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TRANSCRIPT
REVIEW
Nanotechnology for Medical and Surgical GlaucomaTherapy—A Review
Marcelo Luıs Occhiutto . Raul C. Maranhao . Vital Paulino Costa .
Anastasios G. Konstas
Received: August 7, 2019 / Published online: December 10, 2019� The Author(s) 2019
ABSTRACT
Glaucoma is the second leading cause ofblindness worldwide. Even though significantadvances have been made in its management,currently available antiglaucoma therapies suf-fer from considerable drawbacks. Typically, thesuccess and efficacy of glaucoma medicationsare undermined by their limited bioavailabilityto target tissues and the inadequate adherencedemonstrated by patients with glaucoma. The
latter is due to a gradual decrease in tolerabilityof lifelong topical therapies and the significantburden to patients of prescribed stepwiseantiglaucoma regimens with frequent dosingwhich impact quality of life. On the other hand,glaucoma surgery is restricted by the inability ofantifibrotic agents to efficiently control thewound healing process without causing severecollateral damage and long-term complications.Evolution of the treatment paradigm forpatients with glaucoma will ideally includeprevention of retinal ganglion cell degenerationby the successful delivery of neurotrophic fac-tors, anti-inflammatory drugs, and gene thera-pies. Nanotechnology-based treatments maysurpass the limitations of currently availableglaucoma therapies through optimized targeteddrug delivery, increased bioavailability, andcontrolled release. This review addresses therecent advances in glaucoma treatment strate-gies employing nanotechnology, includingmedical and surgical management, neurore-generation, and neuroprotection.
Keywords: Glaucoma; Nanomedicine;Nanoparticles; Nanosystems; Nanotechnology;Ocular drug delivery; Ophthamlology
Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.10265768.
M. L. Occhiutto � V. P. CostaDepartment of Ophthalmology, University ofCampinas (UNICAMP), Campinas, Brazil
R. C. MaranhaoLaboratory of Metabolism and Lipids, HeartInstitute (InCor), Medical School Hospital,University of Sao Paulo, Sao Paulo, Brazil
R. C. MaranhaoFaculty of Pharmaceutical Sciences, University ofSao Paulo, Sao Paulo, Brazil
A. G. Konstas (&)1st and 3rd University Departments ofOphthalmology, Aristotle University ofThessaloniki, Thessaloniki, Greecee-mail: [email protected]
Adv Ther (2020) 37:155–199
https://doi.org/10.1007/s12325-019-01163-6
Key Summary Points
This article offers a comprehensive reviewof nanotechnology-based treatments forpatients with glaucoma.
Nanotechnology-based drugs will probablybe incorporated into the arsenal of glaucomaspecialists in the near future, allowingbenefits such as reduced side effects, and lessfrequent dosing, among others.
Toxicity issues related to nanotechnology-based treatments have yet to be addressedto test their safety.
Further human studies in nanomedicine forglaucoma treatment are needed until thispromising pharmacological innovationbecomes available in the ophthalmologist’sdaily therapeutic practice.
INTRODUCTION
Glaucoma is the second leading cause of blind-ness worldwide [1, 2] and the most frequent causeof irreversible blindness. Indeed, the WorldHealth Organization estimates that 5.2 millioncases of blindness are a result of glaucoma (15% ofthe total burden of world blindness) [3]. Glau-coma is often characterized by elevated intraoc-ular pressure (IOP), caused predominantly byblockage of the outflow system leading to theprogressive death of retinal ganglion cells (RGCs)and resulting in optic neuropathy [4].
The main goal of virtually all glaucomatherapies today is to reduce IOP by either sup-pressing aqueous synthesis or by enhancingtrabecular meshwork (TM) and uveoscleraloutflow of aqueous humor [5–7]. Other pro-posed modalities for the treatment of glaucomainclude laser [8], surgery [9], and non-IOP-de-pendent therapies such as neuroprotection [10].
Recently, research has focused on nanopar-ticles and their unique properties, which canprovide a platform to surpass the limitations of
traditional glaucoma therapies. Although somereviews have been published [11–15], we aimedto expand available evidence and provide acomprehensive summary of recent advances innanotechnology-based antiglaucoma therapieswith a focus on the following topics: hypoten-sive drugs, wound healing modulation, neuro-protection, and neuroregeneration.
Figure 1 summarizes the main therapeutictargets in glaucoma treatment according totheir anatomical location. Importantly, all ofthem could benefit from nanotechnology-basedstrategies.
TARGETING INTRAOCULARPRESSURE REDUCTION
Elevated IOP is considered the key risk factor foroptic nerve damage in glaucoma, and mostpatients benefit from IOP-lowering therapies [16].Despite the evidence that factors other than IOPare involved in the pathogenesis of glaucoma[17, 18], current treatment algorithms are basedon decreasing IOP. First-line glaucoma therapytypically starts with eye drops that lower IOP bytwo mechanisms: suppression of aqueous humorproduction (beta-blockers, alpha-agonists, andcarbonic anhydrase inhibitors) or increase ofaqueous humor outflow though the trabecular oruveoscleral pathways (pilocarpine, epinephrine,or prostaglandin analogues) [19]. In patientswhere topical medications are not sufficient tocontroI IOP, laser or surgery can be indicated. Wewill discuss both treatment strategies in the sce-nario of recent advancements in nanomedicine.This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed by anyof the authors.
DRUG DELIVERY ROUTES,FEATURES, AND LIMITATIONSOF CURRENT GLAUCOMAMEDICAL THERAPY
Although medical therapy of glaucoma iseffective, it relies on a delivery system that is
156 Adv Ther (2020) 37:155–199
generally inefficient and presents several draw-backs. First, eye drops have to be administered1–3 times daily, which is frequently associatedwith suboptimal use and lack of adherence [20].This is a more pronounced issue in the elderlypopulation that is predominantly affected byglaucoma [21]. A previous report showed that60% of patients expressed one or more prob-lems with taking their glaucoma medications,which results in a decreased adherence to long-term therapy [22]. Furthermore, followinginstillation, the bioavailability of topical glau-coma medications in the anterior chamber isvery low [23]. Typical aqueous humor bioavail-ability of a drug following the administration of
eye drops ranges from 1% to 10% in animal [24]and human studies [25]. This is due to the var-ious physiological barriers to drug penetrationinto the eye [26].
There are two routes that control and influ-ence the absorption of topically administeredmedication: the corneal and the non-cornealroutes. Small molecules with a hydroxyl grouphave high corneal permeability, favoring thecorneal route [27]. The trajectory of the drugmolecules starts with their passive diffusion viathe corneal epithelium, through the stroma andendothelium into the anterior chamber, wherethe drug will carry out its pharmacologicalaction [28] or will bind to melanin in the ciliary
Fig. 1 Glaucoma therapeutic strategies and nanotechnology-based potential applications
Adv Ther (2020) 37:155–199 157
body and iris [29], or plasma proteins [30],which prolongs its half-life.
The remaining drug and drug metaboliteswill be removed via the trabecular meshworkthrough Schlemm’s canal into the systemicbloodstream (conventional route), or via theuveoscleral route (unconventional outflow).Both of these pathways lead to the systemicblood circulation [31]. The ‘‘unconventional’’route that includes the ciliary muscle, supracil-iary and suprachoroidal spaces, may drainaqueous humor and/or drugs and theirmetabolites through two possible pathways: auveovortex pathway where they enter thechoroid to drain through the vortex veins, and auveoscleral pathway where they pass across thesclera to be resorbed by orbital vessels [32]. Inaddition to these two routes, there is a thirdroute, the ‘‘uveolymphatic pathway’’, defined byYucel et al. to describe a novel pathway foraqueous humor drainage through lymphaticchannels in the human ciliary body, which canbecome a novel target for glaucoma treatment[33–35]. Drug penetration in the iris and diffu-sion via the aqueous humor flow occurs with asmall portion of the drug (depending on themolecular weight and lipophilicity). Drug con-centrations in the vitreous will be 10–100 timeslower than in the aqueous humor and cornea,respectively [27].
The so-called non-corneal absorption route ispreferred by drugs with low corneal permeabil-ity, such as proteins and large molecules. Theselarge compounds penetrate the eye via theconjunctiva and/or sclera [36, 37]. This routedelivers drugs to the vitreous via passive diffu-sion and allows 20 times lower drug concen-tration in the anterior chamber compared to thecorneal route [38]. However, the conjunctivaand underlying sclera are more permeable andhave a higher surface of absorption for thebloodstream than the cornea [39]. Furthermore,some hypotensive topical drugs, such as timololand betaxolol, have been shown to accumulatein Tenon’s capsule, periocular tissues, and scleraof normal cynomolgus monkeys, and of glau-comatous patients under long-term topicaltherapy [40, 41]. These findings indicate thatperiocular accumulation of certain medicationscould provide differentiated access to the
posterior segment and proximal vasculature ofthe eye.
Systemic absorption of topical medicationscan lead to systemic side effects such ashypotension, bronchospasm, and bradycardia(beta-blockers), or dry mouth and fatigue (al-pha-agonists) [19]. Prostaglandin analogues areprodrugs which have the advantage of beingcleaved to their active forms inside the eye,thereby minimizing side effects in nontargetorgans [42].
There are numerous ongoing studies aimedat offering neuroprotective or neuroregenera-tive treatments [16], but clinical trials have beenunsuccessful in the past at demonstrating theireffectiveness in preventing glaucoma progres-sion [43–45]. One of the main challenges of thisapproach has been how to allow access of thedrug to the back of the eye, where the opticnerve and RGCs reside. There are two pathwaysto allow drugs to reach these posterior struc-tures: crossing the vitreous and the inner lim-iting membrane of the retina, or accessing theretina through the vascular system. Intravitrealinjections allow direct access to the vitreouscavity and bypass this barrier, but increase therisk for serious ocular adverse events, such asendophthalmitis [46]. The intravenous route isaccompanied by systemic side effects and isparticularly problematic since drugs must crossthe blood–retinal barrier to reach the targettissue [47].
To overcome the multiple limitations ofcurrent medical antiglaucoma treatments, thedevelopment of safer and more efficient drugdelivery systems is imperative. These attributesmay be reached through the use of nanomedi-cine, which may improve solubility, reduce tis-sue irritation, prolong shelf life, and providedose accuracy, sustained release, targeteddelivery, and bioavailability [12].
Even though nanoparticulate systems canpotentially improve drug bioavailability of theactive loaded ingredients, they can also beselectively removed more or less quickly fromthe target organ by conventional, uveoscleral,and uveolymphatic routes, depending on thedirect uptake of the nanoparticle, and theirphysicochemical specificities. Therefore, furtherpharmacokinetic studies specific for each
158 Adv Ther (2020) 37:155–199
nanosystem employed for therapeutic purposeswill be required.
ROLE AND VALUEOF NANOPARTICLES
Nanoparticles (NPs) are tiny structures mostcommonly spherical in shape with sizes in thenanometer range (1–100 nm). As a result oftheir minuscule size, nanoparticles can bypassbiological barriers, providing drug accessdirectly to the target cells [48]. Moreover,smaller nanoparticles have a higher drug-load-ing capacity than the larger ones, owing to theirhigher surface area [49].
NPs are utilized in a wide range of shapessuch as nanoemulsion [50], liposomes [51],dendrimers [52], nanospheres [53], hydrogels[54], nanocrystals [55], cyclodextrins [56], nan-odiamonds [57], microspheres [58], niosomes[59], nanofibers [60], and nanocapsules [61].Figure 2 shows a schematic representation ofvarious nanoparticles mentioned throughoutthis article.
