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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5640_Библиотеки_им_академика_М_И_Перельмана.pdf
Table 1
(continued)
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 259
Route of drug
S. No.
administration Advantages
7 Systemic Patient compliant and
non-invasive
and improve the efficacy, high drug concentrations with repeated
administration is commonly practised that may end up with poor
patient compliance and serious side effects [25]. Therefore, to
improve
ocular bioavailability, newer approaches, viz. nanocarriers,
collagen corneal shields, contact lenses, etc., are explored to
increase the pre-corneal retention time, increase stability, and
enhance the corneal, scleral, or conjunctival permeability [26
4.2 Subconjunctival Administration
Subconjunctival drug administration is a minimally invasive route
that avoids the corneal and blood-aqueous barriers, potential side
effects, and first-pass metabolism of some systemic agents [27]. It is
an
effective route to deliver drugs to treat diseases of anterior
segment of eye, such as uveitis, corneal opacity, etc. This route is
commonly used in cases of very low drug permeation into the
anterior part of eye after topical administration. However, drug
loss due to blood and lymphatic drainage through the conjunctiva
occurs by this route [28].
Disadvantages/
challenges encountered Applications
BAB, BRB, low
bioavailability (<2%),
high dosing causes
toxicity
Scleritis, uveitis,
glaucoma
].
4.3 Transscleral Administration
4.4 Intracameral Administration
It is a simple, minimally invasive, and more appropriate method for
treatment of posterior segment diseases, such as trauma or diabeticrelated conditions, that are not manageable through conventional
topical route. This route bypasses the obstacles in anterior segment
of eye. Molecules up to 70 kDa can easily infiltrate the sclera, which
are otherwise impermeable to cornea. Besides, large surface area of
sclera (about 95% of total surface area of eye) helps in delivering
antioxidants, neuro-protective agents, or anti-angiogenic agents to
targeted sites in retina [29]. Nevertheless, intraocular drug bioavailability
by this method is lower than direct intravitreal injection
route due to certain dynamic barriers.
Intracameral administration involves relatively easy and efficient
drug delivery directly into the anterior chamber. Direct drug delivery by this method avoids barriers of cornea, conjunctiva, and BAB,
as well as decreases the side effects and first-pass metabolism of
some systemic agents. It is used for prophylactic antibiotics or
anesthetics associated with eye surgeries, especially subsequent to
cataract surgery to avoid endophthalmitis [30]. This method is
260 Anuradha Nema
Table 2
Some common ocular drugs with their preferred route of administration and uses
Route of
Drug Class
Antibiotics
administration
Uses
Moxifloxacin Fluoroquinolone Topical/
intracameral
Ciprofloxacin Fluoroquinolone Topical Corneal ulcers, bacterial conjunctivitis
Gatifloxacin Fluoroquinolone Topical Corneal ulcers, bacterial conjunctivitis
Gentamicin Aminoglycoside Topical/
subconjunctival
Tobramycin Aminoglycoside Topical Bacterial conjunctivitis
Neomycin-
Polymyxin
B-Bacitracin
Steroids and NSAIDs
Loteprednol Corticosteroid Topical Intraocular inflammation
Dexamethasone Corticosteroid Topical/
Triamcinolone Corticosteroid Topical/
Ketorolac NSAIDs Topical Moderate-severe pain, post-operative
Mixture Topical Superficial bacterial ocular infections
subconjunctival/
intravitreal
subconjunctival/
intravitreal/
retrobulbar
Corneal ulcers, bacterial conjunctivitis
Bacterial conjunctivitis, post-op and post-
injury infection
Intraocular inflammation
Intraocular inflammation
pain
Pressure regulators
Dorzolamide Carbonic
anhydrase
inhibitor
Brinzolamide Carbonic
anhydrase
inhibitor
Timolol Beta blocker Topical Decreases production of aqueous humor
Latanoprost Prostoglandin
analogue
ravoprost
T
Pilocarpine Cholinergic Topical Increases aqueous outflow
Prostoglandin
analogue
Topical Decreases production of aqueous humor
Topical Decreases production of aqueous humor
Topical Increases aqueous outflow in open-angle
glaucoma
Topical Increases aqueous outflow in open-angle
glaucoma
through
trabecular meshwork in acute angle
closure glaucoma
(continued)
Table 2
(continued)
Drug Class
Cycloplegics and pupil dilators
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 261
Route of
administration Uses
Atropine Anticholinergic/
parasympatholytic
Tropicamide Anticholinergic/
parasympatholytic
Phenylephrine Adrenergic Topical Fundus examination
Immunomodulators
Cyclosporine Calcineurin
inhibitor
Tacrolimus macrolide Topical Allergic conjunctivitis,
Topical Hyphema, uveitis
Topical Fundus examination
Topical Allergic conjunctivitis,
dr
y eye
y eye
dr
limited to diseases of only anterior segment of eye. Additionally,
drug delivery typically require sterility, appropriate dilution, drugs
with no preservatives, and proper doses. In inappropriate doses and
preparations, corneal endothelial cell toxicity and anterior segment
toxicity may occur [31].
