injection of the microspheres.
Peyman et al. (1992) evaluated the release kinetic of radiolabeled 5-FU and cytosine arabinoside in primates. Both drugs exhibited similar release kinetics with
detectable drug levels in the vitreous up to 11 days after the administration of the
formulation.
Giordano et al. (1993) studied the intravitreous release of RA in a rabbit model
of PVR caused by lipopolysaccharide (LPS) injection. The incidence of tractional
retinal detachment (TRD) resulted effectively reduced when compared to blank
microspheres 2 months after a single injection of 5
(110 mg RA). In the same study, 82% of the encapsulated RA was released in vitro
for 40 days at room temperature.
In all reported studies, the rate or incidence of retinal traction detachment
decreased after injection of PLGA microspheres.
mg of RA-loaded microspheres
10.9.2 Uveitis
The term “uveitis” is used to denote any intraocular inflammatory condition without
reference to the underlying cause (Rodríguez et al. 1996). In fact, uveitis is considered to be an intraocular autoimmune or inflammatory disease involving the ciliary
body, choroids, and/or adjacent tissues. The disease has both acute and chronic
manifestations.
Corticosteroids have demonstrated to be the most efficient anti-inflammatory
drugs for the treatment of acute ocular inflammations, including uveitis. Current
treatment for chronic features usually includes topical, periocular, or systemic
corticosteroids (Smith
attained through the administration of steroids by intravitreal injections (Gaudio
2004). Nevertheless, therapeutic drug concentrations are difficult to attain in the
vitreous for a prolonged period of time due to the short, intravitreal half-life of
corticosteroids (Kwak and D¢Amico 1992).
Barcia et al. (2009) developed PLGA microspheres for the sustained delivery of
dexamethasone destined to prevent intraocular inflammation. Ten milligrams of the
PLGA 50:50 (0.2 dl/g) microspheres containing 1,410 mg of dexamethasone were
injected in 0.1 ml of PBS in an animal model of inflammation. The active substance
was released in vitro for at least 45 days. In this study, a LPS injection was carried
out 7 days after the injection of the microspheres (53–106 mm). Intraocular inflammation, caused by LPS injection was significantly lower in animals receiving the
dexamethasone loaded microspheres than blank microspheres. In order to simulate
secondary uveitis, a second injection of LPS was performed 30 days after microparticles injection. No inflammation was observed in the animals treated with dexamethasone loaded PLGA microspheres after second LPS injection (Fig. 10.12).
2004). In fact, transitory therapeutic drug levels can be
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R. Herrero-Vanrell
MICROSPHERES LOADED WITH DEXAMETHASONE FOR
THE TREATMENT OF UVEITIS
0.0
0246810
*microparticles were injected 7 days before LPS inyection
12 14 16
Inflammation grade
Days
18 20 22 24 26 28 30 32 34 36
0.5
1.5
1.0
2.0
LPS
Non treated animals
Blank microspheres
Dexamethasone loaded microspheres
LPS
2.5
3.0
3.5
4.0
4.5
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Fig. 10.12 Intraocular inflammation after injection of sterilized 10 mg of PLGA 50:50 (53–106 mm)
unloaded and loaded with dexamethasone (140 mg/mg microspheres). Microparticles were administered 1 week before lipopolysaccharide (LPS) injection. Adapted from Barcia et al. (2009)
Immunosuppressant drugs are useful in the treatment of uveitis. Cyclosporine
(CyS) PLGA (75:25) microparticles of approximately 50 mm maintained therapeutic CyS concentrations for at least 65 days in disease-related tissues such as the
choroid-retina and iris-ciliary body. The molecular weight of the polymer was
15,000 Da. In this study, microspheres loaded with CyS increased the mean residence
time of the active substance around 10 times compared to CyS solution. The therapeutic level was maintained for 65 days (He et al. 2006).
10.9.3 Age-Related Macular Degeneration (AMD)
AMD is the most common cause of blindness in the elderly populations of
western countries. The exudative form of AMD might lead to CNV. PLGA
microspheres loaded with anti vascular endothelial growth factor (VEGF)
have been assayed for reducing the formation of new blood vessels in the eye
(Gomes Dos Santos et al. 2005).
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10.9.4 Diabetic Retinopathy
Microparticles loaded with budesonide were injected subconjunctivally for the
treatment of diabetic retinopathy. In this study, delivery of the active substance was
sustained better in microparticles (3.6 mm) compared with nanoparticles (345 nm)
(Kompella et al. 2003; Amrite and Kompella 2005). Nanoparticles were removed
more rapidly from the subconjunctival site of administration compared with the
microparticles. Microparticles were able to alleviate biochemical changes associated with diabetic retinopathy.
Sterilized celecoxib PLGA (85:15) microspheres (1.11 ± 0.08 mm) prepared by
the solvent evaporation method were injected in a streptozotocin diabetic rat model.