NPs can be designed to enhance activecompound penetration [62] and drug targeting[63] and to promote controlled release [64].Currently, NPs are generally made from sundrymaterials including polymers, lipids, and met-als. Lipid and polymer NPs may be employedsuccessfully to carry drugs [65], isolate theircontents from degradation, and regulate theirrelease [66]. Metallic NPs have specific physic-ochemical properties that serve both diagnostic[67] and therapeutic purposes [68, 69]. Injectednanoparticles accumulate in the liver andspleen and are mostly eliminated by the retic-uloendothelial system soon after administra-tion. It is, however, possible to employ a coatingthat can prevent opsonization and recognitionof NPs by the macrophages. Indeed, NPs may becovered by extra layers to achieve special ther-apeutic properties, to reduce side effects, or toincrease solubility [70]. Engineered NPs may becreated to help the molecule to find its target.For instance, docetaxel and ketoconazole loa-ded in solid lipid nanoparticles had their surfacemodified with folic acid to improve brain tar-geting [71]. Another example is hyaluronic acid-
modified lipid–polymer hybrid NPs, which weredesigned to improve the ocular bioavailabilityof hydrophilic moxifloxacin hydrochloride, inorder to prolong precorneal retention, andenhance its corneal permeability and ocularbioavailability [72].
The selection of the appropriate systemdepends on the target tissue, route of adminis-tration, and the characteristics of the drug to beincorporated into the NPs (size, stability,hydrophobicity, etc.). However, there are com-mon physicochemical properties that allnanosystems must possess, such as biocompat-ibility, biodegradability, absence of toxicity,and stability, which can provide effective andsafe pharmacological action, better than thoseobtained by traditional drug formulations.
EMERGENCE OF NANOMEDICINEFORMULATIONS IN GLAUCOMA
Several drugs traditionally employed in glau-coma treatment, e.g., timolol, carteolol, bri-monidine, pilocarpine, brinzolamide,bimatoprost, travoprost, and latanoprost [73],have been investigated in nanomedicine for-mulations [11, 12, 15]. We emphasize here thatall of these formulations are still under investi-gation and are not currently approved for clin-ical use. In the following pages, we describenanosystems loaded with the most utilizeddrugs for the treatment of glaucoma.
Pilocarpine
Pilocarpine has by and large been avoided byophthalmologists because of several undesirableadverse effects, most of which are due to itsnon-selective ocular and systemic action as amuscarinic receptor agonist: intense miosis,ocular irritation, myopic shift, bronchial mucussecretion, bronchospasm, vasodilation, brady-cardia, excessive salivation, sweating, and diar-rhea. Pilocarpine has been used in a nitrate orhydrochloride pharmaceutical formulation,usually at a 0.5–4% concentration administeredfour times daily because of the short duration ofaction. When administered as a solution, it has
Adv Ther (2020) 37:155–199 159
Fig. 2 Schematic depiction of some nanoparticles
160 Adv Ther (2020) 37:155–199
a reasonable water solubility, which shortensthe residence time of aqueous solutions in theeye. Hence, the real obstacle with pilocarpinesolutions has been its very low ocular bioavail-ability (0.1–3%) [74, 75] arising from its poorlipophilicity.
Research efforts have been devoted to opti-mizing the activity and tolerability of pilo-carpine [76]. Many nanosystems have been triedin order to improve pilocarpine’s bioavailabil-ity, solubility, and stability and to extend itspharmacological activity [77]. Table 1 showsexamples of pilocarpine nanoparticulate drugdelivery systems.
Timolol Maleate
Timolol maleate is a non-selective beta-adren-ergic blocker that acts by inhibiting the beta-adrenergic receptors in the ciliary body epithe-lium, promoting the reduction of aqueoushumor production and resulting in decreasedIOP [87]. The hydrophilic nature of timololmaleate leads to slow corneal diffusion and lowbioavailability [88]. Timolol maleate absorptionfrom the eye into the systemic circulation, vianasolacrimal drainage, causes systemic adren-ergic beta-blockage and high incidence of res-piratory and cardiovascular side effects [89]. Toimprove the pharmacological features of timo-lol maleate, it is necessary to enhance its cor-neal penetration and reduce systemicabsorption, which may be attained by the use ofnanocarriers. Table 2 shows examples of timololmaleate-loaded nanoparticulate drug deliverysystems.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase (CA) is a generic denomi-nation to designate several isoenzymes dis-tributed in diverse proportions in the varioustissues responsible for catalyzing the reversiblehydration of carbon dioxide [104]. In the eye,CA is a key enzyme in aqueous humor produc-tion. Nonpigmented ciliary epithelial cells arethe site of aqueous humor secretion, where twoCA isoenzymes (CA-II and CA-IV) are the pre-dominant forms. The inhibition of CA activity
in the ciliary processes promotes decreasedaqueous humor secretion and consequentlyleads to lowering of the IOP [105]. CA-II isconsidered the most relevant intracytoplasmicisoenzyme responsible for aqueous humorsecretion [106]. Therefore, selective pharmaco-logical inhibition of CA-II to achieve an ocularhypotensive effect is the objective in the treat-ment of glaucoma [106].
Three different CA inhibitors (CAI) mole-cules, all of them sulfonamide derivatives, arecurrently used in clinical practice to reduceelevated IOP in glaucoma. Acetazolamide isadministered orally, and dorzolamide andbrinzolamide are both administered topically[107]. Acetazolamide is a compound thatindiscriminately inhibits most of the CA iso-zymes (CA-I, CA-II, CA-IV, CA-VA, CA-VB, CA-VII, CA-XIII, and CA-XIV) present in otherorgans than the eye [108–110], and althoughsystemically administered acetazolamide is veryeffective as an intraocular hypotensive agent,the non-selective inhibition of the enzymeresults in a myriad of undesirable side effects[108–110]. Dorzolamide and brinzolamide arepotent nanomolar inhibitors of human CA-IIisozyme [106, 111–113], with less activityagainst CA-IV, CA-XII, and CA-I [114].
AcetazolamideAcetazolamide (ACZ) is a CAI used systemicallyto obtain a substantial and immediate reductionof IOP in glaucoma management. It is currentlyconsidered one of the most effective availableIOP-lowering agents [115]. Limitations of orallyadministered ACZ include several systemicadverse events (e.g., metabolic acidosis, pares-thesias, fatigue, diuresis, malaise, anorexia, lossof libido, renal function impediment, etc.)[116]. As a rule, large oral doses of ACZ arenecessary to obtain the desired IOP reduction,probably because of its low bioavailability andrelative instability [117]. Topical administrationof ACZ would have been preferred over systemicadministration, but as a result of the pharma-cological limitations of topical ACZ (e.g., poorpermeability via the corneal epithelium, shortresidence time, frequent instillations, loss ofdrug through nasolacrimal drainage, poor pen-etration coefficient (only 1–6% of the active
Adv Ther (2020) 37:155–199 161
Table1
Experim
entalevidence
withpilocarpine-loaded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Com
plex
ofpilocarpineprodrug,
O,O
0 -dipropionyl-(1,4-
xylylene)bispilocarpate,with
variousb-cyclodextrin
derivatives
Cyclodextrin
Experim
ental/pigm
entedrabbits
Ocularirritation
caused
bypilocarpineprodrugis
elim
inated
withviscousSB
E7-b-CyD
solution
without
comprom
isingtheocular
absorption
of
theprodrug
[78]
Poly(amidoamine)
(PAMAM)
dend
rimers(withprim
ary
amino(G
2,G4),h
ydroxyl
(G2(OH),G4(OH)),and
carboxylate(G
1.5,
G3.5)
surfacegroups
Dendrim
ers
Experim
ental/New
Zealand
albino
rabbits
Intensityof
pilocarpine’spharmacologicalactivity
associated
withG1.5andG4(OH)dend
rimer
solutionswas
reported
tobe
superior
[79]
PilocarpineHClencapsulated
neutralandnegativelycharged
multilamellarvesicles
(MLVs)
Liposom
esExperim
ental/pigm
entedrabbits
NeutralMLVslowered
theIO
Pfrom
20.7
to
15mmHgfor4–
5h
NegativelychargedMLVsdecreasedtheIO
Pfora
shorterperiod
oftime(*
1h),w
hich
was
similar
tothefree
drug
[80]
Pilocarpinenitrate–cyclodextrin
complex
Cyclodextrin
Invitroperm
eabilitystudyusing
isolated
excisedcorneasof
albino
rabbits
HP-b-CD
prom
oted
anincrease
inthecorneal
perm
eabilityof
pilocarpinenitrate(permeability
coefficient
=6.38
910
-5±
2.82
910
-7cm
/s,
comparedto
1.67
910
-5±
2.12
910
-7cm
/s
withneat
pilocarpinenitrate)
[81]
Pilocarpine-loaded
poly(e-
caprolactone)(PCL)
nanocapsules
(PILO-PCL
NCs)andpilocarpine-loaded
PCLnanospheres(PILO-PCL
NSs)
Nanocapsulesand
nanospheres
Invitropilocarpinecumulative
releasestudies,andin
vivo
studies(glaucom
atousrabbit
eyes
intracam
erallyinjected
with
PILO-PCLNSs
orPILO-PCL
NCs)
Pilocarpineloadingcapacity
ofPC
LNCswasnearly
3times
greaterthan
that
inPILO-PCLNSs.
PILO-PCLNC-treated
groupreducedIO
Pforthe
entire
period
ofthestudy(42days),exhibiting
a
sustaineddrug
releaseprofile
[82]
162 Adv Ther (2020) 37:155–199
Table1
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Pilocarpine-loaded
hydrogels
(three
differenthydrogels
containing
L-valineresidues,
HVa)
Hydrogels
Invitropilocarpinereleaseandits
effect
oncellproliferation
Cytotoxicityexperimentswith
mouse
immortalized
fibroblast
NIH
3T3cells
Cellviability,after
24hof
incubation
withthenative
and
pilocarpine-loaded
hydrogel
Pilocarpine-loaded
inHVahydrogelsshow
eda3
times
greaterreleasingprofile
[83]
Hydrogelswerenon-toxicto
themouse
fibroblast
NIH
3T3cells
Cellp
roliferationwasincreasedwiththepresence
of
pilocarpine,even
after2days
Pilocarpinenitrate-loaded
liquid
crystalnanoparticles(PN-
loaded
LCNPs)
Liquidcrystal
nanoparticles
Invitroreleaseprofileof
PNMaxim
umdecrease
inIO
Pwas
41.93±
16.79%
withthecommercialdrug
(peakeffect
at2h),
versus
59.21±
7.04%
(peakafter5h)
withPN
-
LCNPs
[84]
Exvivo
penetrationstudy(freshly
excisedalbino
rabbitcornea)
Exvivo
drug
penetrationstudydemonstratedthat
theam
ount
ofPN
penetrationacrossthecornea
at
1hwas
0.54
±0.20
lgwithPN
-LCNPs
and
0.12
±0.06
lgwithPN
solution
Pilocarpinehydrochloride-
loaded
nanocomposite
form
ulations
(cellulose
nanocrystalsandtriblock
poloxamer
copolymer)
Hydrogel/nanocrystals
Invivo
IOPmeasurementsusing
anindentationtonometer
Invitroreleaseof
pilocarpinehydrochloridefrom
thenanocomposite
hydrogelswas
extend
ed
comparedto
thepure
poloxamer
gel
[85]
Invitrodrug
releaseanalysisand
toxicity
assayof
invitrogel
The
greatertheconcentrationof
cellulose
nanocrystals,the
higher
thesustaineddrug
release
property
ofthenanocomposite
hydrogels
Nanocom
posite
form
ulationexhibitednon-toxic
behavior
Adv Ther (2020) 37:155–199 163
compound actually reaches intraocular tissues)[118], poor biphasic solubility, and poor cornealbioavailability) [119], many researchers havetried to develop optimized ACZ topical drugdelivery systems, some employing nanotech-nology-based approaches [115, 117, 120–124].Table 3 shows examples of ACZ-loadednanoparticulate systems.