4.5 Intravitreal Injections/Implants (IVIs)
Intravitreal injection is an ideal method of drug delivery into the
vitreous that is close to retina in the posterior part of eye. However,
due to vitreous fluid turnover, free drugs are removed quickly.
Hence, to achieve good therapeutic results, frequent IVIs are
required, resulting into adverse effects such as endophthalmitis,
retinal detachment, and elevated intraocular pressure. Therefore,
to maintain therapeutic effects, delay treatment intervals, and protect normal ocular tissues, safer and more efficient alternatives, such
as nanocarriers, intravitreal implants, and hydrogels, are required to
combat ocular diseases [32]. A new approach for treatment of
glaucoma
includes a single intravitreal injection of vitamin
E/poly-lactic-co-glycolic acid microspheres enclosing glial cell
line derived neurotrophic factor [33].
4.6 Retrobulbar Administration
Through this route drugs are delivered in retrobulbar space by
passing needle through eyelid and orbital fascia [34]. This route is
b
eneficial in administering drug in depot form. Retrobulbar injection of triamcinolone acetonide is used to treat condition caused by
retinal vein occlusion [35]. Retrobulbar injection of amphotericin
has higher antifungal efficacy than intravenous injection [36].
B
262 Anuradha Nema
4.7 Systemic Administration
Parenteral and oral dosing as systemic administration is an alternative method of ocular drug delivery. Antibiotics, anti-inflammatory,
and anti-glaucomatous drugs are given by this method to treat
diseases such as uveitis, elevated intraocular pressure, and
endophthalmitis [
37]. However, due to the ocular barriers, only
1–2% of drug reaches retinal and vitreous area. Hence, to obtain the
desired therapeutic effect, frequent administrations are essential,
resulting into systemic side effects and poor patient compliance
38]. Therefore, it is not considered an ideal mode of drug
[
administration.
5 Nanotechnology-Based Ocular Drug Delivery Platforms
To improve drug bioavailability by overcoming various ocular barriers, the development of nanotechnology-based ocular drug delivery system (ODDS) is a boon. Advancement in nanocarriers has
taken ocular treatment to the next level with several advantages,
including overcoming ocular barriers, increasing transcorneal permeability, lengthening drug residence time, reducing drug degradation, decreasing dosing frequency, improving patient
compliance, attaining sustained/controlled release, drug targeting,
and gene delivery. Many nanocarriers such as nanoparticles, nanomicelles, nanosuspensions, nanoemulsions, nanofibers, dendrimers, niosomes, liposomes, nanowafers, etc. have proven superb
delivery potential in both in-vitro and in-vivo studies, enhancing
drug per meability across the ocular barriers and increasing drug
bioavailability in the eye [
lar drug delivery systems (ODDSs) are depicted in Fig.
exemplifies some nanotechnology-based ocular drugs with their
characteristics.