The efficacy of the formulation was demonstrated by dividing the animals in groups
of normal and diabetic animals. Both groups received no treatment, blank microspheres or celecoxib-loaded microspheres. Fifty microliters of PBS of microparticle
suspensions were injected into the posterior subconjunctival space (ipsilateral)
through a 27-G needle. The dose of celecoxib assayed was 750 mg. The microparticulate system was able to delay the development or progression of the early
pathophysiological changes in the retina as a result of diabetes. These findings were
demonstrated by means of reduction of diabetes induced retinal PGE2, VEGF, and
breakdown of the blood retinal barrier at the end of 60 days of diabetes (Amrite
et al. 2006).
10.9.5 Macular edema
Macular edema is usually treated with corticosteroids, among which TA is the most
commonly used. Cardillo et al. (2006) reported human studies of PLGA microspheres loaded with triamcinolone (referred in the study as RETAAC system).
Microspheres loaded with TA were suspended in PBS and then injected intravitreally into nine patients suffering diffuse macular edema and their efficacy compared
to conventional TA injections. Eyes treated with TA microspheres showed marked
decrease of retinal thickness as well as improved visual acuity (VA) for 12 months.
In addition, the authors reported preliminary results with good tolerance for the
PLGA microparticles.
10.9.6 Acute Retinal Necrosis (ARN)
ARN is a viral infection characterized by necrosis of retinal cells that can lead to
irreversible blindness. Some herpes viruses that infect humans are herpes simplex
virus (HSV) types 1 and 2, varicella zoster, and Epstein–Barr viruses. The therapy
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for ARN usually involves intravenous or intravitreal administration of acycloguanosine
(acyclovir). Intravitreal administration of acyclovir has demonstrated to be more
effective than the intravenous administration of the drug and have fewer side effects.
Although the intravitreal therapy is effective, the relatively high dose that is required
has untoward side effects. Conte et al. (1997) developed a controlled release formulation from different PLA and PLGA polymers loaded with acyclovir using the
spray drying technique. In vivo evaluation was studied by injecting 0.5 mg of
microparticles (25 mm diameter) from D,L-PLA (28,000 Da) into rabbit eyes. Drug
levels were detected in the vitreous for 14 days after microparticles administration.
Chowdhury and Mitra (2000) have described guanosine-loaded PLGA (75,000–
100,000 Da) microspheres developed for a drug release of 1 week after intravitreal
injection of the particles. Martinez-Sancho et al. (2003a) prepared PLGA microspheres
loaded with acyclovir for intraocular injection. The authors employed several additives
(aqueous soluble substances and oils) to optimize the release rate of the active substance from the particles. Microspheres were prepared by the O/W emulsion technique.
The dose of microparticles needed for therapeutic effect was significantly reduced
when adding gelatin in the external phase of the emulsion (Martinez et al. 2003b).
10.9.7 Cytomegalovirus (CMV) Retinitis
CMV retinitis occurs in immunodeficiency patients. The CMV infection is progressive
and can result in blindness from RD associated with retinal necrosis (Jab et al. 1989;
Henry et al. 1987). Although intravitreal ganciclovir injections provide effective intraocular drug concentrations, frequent injections are required to maintain therapeutic drug
levels. Veloso et al. (1997) tested the antiviral effect of ganciclovir released from PLGA
microspheres in rabbit eyes inoculated with the human cytomegalovirus (HCMV). Ten
milligram injection of 300–500
PLGA 50:50 (inherent viscosity 0.39
the progression of fundus disease in the HCMV-inoculated rabbit eyes.
mm ganciclovir-loaded microspheres prepared from
dl/g) containing 864.04 mg of the drug controlled
10.9.8 Choroidal Neovascularization
Poly(d,L lactide-co-glycolide) glucose microspheres loaded with a kinase inhibitor
PKC412 were injected in a porcine model of CNV (Saishin et al. 2003). Laser
photo-coagulation was used to rupture Bruch’s membrane in eight locations.
After that, periocular injection of microspheres suspended in 1 ml of an aqueous
vehicle was performed in the animals. Microspheres containing 25 or 50% of
PCK412 were compared to blank microspheres. After 10 days of injection the
integrated areas of CNV at Bruch’s membrane rupture sites measured by image
analysis resulted lower after injection of PCK412 microspheres. Twenty days
after periocular injection PCK412 levels were detected for the PCK412 loaded
microparticles.
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10.9.9 Diseases Affecting the Optic Nerve
Neuroprotection has been proposed as a therapeutic option for the treatment of
glaucoma (Jiang et al. 2007). This treatment focuses on promoting the survival of
retinal ganglion cells (RGC). RGC survival can be achieved by neurotrophins.
PLGA50:50 (Mw 25,000 Da) microspheres containing glial-cell-line-derived neurotrophic factor (GDNF) were assayed in mice. Checa et al. (2011) have developed
“combo microparticles” loaded with antioxidants and neurotrophic factors to
increase the survival of RGC.
10.9.10 Intraocular Inflammation and Infection
After Cataract Surgery
Ocular inflammation and infection after cataract surgery can be prevented with a
combination of steroids and antibiotic agents delivered from microparticles.