DorzolamideDorzolamide (DRZ) is a CAI used extensively inthe treatment of glaucoma. Inhibition of car-bonic anhydrase results in decrease of aqueoushumor production and IOP reduction. The firstcommercially available topical CAI was 2% DRZhydrochloride solution (Trusopt�) [131], avail-able since 1995. When topical 2% DRZ is used asmonotherapy, it reduces IOP by up to 23% frombaseline [132]. However, as a result of its low pHand high viscosity, 2% DRZ causes significantocular irritation, stinging, or burning [133].Moreover, topical 2% DRZ requires 2–3 dailydoses, which hinders long-term adherence totreatment [134]. Therefore, there is a clearclinical demand to enhance the delivery effi-ciency of DRZ, and nano-based drug systemsappear to have the potential to fulfil this goal.Table 4 demonstrates examples of dorzolamide-loaded nanoparticulate systems.
BrinzolamideBrinzolamide is a water-insoluble CAI, whichacts on the ciliary processes and decreasesaqueous humor secretion. This medication isemployed widely in stepwise glaucoma therapymost often in combination with prostaglandinanalogues or in conjunction with brimonidineand beta-blockers [141]. Brinzolamide is for-mulated commercially as a 1% aqueous sus-pension, because lower concentrations resultedin insufficient therapeutic effect [114]. As aresult of the solubilization demand of particleson the ocular surface and because of its highlipophilicity, brinzolamide aqueous suspensionhas a low bioavailability [142], which may elicitblurred vision after administration [143] andforeign body sensation, often leading to dis-comfort after instillation [144]. For these rea-sons, novel topical ocular delivery systems for
Table1
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Pilocarpine-loaded
chitosan/
Carbopolnanoparticle
ophthalmicForm
ulation
Hydrogel
Invitroreleaseprofile
Invitroanalysisshow
edthat
nanoparticlesdisplayed
thebestsustainedreleaseprofilefor24
hcompared
totheother3form
ulations
[86]
Invivo
(albinorabbits)miotic
effect
ofpilocarpinechitosan/
Carbopolnanoparticleswas
comparedwithvarious
pilocarpineform
ulations
(traditionaleyedrops,gels,
and
liposom
es)
Invivo
studyshow
edextend
edmiosisof
pilocarpine-
loaded
chitosan/C
arbopolnanoparticles,which
wassuperior
tothoseof
liposom
es,pilocarpinegel,
andpilocarpinedrops
164 Adv Ther (2020) 37:155–199
Table2
Experim
entalevidence
withtimolol
maleate-lo
aded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Tim
olol-lo
aded
gold
nanoparticles(G
NPs)
Gold nanoparticles
Invitroreleasestudy
Maxim
umtimolol
concentrationforblankcontact
lenses
at1hwas
581lg/ml,whilein
theGNP-
ladenCLsitwas
1685
lg/m
l
[90]
Invivo
drug
releaseand
pharmacodynam
icstudies(N
ew
Zealand
AlbinoRabbits)
IntheGNP-ladenCLsgroup,
IOPdecreasedby
4mmHgafter1h,
which
progressivelyincreased
after72
h.In
themarketedeyedrop
group,
maxim
umIO
Pdecrease
was
3mmHgafter3h,
which
returned
tobaselin
eIO
Pafter12
h
Oculartissue
distribution
study
Analysisof
therabbittearfluid
show
edhighertimolol
concentrations
withtheGNP-CLsat
alltime
points
GNPs
wereincorporated
into
contactlenses
(CLs)
After
24hof
GNP-ladenCLwear,atwofoldanda
fourfold
increase
inthetimolol
concentrationin
theconjun
ctivaandin
theiris-ciliarymuscle
occurred,respectively
Tim
olol
maleate/gelatin
nanoparticleconjugate
Hydrogel
Experim
ental/New
Zealand
albino
rabbits
The
average24-h
IOPreductionwas
52%,com
pared
to31%
provided
byregulartimolol
eyedrops
[91]
Tim
olol-lo
aded
nanoparticlesinto
apoly(hydroxyl
ethylmethacrylate)
(p-H
EMA)matrix
Hydrogel
Invitrodrug
releaseexperiments
The
higher
theam
ount
ofnanoparticlesin
the
HEMA,the
highertherateof
drug
release(particle
toHEMAratio25:75provided
atotalreleaseat
95�C
of283.08
±4.48
lg;particleto
HEMA
ratio100:0provided
atotalreleaseat
95�C
of
743.27
±25.40lg,and
also
increasedtherelease
duration)
[92]
Tim
olol-lo
aded
multilamellarvesicles
(MLVs)
Liposom
esExperim
ental/New
Zealand
albino
rabbits
PositivelychargedMLVsof
multilamellarliposom
es
provided
asustainedIO
Preductionformorethan
24h(which
extend
edforabout1week),w
hereas
thefree
drug
lowered
IOPfor4h
[93]
Adv Ther (2020) 37:155–199 165
Table2
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Chitosan(REVTMbio1)or
Carbopol
(REVTMbio2
and3)
coated
niosom
altimolol
maleate
(0.25%
)
Niosomes
Invitroreleasepatternof
niosom
al
preparations
Peak
effect
ofIO
Preductionwithmarketed
form
ulationwas
at2h,
comparedto
3hwithall
theREVTMbioform
ulations.H
owever,chitosan-
coated
vesicles
(REVTMbio1)show
edan
effect
sustainedforup
to8h,
comparedto
themarketed
form
ulation,
whose
effect
lasted
for5h.
REVTMbio1
form
ulationcontaining
0.25%
timolol
maleate
show
edsimilareffect
comparedto
0.5%
marketedgelform
ulation
[94]
Tim
olol
maleate
entrappedin
PVA
orPC
L
nanofibers
Biodegradable
polymeric
nanofibers
Invitrodrug
releasestudiesand
invivo
studies(N
ewZealand
albino
rabbits)
Nanofiberswerecapableof
controlleddrug
delivery
forup
to24
h
[95]
Nanofiberform
ulationshow
edasignificant
IOP
reductionfor72
h,whilethemarketedform
ulation
kept
theIO
Preducedfor4h
Chitosan-coated
timolol
maleate
(TM)
mucoadhesivefilm
Hydrogel
Invitrodrug
releasestudiesand
invivo
studies(N
ewZealand
albino
rabbits)
Invitrostudyshow
edthat
85%
oftimolol
was
released
from
themucoadhesivefilmsin
2weeks,
andthetotalcontentwas
released
within4weeks
[96]
IOP-loweringefficacyof
the0.5%
TM
commercial
ophthalmicsolution
was
similarto
thefilms.
How
ever,animalsthat
received
TM-lo
aded
chitosan
filmskept
theirIO
Pat
lower
levelsover
a
10-weekperiod,w
hiletheeffect
ofthetimolol
commercialeyedropsgroupwas
maintainedfor
12days
166 Adv Ther (2020) 37:155–199
Table2
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Nanoencapsulation
oftimololin
neatchitosan
(CS)
andN-alkylated
chitosans[chitosanderivatives
withsuccinicanhydride(C
SUC)and
2-carboxybenzaldehyde(C
BCS)]
Hydrogel
Invitrodrug
releasestudy
Inthemajorityof
nanoparticlesform
ulations,tim
olol
isentrappedin
amorphousform
,but
thepresent
study,usingdifferentdiam
etersof
nanoparticles
andCSandtwoN-acylatedderivativesof
CSas
carriers,provedthatdrug
entrapmentefficiencywas
higherin
CBCSderivative.D
ifferenttimololrelease
ratesam
ongthetested
form
ulations
ratifiedthat
they
vary
accordingto
specificcarrier,nanoparticle
size,and
drug
loading
[97]
Tim
olol
maleate
encapsulated
inPL
GA/PLA
microspheres
Microspheres
Invitrodrug
releasestudy
PLGA502H
:PLAblendedmicrospheresreleased
30%
oftheirtimolol
maleate
contentafter1day.
How
ever,the
remaining
drug
was
released
ina
sustainedmannerover
107days
[98]
Tim
olol-lo
aded
chitosan–sodium
alginate
(CS-SA
blend)
nanoparticles
Hydrogel
Invitrodrug
releasestudy
Invitroreleasefrom
theCS-SA
nanoparticlesshow
ed
aburstof
about20%withinthefirsthour
and35%
oftimolol
was
released
afteraperiod
of5h,
demonstrating
that
itmay
bereleased
from
synthesizedparticlesin
asustainedmode
[99]
Tim
olol
maleate
chitosan
coated
liposom
es(TM-
CHL)
Liposom
esIn
vitrodrug
releasestudy
TM-CHLproduced
a3.18-foldincrease
inthe
cornealperm
eation
coefficient
[100]
Invivo
transcornealperm
eation
studies(N
ewZealand
rabbits)
TM-CHLwas
moreeffectivein
loweringIO
Pthan
timolol
eyedrops(final
IOP=19.67±
1.14
mmHgversus
23.80±
1.49
mmHg,respectively)
Tim
olol
liposom
es(TLP),and
TLPwith0.02%
Trancutol
P(TLPG
)
Liposom
al
hydrogel
Invitrotranscornealperm
eation
study
Invivo
pharmacodynam
ics(N
ew
Zealand
andpigm
ented
glaucomatousrabbits)
Tim
olol–liposom
esystem
show
edatranscorneal
penetration1.50-foldhigher
than
that
ofthe
marketedeyedrop,w
hiletheaddition
ofTrancutol
Penhanced
it2.19
times
Tim
ololliposom
algelshowed
superior
IOPreduction
comparedwithTim
ololeyedropsateach
timepoint
[101]
Adv Ther (2020) 37:155–199 167
Table2
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Tim
olol
maleate-lo
aded
galactosylated
chitosan
nanoparticles
Hydrogel
Invitroreleasestudy
Tim
olol
maleate-lo
aded
galactosylated
chitosan
nanoparticlesshow
edan
initialburstreleaseof
91%
in8handhadasustainedreleasecomparedwith
thecommercialtimolol
eyedrops
[102]
Invitrotranscornealperm
eation
study
Preocularretentionof
timolol
maleate-lo
aded
galactosylated
chitosan
nanoparticleswas
longer
than
that
oftimolol
eyedrops
Preocularretentionstudy
IOP-loweringeffect
oftimolol
maleate-lo
aded
galactosylated
chitosan
nanoparticlesreached
10.5
±0.51
mmHg4hafterinstillation,
whilethe
peak
effect
ofthecommercialeyedropswas
6.8±
0.35
mmHgat
3h
Invivo
pharmacodynam
icsstudy
(albinorabbits)
IOP-loweringeffect
oftimolol
maleate-lo
aded
galactosylated
chitosan
nanoparticlescontinuedfor
upto
12h,whiletheeffectof
commercialeyedrops
ceased
after8h
Tim
olol-lo
aded
liposom
eincorporated
ion-sensitive
insitu
gels
Liposom
esIn
vitroreleasestudies
Tim
olol-lo
aded
liposom
eform
ulations
show
eda1.93-
fold
increase
inperm
eabilitycoefficients
[103]
Deacetylated
gellangum
Pharmacodynam
icsstudy
(measurementof
intraocular
pressure
innorm
alalbino
rabbits
andin
ocular
hypotensiverabbits)
Tim
olol-lo
aded
liposom
eform
ulations
reducedIO
P
from
30to
300min
afterinstillation(m
inim
um
IOP=11.96±
0.74
mmHgat
1h),w
hilethe
IOPdecreasedfrom
30to
180min
(minim
um
IOP=13.61±
0.95
mmHgat
2h)
withtimolol
eyedrops
168 Adv Ther (2020) 37:155–199
Table3
Experim
entalevidence
derivedfrom
acetazolam
ide-loaded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Eudragitnanoparticles(N
Ps)of
ACZ
incorporated
into
anocular
insert
Eudragitnanoparticles
Invitrodrug
diffusionstudy
Exvivo
transcornealperm
eabilitystudy(excised
freshgoat
corneas)
Invivo
ocular
tolerabilityandIO
Preduction
study(albinorabbits):anim
alsreceived
drinking
water
(40ml/kg
ofbody
weightof
rabbit)to
increase
IOP
3groups:(1)ACZreferencesolution,(2)
EudragitNPs
dispersion,and
(3)ocular
insert
ofEudragitNPs
Exvivo
transcornealperm
eation
studyshow
ed
thefollowingresults.F
lowacrosscorneal
tissue
(lg/min):drug
suspension.