39]. Nanotechnology-based various ocu-
4. Table 3
5.1 Nanoparticles (NPs)
5.1.1 Polymeric Nanoparticles (PNPs)
NPs are colloidal drug carriers with ideal sizes ranging from
10 to 100 nm. They are mainly divided into polymer and lipid
40]. The effective ocular absorption of NPs depends on
NPs [
surface charge that can be either positive or negative. Cationic
NPs have a higher retention time on the corneal and conjunctival
negatively charged surfaces than anionic NPs. Presently, NPs are
widely used for targeted drug delivery in eye, with advantages of
smaller size and less irritation, non-specific uptake or premature
degradation avoidance, sustained drug release to avoid repeated
dosing, better absorption and increased intracellular permeation,
and targeted delivery to desired tissues [
41].
Polymeric nanoparticles used in ocular preparations are composed
of natural or synthetic polymers such as sodium alginate, chitosan,
polylactide-coglycolide (PLGA), polylactic acid (PLA), and polycaprolactone (PCL). Among all, PLGA is widely accepted due to its
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 263
Fig. 4 (1) Polymeric NPs; (2) lipid NP; (3) liposome; (4) nanoemulsion; (5) nanomicelle; (6) nanocrystals;
(7) nanosuspension; (8) dendrimer; (9) microneedles; (10) nanofibers; (11) nanowafer; (12) niosome;
(13) hydrogel
excellent biocompatibility, biodegradability, and capacity to modulate drug release by altering terminal groups, molecular weight, and
lactide-to-glycoside ratio [ ]. As per their structure, these are
42
classified as nanospheres and nanocapsules. Nanospheres are small
solid spheres composed of a dense polymeric matrix type network
with a large surface area. Nanocapsules are composed of a polymeric membrane with small liquid core. In both types, drug is
either adsorbed on the surface or entrapped in-situ. Polymeric
nanoparticles have an approach to both the segments of eye
[ ]. Patient compliance is improved due to their small particle
43
size, prolonged drug release, improved permeation, and reduced
elimination rate [ ]. Polymeric nanoparticles for dexamethasone
17
utilizing glycol chitosan, N-(3-dimethylaminopropyl)-N′-
-ethylcarbodiimide hydrochloride, and N-hydroxysuccinimide
have small particle size, enhanced retention time, and sustained
release [ ]. Efficacy and sustained release of lutein are enhanced
44
with poly(lactic-co-glycolic acid), tween 80, and Poloxamer
407 [ ]. Enhanced efficacy and ocular permeation of acetazol-
45
amide using chitosan, Tween
lyphosphate are seen [ ]. Subconjunctival injection of chitosan-
46
®
80/20, span 60, and sodium tripo-
coated polylactide-glycolic acid NPs (CS-PLGA NPs) has better
permeability that delivers Bev (anti-VEGF drug) with higher concentrations (above 22 ng/mL for 6 weeks) for 12 weeks in the
posterior segment of eye as compared to traditional local and
intravitreal injections in diabetic retinopathy cases
264 Anuradha Nema
Table 3
Examples of various nanotechnology based ocular drugs with their characteristics
Nanostructured
Drug
platform
Additional components Characteristics
Acetazolamide Polymeric
nanoparticles
Cyclosporine A Polymeric
nanoparticles
Dexamethasone Polymeric
nanoparticles
Triamcinolone
acetonide
Lipid
nanoparticles
Chitosan and span 60 Enhanced ocular permeation and
efficacy
Span 80 and hyaluronic
acid
Increased cellular uptake and
efficacy
Glycol chitosan Enhanced retention time and
sustained release
®
Pluronic
gellan gum
F-68 and
Improved residence time and
increased delivered drug
concentration
Tobramycin Lipid
nanoparticles
Stearic acid, Epikuron
200, and
Higher concentration in both
segments of eye
sodium taurocholate