Paganelly et al. (2009) injected periocularly 2 mg of PLGA (50:50) microspheres
(mean size 1.07 ± 0.35 mm) loaded with ciprofloxacin (0.99 mg) with 25 mg of TA
in humans. The combined treatment was compared with topical administration of
prednisolone (1%) and ciprofloxacin (3%) eye drops administered during 4 weeks.
These patients received an injection of blank microspheres. Both treatments were
evaluated in terms of efficacy (anterior chamber cell and flare, conjunctival erythema, ciliary flush, or symptoms of ocular inflammation) and safety (intraocular
pressure, biomicroscopy, and ophthalmoscopic findings). The authors stated the
same therapeutic response and ocular tolerance with both pharmacological therapies after age-related cataract surgery.
10.9.11 Microparticles in Retinal Repair
Failure of the adult mammalian retina to regenerate can be partly attributed to the
barrier formed after degeneration that separates a subretinal graft from integrating
into the host retina. This mentioned barrier is formed by inhibitory extracellular
matrix (ECM) and cell adhesion molecules, such as CD44 and neurocan.
Matrix metalloproteinase 2 (MMP2) can promote host-donor integration by
degrading these molecules. In order to enhance cellular integration and promote retinal repopulation, a retinal combination of PLGA microspheres loaded with MMP2
and retinal progenitor cells (RPCs) have been assayed (Yao et al. 2011). In this study,
PLGA microspheres loaded with MMP2 and RPCs were co-transplanted to the
subretinal space of adult retinal degenerative Rho−/− mice. High porous microspheres loaded with MMP2 were prepared by a double emulsion technique.
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Following delivery of MMP2 from microspheres (2–20 mm), significant degradation
of CD44 and neurocan at the outer surface of the degenerative retina without disruption of the host retinal architecture was observed. Furthermore no changes in the
differentiation characteristics of RPCs were observed due to the microspheres. The
results suggest the co-transplantation of MMP2 microspheres and RPCs as a practical
and effective strategy for retinal repair.
10.10 Conclusions
The aim in the development of microparticles for the back of the eye has been to
obtain long-acting injectable drug depot formulations and specific drug targeting
options. For the posterior segment diseases, microparticles represent an alternative
to repeated intraocular injections. Injection of microparticles is performed as a conventional suspension with no surgical procedures. PLA and PLGA polymers are
widely employed in the elaboration of microspheres for intraocular drug delivery.
After their injection the biomaterial is being degraded in the target site. Finally, the
polymer disappears avoiding the need of a second surgery. PLGA microspheres are
well tolerated after periocular and intravitreal injection in animals and humans.
Microspheres prepared from PLA, PGA, or their copolymers behaved as an implant
as they suffer aggregation after their injection. Microparticles can be loaded with
one or more active substances to be released in the vitreous cavity. Administration
of the optimal dose for an individual patient is feasible by changing the amount of
the injected microparticles. PLGA microspheres are biodegradable and they disappear from the site of administration after delivering the drug. They can be sterilized
by gamma radiation at low temperature. Biodegradable microspheres are potential
tools for retinal repair in combination with RPCs.
Acknowledgments The author thanks Vanessa Andres and Patricia Checa for their technical
assistance. MAT 2010–6528, RETICS RD07/0062, and Research Group 920415 (CG/10) are
acknowledged for financial support.
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Chapter 11
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Nanotechnology and Nanoparticles
Shelley A. Durazo and Uday B. Kompella
Abstract
is an extremely difficult task due to the inability to deliver therapeutically relevant
drug levels to the back of the eye using traditional methods (topical and systemic
modes of administration). Innovative techniques and approaches are required to
overcome the limitations associated with developing effective therapeutics to treat
disorders of the back of the eye. Nanotechnology is a field that advances materials
with a nano-dimension and provides several means for innovative design of nanosize drug delivery systems (nanosystems) to overcome biological barriers.
Nanosystems based on polymers, lipids, proteins, and carbohydrates hold significant promise in enhancing drug delivery and hence, efficacy of small as well as large
molecules intended for treating disorders of the back of the eye.
Developing effective therapeutics to treat disorders of the back of the eye
11.1 Introduction
Nanotechnology, the design and fabrication of diverse materials at the nano-scale
(one-billionth of a meter), is exceptionally promising in almost every field including
energy (Kamat 2007), electronics (Hughes 2000), information systems (Waser and
Aono 2007), buildings (Paradise and Goswami 2007), vehicles (Llyod and Lave 2003),
aerospace (Njuguna and Pielichowski 2003), as well as all areas of health sciences
with the development of improved surgical tools (Satava 2002), nano-foods
U.B. Kompella (*)
Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences,
University of Colorado, 12850 East Montview Blvd., C238-V20, Aurora, CO 80045, USA
Department of Ophthalmology, University of Colorado, Aurora, CO, USA
e-mail: uday.kompella@ucdenver.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_11,
© American Association of Pharmaceutical Scientists, 2011
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