0.671±
0.020;
NPs
suspension.
2.460±
0.028;
ocular
insert,2.402
±0.032,
which
means
that
ACZ-lo
aded
EudragitNPs
displayedbetter
perm
eabilityandflowacross
cornealtissue
than
thedrug
suspension
Invivo
studieswithoptimized
ACZloaded
EudragitNPs
andocular
insertdemonstrated
substantialIOPloweringandim
proved
ocular
tolerabilitywhencomparedto
ACZ
suspension
[125]
ACZ-lo
aded
nanoparticulatein
situ
gels(N
P-
ISG)
Polymericnanoparticles
withEudragitRL100,
EudragitRS100,o
r
poly(lactide-co-glycolide)
75:25(PLGA)
Exvivo
transcornealperm
eabilitystudy(fresh
goat
cornea)
Exvivo
transcornealperm
eation
studydisplayed
higher
ACZperm
eation
at8hwithNP1
0
(93.5±
2.25
mg/cm
2 )andwithNP-ISG5
(74.50
±2.20
mg/cm
2 )than
withACZeye
drops(20.08
±3.12
mg/cm
2 )andACZ
suspension
(16.03
±2.14
mg/cm
2 )
[126]
Exvivo
cornealtoxicity
study(fresh
goat
cornea)
NP-ISG
didnotdisplayharm
fuleffectson
any
corneallayer
Invivo
pharmacodynam
icactivity
study
(normotensive
rabbit)
1%ACZnanoparticulatein
situ
gelexhibited
greaterIO
P-loweringeffect
1hafter
administration,which
wassustainedforup
to
8h,
while1%
ACZeyedropsonlysustained
itsaction
forapproxim
ately2h
Adv Ther (2020) 37:155–199 169
Table3
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
ACZ-lo
aded
water-solublemucoadhesive
carbosilane
dend
rimers
C–S
ibackbone
(carbosilane)cationic
dend
rimers
Invitro(cytotoxicityandcellviability)
investigation(using
telomerase-im
mortalized,
human
corneal-lim
balepithelialcelllin
e,
HCLE)
Generations
1and2of
thecationicdend
rimers
andall3generationsof
theanionic
dend
rimerswerewelltoleratedat
10lM,
withhigher
than
80%
cellsurvivalforallof
them
,exceptfortheG3-C
(from
the3rd
generation
ofcarbosilane
cationic
dend
rimers)
[127]
Invivo
(oculartolerability)
study(normotensive
New
Zealand
rabbits):specular
microscopy,
slitlampexam
ination,
andIO
P
measurements
Form
ulationcontaining
ACZ0.07%
(289.4mOsm
;5.6pH
;41.7mN/m
)andG3
cationiccarbosilane
dend
rimers(5
lM)
demonstratedthebestIO
P-loweringeffect.It
obtained
arapid(1
hpost-in
stillation)
and
sustained(upto
7h)
hypotensiveeffect,
reaching
apeak
22.6%
IOPreduction
ACZ-lo
aded
hyperbranched
poly(propylene
imine)
(PPI)dend
rimers
PPIdend
rimers
Invitrodrug
releasestudies
Exvivo
studies(effecton
themorphologyof
human
erythrocytes)
Invivo
studies(normotensive
New
Zealand
rabbits):determ
inationof
ocular
irritation
index,ocular
residencetime,IO
Preduction
(25lL
ofdend
rimer
form
ulationwas
administeredinto
thelower
cul-d
e-sacof
the
eye)
Hem
olytictoxicity
studyshow
edaslightly
higher
hemolysisrate
ofdend
rimer
form
ulations
(D1=4.8%
,D2=5.6%
,
D3=7.2%
)whencomparedto
plaindrug
(3.3%)andplain5.0G
PPIdend
rimer
(7.9%)
PlainACZsolution
produced
IOPreductions
upto
2hafterinstillation,
whereas
the
dend
rimer-based
form
ulationlowered
IOPfor
longer
(4h)
[128]
170 Adv Ther (2020) 37:155–199
Table3
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
ACZ-lo
aded
ion-activatednanoem
ulsion-based
insitu
gelling
system
susinggellangum
polymer
aloneandin
combination
with
otherpolymers(xanthan
gum,
hydroxym
ethylcellulose,o
rCarbopol)
Nanoemulsion
Gellangum
(invarious
concentrations:0.1%
,
0.2%
,0.3%,0
.4%,0
.5%,
and0.6%
)
Invitroreleasestudies
Optim
ized
form
ulaof
ion-induced
nanoem
ulsion-based
insitu
gelsdemonstrated
asignificantlysustaineddrug
releaseprofile
[129]
Invivo
studies:ocular
irritation
and
pharmacodynam
icstudiesin
adultmaleNew
Zealand
albino
rabbits
Ocularirritation
studyrevealed
nodamageto
theocular
surfaceandotherpartsof
theeye
Areaun
derthecurveof
percentage
decrease
in
IOPversus
timefrom
0to
10h:
nanoem
ulsion
form
ula=189.15
±10.18;
Azopt
�=82.51±
7.53,and
Cidam
ex�=79.77±
7.58
ACZ-lo
aded
EudragitRL100nanoparticle
suspension
(ACZ-E-N
Ps)
Polymericnanoparticles
withEudragitRL100
Invitrodrug
releasestudy
Invivo
studies(albinorabbits):
Group
1received
0.5%
ACZsolution
Group
2received
form
ulationE3(drug
polymer
ratio1:10;organicaqueousphase
ratio1:4;
organicphaseacetone)
Group
3received
form
ulationE8(drug
polymer
ratio1:10;organicaqueousphase
ratio1:3;
organicphaseacetoneandethanol)
Plainsolution
ofACZwas
ableto
lower
the
IOPforabout3hafterinstillation,
whereas
ACZ-E-N
Psolutionsshow
edagreater
efficacy(IOPloweringforup
to8hafter
instillation).T
hepeak
IOPreductionby
plainACZsolution
was
2.98
±0.11
mmHg
at2haftertopicaladministration,
whereas
bestACZ-E-N
Pform
ulations
(E3andE8)
progressivelyreducedIO
P,peakingat
8h
afterinstillation(F3=5.32
±0.07
mmHg;
E8=5.19
±0.06
mmHg;mean±
SD)
[130]
Adv Ther (2020) 37:155–199 171
Table4
Examples
ofdorzolam
ide-loaded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Chitosan(C
S)andwater-soluble
6-O-carboxymethyl(O
CM-CS)
derivative
ofCSnanoparticles
(NPs)loaded
withDRZ
CSor
OCM-CS
nanoparticles
Invitrostudies(drugreleaseandmucoadhesionof
NPs)
IOPpeak
effect
andduration
ofaction
were
[135]
Invivo
studies(innorm
otensive
albino
rabbits):three
groups
(OCM-CSNPs,C
SNPs,and
marketedeyedrops)
received
asingledose
followed
byIO
Pmeasurements
(after
30min
ofdrug
administrationandthen
every1h
over
aperiod
of8h)
Withthecommercialform
ulation:
2.9mmHg2hafter
instillation,
andtheeffect
disappearedafter4h
WiththeDRZ-lo
aded
OCM-CSNPs:p
eakeffectwasseen
at4h,withan
IOPreductionof
2.2mmHg,andtheeffect
was
sustainedfor8h
WithDRZ-lo
aded
CSNPs:peak
effect
seen
at3h;
IOP
reductionwas
1.9mmHg,andtheeffect
was
sustainedfor
6h
DRZ/c-cyclodextrin(c-CD)(18%
w/v)complexes
stabilizedby
hydroxypropylmethylcellulose
(HPM
C)(0.5%
w/v)
Cyclodextrins
Invitromucoadhesiveandperm
eation
studies
DRZdistribution
24haftertopicalinstillation
indicatedthat
itpenetrates
effectivelyinto
theeye,includingthe
posteriorsegm
ent,whileserum
DRZconcentrations
were
very
low
[136]
Invivo
(using
pigm
entedrabbits):DRZmicroparticle
suspension
was
administeredto
both
eyes.A
fter
administrationtheanim
alswereanesthetized,and
a
sampleof
aqueoushumor
was
collected
once.B
lood
sampleswerealso
collected
ateach
timepoint(2,4,8,and
24h)
DRZ-c-CD
suspension
provided
sustaineddeliveryof
DRZ
intheaqueoushumor
forup
to24
h.Com
mercialDRZ
ledto
concentrations
intheaqueoushumor
near
zero
8h
aftertopicaladministration.