Cyclosporine A Nanomicelles Hyaluronic acid Improved and sustained release and
permeation
Tacrolimus Nanomicelles Amino lactic acid and
hydroxypropyl
Enhanced ocular permeation and
prolonged release
methylcellulose
Pimecrolimus Nanomicelles Polyethylene glycol and
poly (ε-caprolactone)
Cyclosporine A Nanoemulsions Chitosan, Carbopol
and Transcutol
®
Timolol Nanoemulsions Chitosan,
hydroxyethylcellulose,
Sustained release and enhanced
activity
®
Enhanced drug retention, safety,
,
P
and efficacy
Increased permeability and
activity
Polyvinylalcohol, and
polyethylene glycol
Terbinafine
hydrochloride
Nanoemulsions Surfactants,
co-surfactant, and
gellan gum
Pilocarpine Nanosuspensions Eudragit
Diclofenac Nanosuspensions Eudragit
®
RL100 Sustained drug release and
®
S100 and
poloxamer
188
®
Methylprednisolone
acetate
Nanosuspensions Eudragit
polyvinyl
RS 100 and
alcohol
Itraconazole Nanosuspensions Chitosan, lysine, and
poloxamer
188
Sustained release and improved
bioavailability
enhanced activity
Prolonged drug release and
increased
activity
Prolonged release and enhanced
activity
Increased corneal permeation and
stability
(continued)
Table 3
(continued)
Drug
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 265
Nanostructured
platform Additional components Characteristics
Dexamethasone Nanocrystals Benzalkonium chloride
and
cetylpyridinium chloride
Brinzolamide Nanocrystals Poloxamer F68/F127
polysorbate 80
and
Triamcinolone
acetonide
Timolol maleate Liposomes Chitosan Improved ocular permeation,
Hyaluronic acid Liposomes Phosphatidylcholine,
Acetazolamide Niosomes Span 60, cholesterol,
Timolol maleate Niosomes Span 60, cholesterol,
Tacrolimus Niosomes Hyaluronic acid Sustained release and enhanced
Antisense
oligonucleotides
Liposomes Soybean
phosphatidylcholine,
cholesterol,
and dicetylphosphate
stear
cholesterol
and
and
Dendrimers Penetratin, hyaluronic
acid
chitosan,
ylamine,
Carbopol
chitosan
®
934P
Enhanced residence time and
safety
Immediate dissolution and
improved efficacy
Showed superior corneal
permeation and improved activity
precorneal residence time, and
bioavailability
Improved entrapment and
prolonged
Improved duration of action
efficacy
and
Prolonged release and reduced side
effects
activity
Enhanced retention time,
permeability, and distribution in
posterior segment
penetration
Brimonidine tartrate Cubosomes Glyceryl monooleate
poloxamer 407
and
Agomelatine Olaminosomes Oleic acid and
oleylamine
Terconazole Bilosomes Cholesterol, span
and edge
60,
activator
[47]. Latanoprost-loaded PLGA NPs are promising in the treatment of glaucoma, due to their enhanced drug residence time
(more than 7 days) with 23 times efficacy as compared to latanoprost eye drop [48].
5.1.2 Lipid
(LNPs)
Nanoparticles
Lipid NPs are solid lipid matrix enclosing lipophilic and hydrophilic
drugs. Triglycerides, fatty acids, steroids, and waxes are used to
prepare LNPs. Surfactants are used to stabilize the lipid dispersion.
Improved permeation and
bioavailability
Enhanced permeation and activity
Improved permeation and activity
266 Anuradha Nema
They have greater permeability, ocular retention time, and prolonged drug release with improved bioavailability. Besides, biocompatibility, safety, and biodegradability with affordable preparation
are other advantages [
etoposide employing Gelucire
50] and triamcinolone acetonide-loaded nanoparticles utiliz-
888 [
ing Pluronic
®
F-68 and gellan gum have increased drug concentration and improved residence time [
nanoparticles of tobramycin, composed
49]. Solid lipid nanoparticles loaded with
®
44/14 and Compritol® ATO
51]. A mucoadhesive solid lipid
of stearic acid, Epikuron
200, and sodium taurocholate, has higher concentration in both
segments of the eye [
52].