The
DRZconcentrationin
theaqueoushumor
ofeyes
treatedwith3%
(w/v)
dorzolam
idewas
45-foldhigher
than
thoseobtained
after
instillationof
theotherthreeform
ulations
DRZ-lo
aded
microparticles
Microparticles
Invitrodrug
releasestudies
Invivo
studies(employingnorm
otensive
Dutch
belted
rabbits)
Subconjunctivalinjectionof
DRZ-PEG3-PS
Amicroparticles
lowered
IOPby
upto
4.0±
1.5mmHg,whencompared
toun
treatedfelloweyes
for35
days
[137]
DRZ-lo
aded
microparticlesor
blankmicroparticleswere
administeredinto
thesubconjunctivalspaceof
the
superotemporalregionof
each
eyeusinga27-gauge
needle
Fluorescein-labeledPE
G3-PS
Amicroparticlesweredetected
severaldaysaftertheinjection(atleast42
days),indicating
avery
long
invivo
nanoparticledegradationperiod
IOPmeasurementsweremadeaftertheinjection
2%DRZeyedropsreducedIO
Pfor\
6h
172 Adv Ther (2020) 37:155–199
Table4
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
DRZ-lo
aded
chitosan
nanoparticles
Insitu
gelling
polymeric
(chitosan)
nanoparticles
Invitroreleasestudy
Exvivo
transcornealperm
eabilitystudies(onfreshlyexcised
goat
cornea)
Mucoadhesionstudyof
drug
loaded
insitu
gel
Invivo
studies(using
albino
rabbits):ocular
tolerancetest,
andgammascintigraphy
studyto
accessprecorneal
retentiontime
Optim
ized
form
ulation(C
2S4)
demonstrated,in
theex
vivo
perm
eabilitystudy,adrug
perm
eation
of35.80%
within
2h,
comparedto
75.30%
withthecommercial
form
ulation(D
RZ2%
ophthalmicsolution)
Optim
ized
form
ulationC2S4show
edappropriategelling
featurewith98.1%
entrapmentefficiency
Gam
mascintigraphy
studyshow
edlong
retentiontimeof
the
proposed
form
ulationin
theeye,indicating
anim
proved
bioavailabilityof
DRZ
[138]
DRZ-lo
aded
nanoliposom
eLiposom
esDRZ-lo
aded
nanoliposom
ewas
administeredto
20patients
withocular
hypertension
orprim
aryopen-angleglaucoma
(inboth
eyes)andwerefollowed
upfor28
days
IOP(days0,
14,and
28)was
comparedbetweenthegroup
that
received
DRZ-lo
aded
nanoliposom
eandthegroup
that
received
themarketedDRZsolution
IOPreductionin
theDRZ-lo
aded
nanoliposom
egroupwas
significantlygreaterthan
that
seen
withthecommercially
availableDRZform
ulationgroup(p\
0.05)
IOPloweringrecorded
at2weeks
was
23.26±
9.24%,and
9.25
±5.76%
fortheDRZ-lo
aded
andthecontrolgroup,
respectively
IOPloweringat
4weeks
was
32.60±
7.90%
and
17.48±
7.62%fortheDRZ-lo
aded
andthecontrolgroup,
respectively
[139]
DRZc-cyclodextrin
(c-CD)
nanoparticle
Cyclodextrins
Self-aggregatingc-CD
nanoparticleeyedropscontaining
3%
DRZwereinstilled
once
adayin
human
eyes,com
pared
withthemarketedDRZinstilled
threetimes
aday,in
a
prospectiverand
omized
single-m
askedcrossovertrial
DRZnanoparticleeyedropsonce
adayandcommercial
form
ulationof
dorzolam
ide2%
threetimes
adaydidnot
show
statistically
significant
differencesin
term
sof
efficacy
atalltimepoints.N
anoparticleeyedropscaused
less
burningsensationthan
themarketedsolution
[140]
Adv Ther (2020) 37:155–199 173
Table5
Examples
ofbrinzolamide-loaded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Brinzolam
ide(BZL)-loaded
liquid
crystalline
nanoparticles(BZLLCNPs)
Liquid
crystalline
nanoparticles
Invitroreleasestudyto
measure
the
releaseof
BZLfrom
LCNPs
Exvivo
cornealpenetrationstudy
(employingNew
Zealand
rabbits)
Efficacy
study(instillation
ofonedrop
of
marketedBZL,1
%BZLsolution,and
BZLLCNPs)
Exvivo
perm
eabilitycoefficient
ofBZL
LCNPs
show
eda3.47-foldincrease
comparedwithcommercialBZL
Twohoursafterinstillation,
peak
IOP
decrease
was
47.67±
3.58%
byBZL
LCNPs,and
33.75±
4.35%
by
commercialBZL
[145]
BZLnanocrystalsuspensions
(BZL-N
psa)
Nanocrystal
Cellulartoxicity
assayusinghuman
cornealepithelialcells
(stand
ardcell
viability
method)
BZL-N
psapH
4.5lowered
IOPafter
60min
(71.4±
5.0%
)moreefficiently
than
BZL-N
psapH
7.4Po
lysorbate80
form
ulation(51.0±
26.3%),and
commercialBZL(49.6±
16.5%)
[146]
Invivo
studies:to
verify
IOPreduction
followingBZL-N
psain
glaucomatous
Wistarrats
Allthetested
form
ulations
and
commercialBZLshow
edmild
orno
toxicity
tothehuman
cornealepithelial
cells
Trimethyllock
(TMLo)
BZLprodrug
nanoparticles
Nanocrystals
Instillationof
nano
eyedropsof
BZL
prodrugin
ocular
norm
otensive
Sprague–Daw
leyrats
TMLoBZLprodrugnano
eyedrops
show
edsimilarefficacyas
commercial
BZLat
1/5themolar
concentration
(5.67mM
TMLoBZLprodrugnano
eyedropswereas
effectiveas
26.1mM
Azopt
TM),withno
toxiceffectsto
the
cornea
[147]
174 Adv Ther (2020) 37:155–199
Table5
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
BZLnanoem
ulsions(BZLNEs)
Sevenprim
aryBZLNEcombinations
wereused
[variationsof
four
nonionic
surfactants(Tyloxapol,L
abrasol,
Cremophor(RH40),andBrij35),two
oils(C
apryol
90andtriacetin),and
one
co-surfactant(TranscutolP
)]
The
amount
ofBZLwas
0.4%
inall
form
ulations
Nanoemulsion
sIn
vitrodrug
releasestudies
Invivo
therapeuticstudies(ocular
norm
otensive
New
Zealand
albino
rabbits):BZLNEswereinstilled,
followed
byIO
Pmeasurementsat
30,
60,1
20,1
80,2
40,3
00,and
360min
afterinstillation
BZLNEsdisplayedasustainedrelease
profilewithproper
physicochemical
characteristics,facilitatingBZL
penetrationinto
thecornealtissuewith
lower
drug
concentrations
(0.4%
vs1%
withcommercialBZL)
[148]
BZL-hydroxypropyl-cyclodextrin(BZL-
HP-b-CD)inclusioncomplex
Cyclodextrins
Invitrocornealperm
eabilityandrelease
studies
Invivo
study(N
ewZealand
norm
otensive
rabbits):G
roup
A:B
ZL-H
P-b-CD0.2%
inclusioncomplex;Group
B:BZL-H
P-
b-CD
0.5%
inclusioncomplex;Group
C:commercialBZL(1%)
IOPmeasured30,60,120,150,180,240,
and300min
afterinstillation
Invitrocornealaccumulationand
perm
eabilityof
theBZL-H
P-b-CD
inclusioncomplex
was
increased2.91-
fold
comparedto
commercialBZL
Solubilityof
BZLincreased10-foldwith
the(BZL-H
P-b-CD)inclusioncomplex
(BZL-H
P-b-CD)inclusioncomplex
(0.5%
BZL)show
edIO
P-lowering
efficacycomparableto
commercialBZL
invivo
[56]
Adv Ther (2020) 37:155–199 175
Table5
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Brinzolam
ide(BZL)-hydropropyl-b
-
cyclodextrin
(HP-b-CD)inclusion
complex
(HP-b-CD/BZL)into
nanoliposom
es
‘‘HP-b-CD/BZL-lo
aded
nanoliposom
es’’
(BCL)
Liposom
es
Cyclodextrins
InvitroBZLreleasestudy
Transcornealperm
eabilitystudy
Invivo
IOPmeasurement
BZLshow
edamoderatesustainedrelease
period
of9h(1–1
0h)
BCLshow
eda9.36-foldincrease
inthe
perm
eabilitycoefficient
comparedwith
commerciallyavailableBZL
BCLform
ulationreducedIO
Pin
less
than
1h,
reachedpeak
efficacy
(-32.3%)at
2handshow
eda
sustainedeffect
for12
h
BZLsuspension
lowered
IOPat
30min
andreacheditspeak
efficacyat
1h.
From
2to
12hafterinstillation,
BCL
resultedin
significantlylower
IOPs
comparedwithBZLsuspension
[149]
Brinzolam
ide(BZL)-loaded
PLGA
nanoparticles
Poly(lactic-co-
glycolicacid)
(PLGA)
nanoparticles
Asinglesubconjunctivalinjectionof
BZL-PLGA
nanoparticles
Invitrodrug
releasestudies
Invivo
IOPmeasurements(on
norm
otensive
albino
rabbits)
Twoform
ulations
ofBZL-lo
aded
PLGA
nanoparticlesdisplayedexcellent
release
efficiencyvalues:A19
released
about
70%
ofthedrug
in6months,while
B11
released
about90%
ofthedrug
in
6months
Aftersubconjunctivaladm
inistrationpeak
IOPloweringwere78.4
±3.4%
for
A19
BZLnanoparticles;71.6
±2.0%
forB11
BZLnanoparticles;and
56.8
±6.3%
forBZLaqueous
suspension
[150]
176 Adv Ther (2020) 37:155–199
Table6
Examples
ofbrim
onidine-loaded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Nanovesiclesof
BRD
Liposom
esand
niosom
es
Invitroandex
invitrodrug
releasestudies
Invivo
IOP-loweringactivity
inalbino
rabbits
Group
1:marketedform
ulation(BRD
0.02%)
Group
2:liposom
es
Group
3:niosom
es
Invitroandex
invitrodrug
releaseprofilesof
allthe
nanovesiculeform
ulations
show
edamoreextend
ed
drug
releasecomparedto
thecurrently
available
commercialsolution
Efficacy
was
greatercomparedto
thecommercial
product,whose
activity
was
notsustainedbeyond
60min
[154]
Eudragit-basedbrim
onidine
tartrate
nanoparticle
form
ulations
(BRD-lo
aded
ERS–
ERLnanoparticles)
Eudragit
nanoparticles
Invitrodrug
releasestudies
Invivo
pharmacodynam
icstudies(employing
glaucomatousNew
Zealand
rabbits):IO
P-lowering
efficacystudiesperformed
byinstillationof
aqueous
dispersion
ofnanoparticlesandconventionaleyedrop
solution
Alltheselected
BRD-lo
aded
ERS–
ERLnanoparticles
show
edan
extensionof
thedrug
releasein
vitro
Resultsof
invivo
pharmacodynam
icefficacystudiesof
selected
BRD-lo
aded
ERS–
ERLnanoparticle
form
ulations
andmarketedBRD
eyedropsshow
ed
asimilarpeak
IOPreduction,
butprolongedIO
P
efficacy(m
arketedeyedropsduration
of6h
comparedto
36–7
2hwiththenanoparticles
form
ulations)
[155]
BRD-lo
aded
microspheresusing
poly(lacticacid)(PLA)
Microspheres
Invitroreleasekinetics
ofBRD
Invivo
experimentaltreatmentgroups
(employingNew
Zealand
rabbits):
Singlemicroneedleinjectionof
BRD-lo
aded
microspheresinto
thesupraciliaryspace
BRD
(0.15%
)commercialeyedrops(adm
inistered
threetimes
adayto
theupperconjun
ctivalsac,fora
week)
After
topicaldeliveryof
BRD,a
consistent
IOP
reductionof
2–4mmHgwasdetected,but
theIO
P
quicklyreturned
tobaselin
eaftertheinterruption
ofthedrops
BRD-lo
aded
microsphereshigh
dose
group(30%
BRD-lo
aded
microspheres)show
edIO
Preduction
ofthetreatedeyefor33
days,afterasingleinjection
into
thesupraciliaryspace
[156]
Adv Ther (2020) 37:155–199 177
Table6
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
Optim
ized
BRD-lo
aded
chitosan
(CS)
andsodium
alginate
(ALG)nanoparticles
CSandALG
nanoparticles
Invitrostudies(drugreleaseandcytotoxicity
assays)
Invivo
studies(m
icestrainsBXD29
andBXD96):a
singledose
ofthetestform
ulations
orcommercial
BRD
eyedrops(BRD
0.15%)wereinstilled
into
the
inferior
conjun
ctivalsac
Invitrotoxicity
studiesdidnotshow
significant
differencesbetweennano-based
form
ulations
and
commercialBRD
eyedrops
Allnano-based
form
ulations
show
edagreater
sustainedIO
P-loweringeffect
comparedto
the
commercialBRD.T
imerequired
forIO
Pto
return
tobaselin
eranged
from
17.2
to25.2hfornano-
basedform
ulations,com
paredto
7–7.4hfor
commercialBRD
[157]
BRD-lo
aded
nanostructured
lipid
carriers
Nanostructured
(NLC)and
solid
(SLN)
lipid
nanoparticles
Invitrodrug
releasestudy
Exvivo
perm
eabilitystudy
Invivo
studies(a
singledose
(50lL
)of
lipid
nanoparticleswasinstilled
into
thelower
conjun
ctival
sacof
anorm
otensive
albino
rabbit).Oculartolerance
analysis,IOPmeasurements,and
ocularhistologywere
performed
BothNLCsandSL
Nsshow
edabiphasicrelease
pattern.SL
Nsshowed
61.74±
2.56%drug
released
after2hand74.34±
0.14%after6h,whileNLCs
show
ed66.89±
3.4%
drug
released
after2hand
95.8
±2.31%
after6h.
Com
mercialBRD
show
ed
aun
ique
burstreleaseof
88.76±
1.78%withinthe
firsthour
NLCsdemonstratedaperm
eabilitycoefficient
1.23-
fold
higher
than
that
ofSL
Ns
Peak
IOPloweringwithNLCs,SL
Ns,and
commercialBRD
eyedropswas
13.14±
1.28,
10.03±
0.32,and
7.84
±1.04
mmHg,respectively
The
peak
IOPeffect
occurred
after6hforNLCs,
after4hforcommercialBRD,and
after2hfor
SLNs
NLCsandSL
Nswerefoun
din
theanterior
cham
ber
oftreatedeyes,ind
icatingthat
lipid
nanoparticles
penetratethroughthecornea
[158]
178 Adv Ther (2020) 37:155–199
this drug must surpass current problems.Table 5 shows examples of brinzolamide-loadednanoparticulate systems.
Brimonidine
Brimonidine (BRD) is an a2-adrenergic agonistwhich acts through two mechanisms: it pro-motes an acute reduction in aqueous produc-tion, associated with an increase in uveoscleraloutflow [151]. Nevertheless, BRD exhibits lowbioavailability through the corneal stroma(1–7%) [152] and shows a short duration ofaction that leads to the necessity of threeinstillations during the day [153]. Conse-quently, BRD demonstrates a relatively reducedadherence, as evidenced by the rate of adher-ence, which ranges from 31% to 67% at12 months [20]. The reluctance of patients toinstill their eye drops many times a day on aregular basis justifies the need to develop newBRD formulations. Table 6 shows examples ofBRD-loaded nanoparticulate systems.
Prostaglandin Analogues
Topically instilled prostaglandin F2a (PGF2a)analogues (latanoprost, travoprost, bimato-prost, and tafluprost) have been the fist-linechoice in the medical management of glaucomaover the last decade, owing to their favorablesafety profile, efficacy, and patient compliance[160, 161]. All PGF2a analogues lead to commonside effects, such as eyelash growth, darkeningof the iris and periocular pigmentation, con-junctival hyperemia, and rare adverse reactions(e.g., damage to the blood–aqueous barrier,cystoid macular edema, and prostaglandin-as-sociated periorbitopathy) [162]. These sideeffects reduce patient compliance. To overcomethe side effects, to reduce dosing, to optimizethe efficacy and safety of this class of drugs, andto get a reliable dosing technology deliveredcontinuously over a prolonged time (weeks ormore), novel nanoformulations of PGF2a ana-logues may prove greatly advantageous. Table 7shows examples of prostaglandin analogue-loa-ded nanoparticulate systems.
Table6
continued
Hypotensive
drug/nanosystem
Pharm
aceutical
form
Stud
ydesign/m
odel
Results
References
BRD-lo
aded
microspheres/carriersystem
(M/C
S)
Microspheres
poly( D,L-lactic-
co-glycolic
acid)
(PLGA)
Invitroreleasestudies
Invivo
studies(IOPmeasurementsafterBRD-lo
aded
M/C
Ssubconjunctivalim
plantation
innorm
aland
glaucomatouseyes)
Afterasingledoseof
theBRD-lo
aded
M/C
S,an
IOP
reductionof
20mmHgwas
achieved
after1day,
andwas
sustainedover
aperiod
of55
days
M/C
Sstructureremainedintactforeasyremovalafter
BRD
wasfully
released,evenaslong
as70
daysafter
implantation
[159]
Adv Ther (2020) 37:155–199 179
Table7
Experim
entalevidence
obtained
withprostaglandinanalogue-lo
aded
nanoparticulatesystem
s
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Latanoprost-lo
aded
liposom
es(large
unilamellarvesicles)
Liposom
esIn
vivo
human
study:asingle
subconjunctivalinjection
ofliposom
al
latanoprostwas
administeredto
one
eyeof
6subjectswithocular
hypertension
orprim
aryopen-angle
glaucoma
BaselineIO
Pwas
27.55±
3.25
mmHg
[163]
MeanIO
Pdecreasedwithin1hto
14.52±
3.31
mmHg(range
10–1
8mmHg)
Aminim
um20%
IOPreductionwas
observed
through3monthsafter
injection
Noadverseeventswerereported
Latanoprostacid
(LA)-loaded
poly(lactide)/monom
ethoxy-
poly(ethyleneglycol)(PLA-PEG)
nanoparticles(N
Ps)
PLA
(40)
PEG
(5)nanoparticles
Invivo
studies:subconjunctival
injections
wereadministeredinto
the
subconjunctivalspaceof
threegroups
ofnorm
otensive
albino
rabbits:
(A)LA-lo
aded
NPs
(equivalentto
8.5mgLA);(B)Afree
LA
solution
ofthesamedrug
content;(C
)blank
NPs
IOPwas
monitored
for8consecutive
days
Invitrostudiesanalyzed
drug
entrapmentefficiency,andreleaseof
LA
Aqueous
humor
(AH)levelsof
LAwere
also
measured6days
post-
administration
IOPwas
lower
intheLA-lo
aded
PLA-
PEG
NPs
groupcomparedto
the
other3studygroups
(freedrug,blank
NP,
andcontrolgroup)
The
drug
entrapmentefficiencywas
18.3%
AH
levelsof
LAwereinitially
higher
in
thefree
LAgroupthan
the
nanoparticlegroup,butthey
decreased
over
time
Inthenanoparticlegroup,
AH
levelsof
LA
increasedwithtime,becoming
higher
onthe6thdaythan
inthefree
LA
group
[164]
180 Adv Ther (2020) 37:155–199
Table7
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Latanoprost-lo
aded
egg-
phosphatidylcholine(EggPC
)
liposom
es
Liposom
esIn
vivo
studies:afterasingle
subconjunctivalinjectionof
the
latanoprost-loaded
form
ulation,
rabbiteyes
wereclinicallymonitored
andtheIO
Precorded
Latanoprost-lo
aded
EggPC
liposom
es
wereableto
provideasustainedIO
P
loweringandgreatereffect
compared
withdaily
instillations
oftopical
latanoprostforup
to90
days
(4.8
±1.5vs
2.5?
0.9mmHg;
P=0.001),w
ithno
signsof
inflammation
[165]
Latanoprost-lo
aded
thermosensitive
chitosan-based
hydrogel(asatopical
eyedrop
form
ulation)
Hydrogel
Invitrodrug
releaseand
biocom
patibilitystudyof
the
latanoprost-loaded
hydrogel(cell
viabilityassays,hem
olysisanalysis,and
ocular
irritation
test)
Invivo
releasestudy(aqueous
humor
levelsof
thedrug)
Latanoprost-lo
aded
hydrogelwas
administeredweeklyinto
thelower
lid
ofan
experimentalglaucomamodel
(rabbit).IOPwas
assessed
Nodifference
wasfoun
din
cellviability
betweenlatanoprost-loaded
hydrogel
groupandthecontrols
Nocytotoxiceffectsweredetected
on
rabbitcornealepithelialcells
Latanoprost-lo
aded
hydrogelinstilled
once
aweekshow
edasimilarIO
P-
loweringeffect
ofcommercial
latanoprostinstilled
once
daily
[166]
Latanoprost-lo
aded
liposom
es,
thym
oquinone-lo
aded
liposom
es,and
latanoprost/thym
oquinone-lo
aded
liposom
es
Liposom
esIn
vitrodrug
release
Invivo
studies:glaucomatouswhite
albino
rabbitsweretreatedwith
latanoprosteyedropsanddiverse
liposom
eform
ulations
foraperiod
of
6weeks
Latanoprost/thymoquinone-lo
aded
liposom
esandlatanoprost-loaded
liposom
eswereableto
providea
significant
IOPloweringthat
lasted
8h
Effectof
thefree
latanoprostdidnot
persistformorethan
24h
[167]
Adv Ther (2020) 37:155–199 181
Table7
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Latanoprost-propylamino-b-
cyclodextrin
(CD)
Cyclodextrins
Invitrostability
andphasesolubility
analyses
Exvivo
cornealperm
eation
studies
Invivo
ocular
tolerabilityevaluation
Histology
study
Latanoprost-propylamino-b-CD
demonstratedasignificant
improvem
entin
itssolubilityand
stability
Clin
icalevaluationsduring
14days
show
edthat
ocular
irritation
was
15.5%
withthelatanoprostmarketed
form
ulation,
9.5%
withthe
latanoprost-propylam
ino-b-CD
form
ulation,
and7.1%
withthe
vehicleof
theform
ulations
Histologicalevaluation
ofocular
tissues
demonstratedthat
Xalatan
�induced
higher
inflammatorycellinfiltrates
than
latanoprost-propylam
ino-b-CD
form
ulationandthevehicle
[168]
Chitosanbimatoprost(BIM
)-loaded
inserts
Hydrogel
Invitrodrug
releasestudies
Biodistribution
studies(freeand
entrappedBIM
,radiolabeledwith
technetium
-99m
)
Invivo
studies(glaucom
ainducedin
Wistarrats):
Group
1:BIM
-loaded
insertswere
administeredonce
into
the
conjun
ctivalsac
Group
2:marketedBIM
drops
Group
3:placeboinserts
Biodistribution
studiesshow
edthat
a
higher
amount
of99mTc-BIM
remainedin
theeyeafterchitosan
insertim
plantation
comparedto
eye
drop
instillation
BIM
-loaded
insertswereableto
lower
IOPfor4weeks
afteroneapplication,
whereasmarketedeyedrop
couldonly
lower
IOPfor1day
[169]
182 Adv Ther (2020) 37:155–199
Table7
continued
Hypotensive
drug/nanosystem
Pharm
aceuticalform
Stud
ydesign/m
odel
Results
References
Adrug-agnosticintraocularly
implantabledevice
was
used
loaded
withbimatoprost.T
hedevice
was
callednanofluidicVitrealSystem
for
TherapeuticAdm
inistration
(nViSTA)
Implantableintraoculardevice
usinga
nanochannelmem
brane
The
nViSTAim
plantabledevice
was
designed
forsustainedandcontrolled
drug
deliveryandbasedon
a
nanochannelmem
brane(which
measuresfrom
2.5to
250nm
),
without
theneed
foractuation,
pumps,o
rrepeated
clinical
intervention
Thisdevice
was
tested
withina
3-dimensionalanatom
icallysimilarin
silicohuman
eyemodelto
obtain
inform
ationon
theintraocular
pharmacokineticprofile
Resultsfrom
invitrotesting
demonstratedaburstof
approxim
ately40
lgof
bimatoprost
during
thefirst2days,followed
bya
sustainedreleaseof
bimatoprostfrom
thenV
iSTA
over
thesubsequent
18days
[170]
Bim
atoprost-lo
aded
nanosponges(N
S);
travoprost-lo
aded
nanosponges(N
S)
Nanosponge
One
travoprostnanosponge
form
ulation(50-nm
),and3
bimatoprostnanosponge
(NS)
form
ulations
weretested:(a)400-nm
NS;
(b)700-nm
NSwitham
orphous
(A-N
S)cross-lin
kers,and
(c)700-nm
NSwitham
orphous/crystalline
(AC-
NS)
cross-lin
kers
Ocularhypertensive
C57
micereceived
NSloaded
with2prostaglandin
analogue
hypotensivedrugs
(travoprostor
bimatoprost)by
a
singleintravitrealinjection
IOPwas
monitored
for7weeks
Toevaluate
thepossibility
ofretinal
deposition
andretinalganglioncell
uptake
ofNS,50-nm
NSloaded
with
Neuro-D
iOwas
injected
intravitreally
TravoprostNSform
ulationlowered
IOP19–2
9%forup
to4days
comparedto
salin
einjection
Outcomes
ofthe3bimatoprostNS
form
ulations
were:
400nm
NSlowered
IOP24–3
3%for
upto
17days
comparedto
salin
e
700nm
A-N
Slowered
IOP22–3
2%
forup
to32
days
700nm
AC-N
Slowered
IOP18–2
6%
forup
to32
days
Confocalmicroscopyandorthogonal
projectionssuggestedinternalization
ofNeuro-D
iOby
retinalganglion
cells,w
hich
means
NSmay
beeffective
attargetingthesecells
[171]
Adv Ther (2020) 37:155–199 183
GLAUCOMA DRAINAGEAND NANODEVICES
Glaucoma drainage implants are oftenemployed in glaucoma care when medicaltherapy, laser procedures, and standard filtra-tion surgery fail to sufficiently control IOP[172]. The main types of glaucoma drainagedevices available commercially are the Molteno,the Baerveldt, and the Ahmed, all of themdesigned to create an alternate aqueous path-way by channeling aqueous humor from theanterior chamber to the collection plate posi-tioned under the conjunctiva [173, 174].