NPs have certain limitations, i.e., insufficient drug loading,
early drug release during storage, difficulty in attaining homogeneous particle dispersion, and surfactant toxicity [53].
5.2 Nanomicelles
Nanomicelles are core–shell nanocarriers composed of anionic,
cationic, or zwitterionic surfactants. Spherical, cylindrical, or starshaped nanomicelles can range from 10 to 100 nm in size. They
may be either positive or reverse micelles based on the core drug.
Positive micelles contain hydrophobic drug within the core and
hydrophilic moiety outward to increase contact with water and are
used to deliver hydrophobic drugs. The opposite reverse micelles
arrangement is used to encapsulate, solubilize, and deliver hydrophilic drugs [
54]. The unique chemical structure of nanomicelles
have simple preparation techniques, increased stability, enhanced
permeation, can solubilize drugs internally, increased bioavailability, reduced adverse reactions, and have a sustained release effect.
Transport of drugs to both segments of the eye makes it a safe
alternative for ocular drug delivery [
17]. Tacrolimus has enhanced
ocular permeation and prolonged release when used with aminoterminated polyethylene glycol-block-poly(D,L)-lactic acid and
hydroxypropyl methylcellulose [
55]. Similarly, hyaluronic acid sus-
tains the release, increases permeation, and increases the activity of
cyclosporine A [
56]. Cyclosporine nanomicelles loaded with
tocopherol polyethylene glycol 1000 succinate (TPGS) (approximately 13 nm) and 5 mg/mL cyclosporine, facilitated drug retention in cornea and sclera, and maintained good acceptance for
ophthalmic applications [
57]. A nano-micelle drug to deliver anti-
VEGF composed of polypropylene glycol, polyethene glycol
(PEG), and polycaprolactone (PCL) is superior to traditional invasive intravitreal injection to treat retinal diseases [
58].
5.3 Nanoemulsions (NEs)
Nanoemulsion, a potential carrier for the ocular delivery ranges
from 20 to 500 nm in size. On the basis of the dispersed phase
system, NEs may be either (a) water-in-oil (W/O) NEs: dispersion
of water droplets in oil, (b) oil-in-water (O/W) NEs: dispersion of
oil droplets in water [
59]. Oils in water nanoemulsions are stabi-
lized by surfactants that help in interaction with corneal surface and
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 267
enhance drug solubility. O/W NEs aids lipophilic drugs to interact
with a lipid layer of tear film and a sustained drug release [
60]. NEs
as a non- invasive, cost-effective drug delivery systems are widely
used for commercial production. NEs have the advantages of prolonged anterior corneal retention time, high penetration ability,
sustained drug release, and enhanced ocular bioavailability
61]. NEs have certain disadvantages, i.e., irritation of eyes, low
[
viscosity, and thermodynamic instability. Reduced ocular tolerance
and blurred vision due to high surfactant concentration and development of milky formulation may occur respectively. These drawbacks aggravate when particle size exceeds 100 nm
[
62]. Nanoemulsions of cyclosporine A using many oils, chitosan,
Carbopol
tion, safety, and efficacy [
(CIP-NE) using oleic acid and Labrafac
oil phase and Tween
increased trans-corneal permeation and sustained release [
®
, and Transcutol® P resulted in enhanced drug reten-
60]. Ciprofloxacin-loaded nanoemulsion
®
80 and Poloxamer 188 as surfactants showed
®
lipophilic WL 1349 as the
63]. Tra-
voprost nanoemulsion is a novel ocular carrier that exhibits controlled drug release, adequate stability, enhanced safety, improved
bioavailability, and sustained IOP reduction for 60 hours
[
64]. Thus, NEs may be promising agents for future clinical oph-
thalmic applications.
5.4 Nanosuspensions
Nanosuspensions are submicron colloidal dispersions of lipophilic
or semi-lipophilic drug nanocrystals in a dispersion medium and
stabilized by surfactants or polymers. It comprises of 100% pure
drug in nanometer range and is one of the most promising
approaches for delivering poorly soluble active ingredients
65]. Nanosuspension has no requirement of a carrier material, as
[
in conventional matrix-framed nano-systems. It is capable of sustained drug release, lengthening residence time, and increased drug
solubility and bioavailability. Eudragit
®
polymer is the most commonly used mucoadhesive agents in preparing
nanosuspensions [17].
A m
ucus-penetrating n
anosuspension eye drops (MOX-PAM
NS) comprise of an insoluble moxifloxacin–pamoate (MOX-PAM)
complex. It has significantly increased ocular drug absorption,
improved bioavailability of moxifloxacin hydrochloride, and had
better antibacterial effects with less dosing frequency as compared
to commercial formulation [
66]. Thus, nanosuspension has a high
clinical significance in treating ocular problems. Despite these
encouraging nanosuspension results, stability issues related to
nanosuspensions remain unresolved. Hence, physical stability and
maximum attainable particle size are crucial aspects for better
67]
effects [
Further
.
more, nanosuspensions can also be combined with
other nanotechnology. A hybrid of nanosuspension and dissolving
microneedles system is effective in the delivery of hydrophobic
268 Anuradha Nema
drug triamcinolone acetonide (TA) via transscleral route. TA nanosuspension is incorporated into the MN array by high-speed centrifugation to form a bilayer structure. Drug deposition by hybrid
method is much higher than that of common drug-loaded
68].
MN [
5.5 Nanocrystals (NCs)
5.6 Liposomes
The major configuration of nanocrystals is the drug itself that is
enclosed and stabilized by other excipients. They have simple formation techniques, small particle size, and high mucoadhesion
properties with improved bioavailability [
69]. Dexamethasone
and polymyxin B nanocrystals, formed using benzalkonium chloride and cetylpyridinium chloride, have small particle size,
enhanced retention time, and safety [
70]. Brinzolamide-loaded
nanocrystals using poloxamer F68/ F127, polysorbate 80, and
hydroxypropyl methycellulose have immediate dissolution with
improved efficacy [
71]. Cellulose nanocrystals of pilocarpine have
sustained drug release with increased safety. Thus, nanocrystals may
be promising nanocarriers for ocular rug deliver y [72].
Liposomes are spherical nanocarriers made up of one or more
concentric phospholipid bilayers with a water compartment in
core. They have a diameter of 25–1000 nm with lipophilic drug
in the lipid area, while the interior could entrap hydrophilic or
lipophilic drug. Their surface charge, sensitivity to ion, pH, or
temperature and particle size depend upon composition and formation technique [
73]. Positively charged liposomes have high
adherence to negatively charged cornea, longer retention time,
and better absorption. This results in less dosing frequency, more
safety, enhanced bioavailability, and patient satisfaction
. B
74]
[
esides, liposomes are simple to prepare and biodegradable.
Positively charged liposomes of penicillin G has fourfold increased
trans-corneal flow [75]. Liposomal system composed of phosphatidylcholine, cholesterol, α-tocopherol, and chitosan has better
corneal uptake, high percent entrapment, high drug targeting,
sustained activity, and enhanced efficacy. Positive tacrolimus liposome eye drop has 300 nm diameter with surface charge of
+30 mV. It interacts more with anionic eye surface with prolonged
retention time and enhanced tacrolimus in the cornea for treating
dry eyes. Thus, liposomes can adhere to the cornea, which are
excellent carriers for drugs with low partition coefficient, low solubility, high molecular weight, and poor absorption [
Liposomes are
also extensively used in the therapy of retinal
76].
diseases. Small liposomes (~50 nm) can penetrate the retina, as
compared to large liposomes (~100 nm). Additionally, anionic
surface charge and PEGylation enhance retinal permeation
77]. However, limited drug loading capacity, short shelf life, and
[
sterilization issues restrict their ophthalmic application.