The long-term success of glaucoma drainageimplants, however, is reduced as a result of thefibrous reaction developing around the end-plate, which leads to encapsulation and reduc-tion of aqueous humor absorption. Epstein[175] was the first author to consider thataqueous humor in the subconjunctival space, initself, would be a stimulus for the fibrovascularproliferation in the episcleral tissue. The inten-sity of the fibrotic reaction was attributed to amultifactorial origin, although not all patho-genetic factors are well understood. Some ele-ments, such as the type of biomaterial, designand/or size of the end-plate, and the patient’simmune response, certainly influence the for-mation of fibrous tissue around the valve plate[176]. Therefore, refinement of biomaterials, aswell as the associated use of antifibrotic agentswith more advanced drug delivery nanosystemsmay meaningfully improve the long-term suc-cess of glaucoma drainage devices.
A novel double-layered porous coating forAhmed glaucoma valves based on biodegrad-able poly(lactic-co-glycolic acid) (PLGA) wasdeveloped by Ponnusamy et al. [177] to achievecontinuous drug release of antifibrotic agents[mitomycin C (MMC) and/or 5-fluorouracil (5-FU)] to the subconjunctival space. This novelporiferous coating for the Ahmed glaucomadrainage implant may have the advantage ofmodifying the degradation pattern of the poly-mer, and the drug release features. The purposeof this double-layered film is to provide a burstof MMC release followed by a slow release of5-FU, which would prevent fibroblast
proliferation over the most active period ofpostoperative wound healing (0–28 days).Results showed a very rapid release of MMCwithin 1 day, followed by the initial release of5-FU within the first 3–5 days, which lasted for 3to 4 weeks. Cytotoxicity assays have demon-strated significant cytotoxic activity from day 1which persisted until the PLGA film was almosttotally degraded.
Pan et al. [178] were able to manufacture anano-drainage device fabricated throughmicroelectromechanical systems (MEMS;miniaturized devices containing submillimeterfeatures). This nano-drainage implant is madeof a nanoporous membrane (mimicking thedrainage function of the trabecular meshwork)connected to an integrated polymeric shaftinserted through the sclera into the anteriorchamber, thus enabling a bypass route for theaqueous humor outflow. The nano-filtrationmembrane provides the designed flow resis-tance to the aqueous humor flow, but cloggingof proteins inside the nanopores from plasmaperfusion significantly increased the resistance.Further efforts will be necessary to apply modi-fications to the nanoporous membrane to reachthe ideal aqueous outflow.
Harake et al. [179] designed an anti-biofoul-ing micro-device which provides an innovativeplatform, also using MEMS, for IOP reduction inpatients with glaucoma. This novel device hasan array of parallel micro-channels built insideto yield controlled aqueous outflow resistance.Polyethylene glycol (PEG), a synthetic hydrogel,was chosen as the primary device materialowing to its favorable biocompatibility and itsantifouling properties, aiming to reduce proteinclogging of the micro-channels [180]. PEG 214and PEG 4000 were jointly used to avoid chan-nel swelling. In vitro, continuous testing underartificial flow conditions showed that the devicedesign containing 23 channels provided apressure drop of about 10 mmHg.
Ferrofluids are the colloidal mixtures ofmagnetic nanoparticles (ferri- or ferromagneticparticles) suspended in a non-magnetic, inertfluid, such as water or an organic solvent [181].As a result of their nanosize (tipically10–100 nm in diameter), the nanoparticles aresubject to Brownian motion. Brownian motion
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or pedesis is the random movement of micro-scopic particles in suspension mixed in a fluid,and it results from the averaged impacts of fast-moving molecules of the surrounding medium[182]. Magnetite (Fe3O4) particles are composedof a single magnetic domain and show super-paramagnetic properties, i.e., a drag force alongfield gradients. If a static magnetic field exists,the interfacial force causes the ferrofluid toconform to its boundaries. Accordingly, a fer-rofluid in a capillary tube can operate as an on/off valve to flow through capillary blockade. Apermanent magnet may be utilized to keep theferrofluid in the capillary and a secondarymagnet may be utilized to regulate the forcenecessary to form the capillary barrier. When-ever the pressure exerted on the ferrofluid bythe liquid surpasses the magnetic force betweenthe ferrofluid and the secondary magnet, flowcan start after the barrier is broken. Paschaliset al. [183] designed a novel, replaceable, ferro-magnetic valve tube able to afford pressureregulation without the requirement of subcon-junctival encapsulation. Preliminary in vivoresults in rabbits showed that during the2 weeks of follow-up, there were no signs ofinflammation or infection at the surgical site.The mean IOP value in the valve implanted eye(11.8 ± 2 mmHg) was significantly lower thanthe contralateral control eye (14 ± 3 mmHg),and a continuous flow at the outlet tip of thevalve was observed until the last follow-up.
Biomaterial improvement provided bynanoparticle-coated glaucoma drainage devices,associated with design changes and innovativedrug delivery systems may potentially reducefibrous reaction, and improve their efficiency.
NANOPARTICLE-BASEDANTIMETABOLITES AND WOUNDHEALING MODULATION
Currently, trabeculectomy is still the goldstandard surgical treatment for glaucoma.Postoperative wound healing produces ahypercellular response in the subconjunctivaltissues, which may gradually close the filtrationsite, limiting its long-term success [184]. Sub-conjunctival antifibrotics, such as MMC and
5-FU, have been used to reduce the generationof scar tissue, by inhibiting fibroblast prolifera-tion [184–187].
In order to improve the efficiency of theseantifibrotics drugs, nanoformulations havebeen recently employed. Hou et al. [188] havedeveloped a new method to prepare MMC-loa-ded polylactic acid (PLA) nanoparticles,employing soybean phosphatidylcholine toimprove the liposolubility of MMC. Resultsshowed refined formulation characteristics andlonger sustained drug release. Gomes dos Santoset al. [189] designed nanosized complexes ofantisense TGFb2 phosphorothioate oligonu-cleotides (PS-ODN) with polyethylenimine(PEI), and naked PS-ODN encapsulated intopoly(lactide-co-glycolide) microspheres, basedon the hypothesis that the encapsulation ofantisense TGFb2 ODN-PEI nanosized complexesin different types of porous particles could be anefficacious system for oligonucleotide deliveryin vivo. Results showed that the MS-AsPS-ODN-PEI nanosized complex significantly improvedthe bleb survival rate following trabeculectomy(100% at 42 days) in rabbits compared to con-trols (0% of survival at day 21). The improvedefficiency of the complexes released frommicrospheres is attributed to a superior intra-cellular delivery in conjunctival cells, alongwith the inhibition of TGFb2.
Mitomycin C is considered the most effectiveantifibrotic agent used in glaucoma filteringsurgery [190]. It is used in more than 85% of thetrabeculectomies, but severe adverse effects,such as conjunctival thinning, bleb leaks,hypotony, and infection, limit its safety [190].Our group has been working on the develop-ment of a safer and effective alternativenanoparticle-based antifibrotic agent. Paclitaxelassociated with lipid nanoemulsions (LDE-PTX)was tested on rabbits undergoing trabeculec-tomy [191]. Subconjunctival injection of LDE-PTX was as effective as MMC in preventingscarring after trabeculectomy, but with sub-stantially less toxicity to the conjunctiva andciliary body. After these promising results in theanimal model, we have recently started the firstclinical trial to investigate the effectiveness ofLDE-PTX in patients with primary open-angleglaucoma (POAG) undergoing trabeculectomy.
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Duan et al. [192] investigated the effects ofIkappaB kinase subunit beta (IKKb) inhibitionusing RNA interference (RNAi) technology onthe proliferation of human Tenon’s capsulefibroblasts (HTFs), which have a fundamentalrole in the scarring process. Ye et al. [193]developed a small interfering RNA (siRNA) tar-geting IKKb (IKKb-siRNA) associated with aternary cationic nano-copolymer called CS-g-(PEI-b-mPEG) as the vehicle delivered intoHTFs. They found that the expression of IKKbwas downregulated, the activation of nuclearfactor kappa B (NF-jB) in the HTFs was inhib-ited, and the proliferation of HTFs was sup-pressed through the blocking of the NF-jBpathway, effects that improved the surgicaloutcome in a non-human primate model oftrabeculectomy.
There is increasing interest in the use ofangiogenesis-inhibiting compounds, especiallythose that act against vascular endothelial growthfactor (VEGF), aiming to modulate the effects ofVEGF on the migration and proliferation ofhuman fibroblasts in Tenon’s capsule [194]. VEGFis upregulated in the aqueous humor of theglaucoma rabbit model as well as in patients withglaucoma, and it stimulates fibroblast prolifera-tion in vitro [195]. Bevacizumab is a full-lengthhumanized non-selective monoclonal antibodydirected against all isoforms of VEGFA, which hasbeen reported to inhibit proliferation of fibrob-lasts in vitro and to reduce angiogenesis andcollagen deposition in eyes undergoing tra-beculectomy [194–197]. Han et al. [198] investi-gated the use of bevacizumab combined withPEG-PCL-PEG (PECE) hydrogel, by intracameralinjection, after experimental glaucoma filtrationsurgery (GFS). Results demonstrated that theantifibrotic effect of bevacizumab-loaded PECEhydrogel was superior to bevacizumab alone inthe prevention of postoperative scarring after GFSin the rabbits.
NEUROPROTECTIONAND NEUROREGENERATIONAND NEUROTROPHIC FACTORS
Although IOP is considered the main risk factorfor the development and progression of
glaucoma, RGC loss may continue in spite ofIOP reduction in some patients with glaucoma[199, 200]. The physiopathology behind RGCdeath is complex and has been attributed tovarious factors, including oxidative stress,intermittent ischemia, defective axon transport,excitotoxicity, loss of electrical activity, andtrophic factor withdrawal [16], which justifiesthe development of neuroprotection/neurore-generation strategies.
Glial cell-derived neurotrophic factor(GDNF) is an important neurotrophic factorimplicated in the growth, differentiation,maintenance, and regeneration of specific neu-ronal populations in the adult brain, as well asin peripheral neurons [201].
In vitro and in vivo studies have shown thatGDNF may rescue photoreceptor and RGCfunctions during retinal degeneration [202].Previous studies have demonstrated thatexogenous GDNF is an interesting therapeuticapproach for neurodegenerative diseases affect-ing the retina, including glaucoma [203].Checa-Casalengua et al. [203] described a novelprotein microencapsulation method to ensureprotection of the biological factor during thisprocedure, allowing the controlled release ofproteins to keep their bioactivity for prolongedperiods of time. GDNF in combination withvitamin E released from the microspheres wasactive for at least 3 months after a singleintravitreal injection in an animal model ofglaucoma. There was a significant increase ofRGC survival compared with GDNF alone,vitamin E alone, or blank microspheres, whichindicates that this novel formulation may beclinically applicable as a neuroprotective tool inthe treatment of glaucomatous optic neuropa-thy. Ward et al. [204] demonstrated long-termRGC survival in a spontaneous glaucoma ani-mal model by injecting slow-release PLGAmicrospheres containing GDNF into the vitre-ous. Early treatment resulted in 3.5 timesgreater RGC density than untreated mice after15 months.
In a rat glaucoma model, animals were trea-ted with GDNF injected into their vitreouscavity. 10% GDNF-microsphere emulsionresulted in a significant reduction of optic nervehead excavation, and increased RGC survival,
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compared with 2% GDNF-microspheres, blankmicrospheres, and saline solution [205]. Inorder to evaluate the pharmacokinetics ofGDNF, Garcıa-Caballero et al. [206] analyzed itslevels after a single intravitreal injection ofGDNF/vitamin E microspheres in rabbits. Thismethod allowed a sustained controlled releaseof GDNF for up to 6 months.
Ciliary neurotrophic factor (CNTF) has alsobeen shown to be neuroprotective on motorneurons following injury to the adult centralnervous system [207], and also for neurons inother regions in degenerative diseases[208–210]. Effective neuroprotection could bereached if sustained and local delivery withoutadverse side effects were achievable, but sus-tained CNTF delivery has proven arduous toaccomplish and control. Nkansah et al. [211]examined the effects of CNTF nanospheres onneural stem cells (NSC) and also on the factorsthat influence controlled CNTF delivery frommicrospheres and nanospheres. Protein bioac-tivity after encapsulation was studied treatingneural stem cells with CNTF released fromnanospheres and compared to those treatedwith unencapsulated CNTF. Results showedthat encapsulated CNTF provided NSC differ-entiation with no loss of potency compared tothe unencapsulated growth factor.
In addition, Pease et al. [212] demonstratedthe neuroprotective effect of virally mediatedoverexpression of CTNF and brain-derivedneurotrophic factor (BDNF) in experimentalglaucoma. Injection of adeno-associated viralvectors carrying either BDNF, CTNF, or both, inlaser-induced glaucoma eyes, was performed.Combined CNTF-BDNF and BDNF overexpres-sion alone had no noticeable improvement inRGC axon survival, but CNTF alone showed asignificant protective effect, with 15% less RGCdeath.
The induction of heat shock proteins (HSPs)has been investigated as a modality for theprotection of optic nerve damage in glaucoma[213–215]. Caprioli et al. [214] conducted thefirst demonstration of the neuroprotectiveeffects of 72-kDa HSPs in cultured RGCs andMuller cells after hyperthermia and sublethalhypoxia. Since then, many researchers havebeen attempting to apply the induction of HSPs
as a neuroprotective strategy in patients withglaucoma.
The calcium (Ca2?)-binding protein onco-modulin is a potent macrophage-derivedgrowth factor for RGCs and other neurons. Yinet al. [216] demonstrated that, in vivo, onco-modulin released from nanoparticles (micro-spheres) promotes regeneration in the maturerat optic nerve.
More recently, Jeun et al. [217] investigated anew approach to use localized HSPs—a promis-ing treatment modality for the ocular neuro-protection—without the unwanted side effectstypically occurring with the current clinicalapproaches to induce HSPs in RGCs. Theseauthors proposed the induction of HSPs by localmagnetic hyperthermia utilizing engineeredsuperparamagnetic Mn0.5Zn0.5Fe2O4 nanoparti-cle agents (EMZF-SPNPAs). The results showedthat the EMZF-SPNPAs possess all the idealcharacteristics as an in vivo localized HSPinduction agent. Moreover, the authors alsoused an innovative infusion technique, whichdelivers the silica-coated EMZF-SPNPAs throughthe vitreous body to the retina forneuroprotection.
ANTI-INFLAMMATORY DRUGS
Inflammation is a common physiological pro-tective response to injury. Inflammation isgenerally beneficial to the organism, promotingtissue survival, repair, and recovery, providedthat it occurs for a limited period of time.Otherwise, it may be detrimental when exten-sive, prolonged, or unregulated [218]. In thecentral nervous system, the activation of astro-cytes and microglia, which is indicative ofinflammation, occurs in patients with Parkin-son’s, Alzheimer’s, Huntington’s diseases, mul-tiple sclerosis, and amyotrophic lateral sclerosis[219–221]. Hence, in the nervous system, pro-longed inflammation may have a dual role,increasing neuronal loss or impeding regenera-tion. This justifies why anti-inflammatory drugsmight also have a neuroprotective activity.
In glaucoma, the neuroinflammatoryresponses during RGC degeneration have notbeen elucidated. However, microglia are
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pleiotrophic immune cells and seem to take partin both neuroprotection and neurodegenera-tion of RGCs [222]. Thus, it is plausible thatlow-grade inflammation may occur in glaucomain response to hypoxia, ischemia, vascular dys-function, and elevated IOP. In fact, genes asso-ciated with cyclooxygenase 2 (COX-2)/PGE2[223, 224], cytokines [225], tumor necrosis fac-tor alpha (TNFa) in glial cells [226], and hypoxiainducible factor 1-alpha (HIFa) [227] are allupregulated in glaucomatous RGCs.
Curcumin [1,7-bis-(4-hydroxy-3-methox-yphenyl)-1,6-heptadiene-3,5-dione] is apolyphenol extracted from Curcuma longa [228].It has been reported that this compound canbeneficially modulate several biochemical pro-cesses involved in neurodegenerative diseases.For example, Dong et al. [229] showed thatlong-term (12-week) curcumin-supplementeddiet increased hippocampal neurogenesis andcognitive function in aged rats. Similarly, Kimet al. [230] demonstrated the beneficial effectsof low dose curcumin on mouse multi-potentneural progenitor cells, which means it canstimulate neural plasticity and repair. Further-more, Belviranlı et al. [231] concluded thatcurcumin supplementation improves cognitivefunction in aged female rats by reducing thelipid peroxidation in brain tissue, whichdemonstrates its protective effect against neuraloxidative stress.
Curcumin has been reported to protect RGCsand the microvasculature against ischemicdamage via inhibition of NF-jB, signal trans-ducer and activator of transcription 3 (STAT3),and monocyte chemotactic protein 1 (MCP-1;also known as C-C motif chemokine 2) overex-pression [232]. Wang et al. conducted a study toinvestigate the ability of curcumin to inhibitretinal ischemia/reperfusion injury. Pretreat-ment with curcumin inhibited ischemia/reper-fusion-induced cell loss in the ganglion celllayer. Also, 0.05% curcumin administered2 days after the injury showed a vasoprotectiveeffect [232]. On the basis of the hypothesis thatlocal and systemic oxidative stress participate inthe pathogenesis of glaucoma, Yue et al. [233]evaluated the antioxidant effects of curcuminboth in vitro (BV-2 microglia cell line) andin vivo and found that curcumin may improve
cell viability and decrease intracellular reactiveoxygen species and apoptosis of RGCs.
Although the therapeutic potential of cur-cumin in ophthalmology is real, its poor watersolubility [234], and low bioavailability[228, 235] are important limiting factors forclinical applicability. To surpass these limita-tions, Davis et al. [236] used a nanotechnologyapproach to provide a hydrophobic environ-ment for a poorly soluble molecule such ascurcumin, and to improve its bioavailabilitythrough the development of a nanocarriersuitable for utilization as a topical formulation.This nanoformulation was able to increase thesolubility of curcumin by a factor of 400,000,which is more than enough to overcome natu-ral ocular barriers. Topical application of cur-cumin-loaded nanocarriers twice-daily for3 weeks, in in vivo models of ocular hyperten-sion and partial optic nerve transection, signif-icantly reduced RGC loss. These results suggestthat topical curcumin nanocarriers havepotential as a neuroprotective therapy inglaucoma.
Ketorolac is a synthetic pyrrolizine car-boxylic acid derivative that belongs to thegroup of NSAIDs. Ketorolac is a non-selectiveinhibitor of the enzymes COX-1 and COX-2.The inhibition of COX-2, upregulated at sites ofinflammation, prevents conversion of arachi-donic acid to pro-inflammatory prostaglandins[237]. Cyclooxygenases are expressed by RGCsin the rodent retina [238] and are upregulatedin the retina after optic nerve injury [239] andischemia [240]. Nadal-Nicolas et al. [241] firstdescribed the neuroprotective effects of ketoro-lac on RGCs after optic nerve axotomy in rats.Two treatments were evaluated: intravitrealadministration of ketorolac tromethaminesolution and/or ketorolac-loaded PLGA micro-spheres, 1 week before the optic nerve lesionand intravitreal administration right after theoptic nerve crush. In all treated groups therewas a significant increase in the number ofRGCs compared to all control groups, whichconfirmed that an NSAID can delay neuronaldeath in an acute model of axonal injury. Pre-treatment (ketorolac solution administered pre-optic nerve lesion) resulted in 63% survival ofRGCs, while simultaneous administration of
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ketorolac solution provided a 53% survival.However, in this study, microspheres did notshow an additional effect, contrary to otherinvestigations where intravitreal administrationof the microparticle formulation was found tobe advantageous [242].
TOXICITY OF NANOMATERIALS
Nanoparticles may generate cellular toxicitythrough oxidative stress, interaction with thecell membrane, and inflammation [243]. Incontrast to chemical toxicity, where compoundpurity and drug concentration are the essentialdeterminants, in nanotoxicity other character-istics should be taken into account, such asnanoparticle size, surface shape, and ioniccharge [244]. In addition, there are a few toxi-city forms that may be independent of the drugdelivered, namely particle toxicity, excipienttoxicity, contaminant toxicity, and inflamma-tory toxicity [243]. Each one must be indepen-dently investigated in vitro and in vivo.
Specific literature about the toxicity of ther-apeutic nanoparticles in the eye remains scarce[243]. Nanotoxicity is a subject of key impor-tance to be determined in conjunction with thetherapeutic potential of each nanoparticle[245, 246], particularly for those that requirerepeat-dose regimens [247]. All nanoparticlesproposed to be utilized for therapeutic purposesmust be thoroughly investigated in terms oflocal and systemic toxicity, before obtaining thefull regulatory approval.
CONCLUSIONS AND PERSPECTIVES
Glaucoma is a complex and multifactorial dis-ease and truly effective treatments need to bedeveloped and specifically targeted to thepathophysiological pathways that have beenidentified to date. We believe that, in the future,glaucoma treatment will include the use ofhypotensive drugs associated with neuropro-tective agents directed to the preservation ofRGCs and the optic nerve.
Nanotechnology has been shown to be arobust and valuable modality for the treatment
of ocular diseases, including glaucoma. In thisreview, we focused on the recent advances inthe development of nanosystems for glaucomatreatment. Bearing in mind the desired thera-peutic targets in glaucoma therapy, nanotech-nology has the ability to meaningfully improvethe efficacy of current treatment approaches. Byimproving the pharmacological characteristicsof drugs, or the features of surgical devices,nanotechnology has remarkable potential infuture glaucoma management. There is con-vincing experimental evidence that manynanoparticles may enhance the solubility oflipophilic drugs, which improves bioavailabil-ity, and promote sustained delivery owing totheir optimized biodegradability and physico-chemical characteristics. Nanomedicine formu-lations designed to lower IOP may not requirefrequent dosing and may reduce drug-relatedside effects, which ultimately will result inoptimizing adherence. In addition, nanofor-mulated drugs have been shown to improvewound healing modulation following filteringsurgery and at the same time reduce the toxicityto the conjunctiva and ciliary body. Nanopar-ticle-coated filtering drainage devices may alsoreduce the fibrotic reaction around the plate,increasing their long-term success.
Although promising, possible toxic effects ofnanoparticles have to be thoroughly analyzedduring preclinical evaluation. The detailedinvestigation of every possible biological reper-cussion is requisite to the future introduction ofnanomaterials. Importantly, the vast majorityof studies on the use of nanoparticles in glau-coma have been performed in animal models.Human studies are needed not only for thedetailed determination of the actual cytotoxic-ity of each nanoparticle but also to investigatetheir tolerability and efficacy.
ACKNOWLEDGEMENTS
Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.
Adv Ther (2020) 37:155–199 189
Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole and have given theirapproval for this version to be published.
Disclosures. Marcelo Luıs Occhiutto, andRaul Cavalcante Maranhao have nothing todisclose. Vital Paulino Costa has receivedresearch funding from Allergan, Alcon, Novar-tis; honoraria from Allergan, Alcon, Novartis,Aerie, Genom, Ofta, Iridex; and congressexpenses from Allergan, Alcon and Novartis.Anastasios-Georgios Konstas has receivedresearch funding from Allergan, Bayer andSanten; honoraria from Allergan, Mundipharmaand Santen; and congress expenses from Via-nex. Anastasios-Georgios Konstas is a memberof the journal’s Editorial Board.
Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.
Data Availability. Data sharing is notapplicable to this article as no data sets weregenerated or analyzed during the current study.
Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.
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