Ocular DDS.pptx

Ophthalmic Vs Ocular
❑ They are specialized & Conventional dosage
forms designed to be instilled onto the external
surface of the eye (topical), administered inside
(intraocular) or adjacent (periocular) to the eye
or used in conjunction with an ophthalmic
device.
● The most commonly employed ophthalmic
dosage forms are solutions, suspensions, and
ointments.
● These preparations when instilled into the eye
are rapidly drained away from the ocular cavity
due to tear flow and lacrimal nasal drainage.
❖ The newest dosage forms for ophthalmic drug
delivery are called as OCULAR DDS: gels, gel-
forming solutions, ocular inserts , intravitreal
injections and implants.

Drugs used in the eye:
● Miotics (Contraction of pupil) e.g. pilocarpine Hcl
● Mydriatics (Dilation of pupil) e.g. atropine
● Cycloplegics (paralyzes the ciliary body) e.g. atropine
● Anti-inflammatories e.g. corticosteroids
● Anti-infectives (antibiotics, antivirals and antibacterials)
● Anti-glucoma drugs (reduce the intra-ocular pressure)
e.g. pilocarpine Hcl
● Surgical adjuncts e.g. irrigating solutions
● Diagnostic drugs e.g. sodiumfluorescein
● Anesthetics e.g. tetracaine

Need of ocular drug delivery
● These Novel devices and/or formulations may help to
surpass ocular barrier and associated side effects
with conventional topical drops.
● It provides prolong drug retention thus better
absorption and consequently improved bioavailability.
● Helps to avoid pre-corneal elimination.
● Patient compliance is facilitated.

Anatomy and Physiology of the
Eye:

Anterior portion – Cornea, Conjunctiva, Aqueous humor, Iris,
Ciliary body, Lens
Posterior Portion – Sclera, Choroid, Retina, Vitreous body
Cornea
Devoid of blood vessels
Derives nourishment form tear fluid and aqueous humor
12mm in diameter, 520µm in thickness

● limited volume of administration (30 μL);
● fast clearance from ocular surface;
● Metabolism of the active by tear enzymes;
● nonproductive uptake into systemic circulation via highly
vascularized conjunctiva, choroid, uveal tract and inner
retina
● anterior membrane barriers (cornea, conjunctiva, and
sclera);
● aqueous humor outflow;
● long diffusional path ; and
● acellular nature of the vitreous, which may negatively
impact the pharmacokinetics and distribution of topically
applied drugs.
Barriers: Ocular DDS

Pathway for ocular absorption:

Barriers for Ocular Drug Absorption
Depending on the route of administration:
1. Topical Precorneal factors
Solution drainage, Blinking, Tear dilution, Tear turnover, Induced lacrimation,
Conjuctival absorption
2. Physical barriers
Cornea
Sclera
Conjuctiva
3. Oral
4. Periocular and intravitreal
5. Parentetal
Blood aqueous barrier
Blood retinal barrier

Barriers for Ocular Drug Absorption –
Topical Route
 Mostly in the form of eye drops
 Employed to treat anterior segment diseases
 Site of action is usually different layers of the cornea,
conjunctiva, sclera, iris and ciliary body.
 Precorneal factors:
• Solution drainage, blinking, tear film, tear turn over, and induced
lacrimation
• Human tear volume is estimated to be 7 μl
• Mucin present in the tear film plays a protective role by forming a
hydrophilic layer that moves over the glycocalyx of the ocular
surface and clears debris and pathogens
• Contact time with the absorptive membranes is lower
• Less than 5% of the applied dose reaches the intraocular tissues

Mechanical barriers for topical drug
absorption
Cornea
Limits the entry of exogenous substances into the eye and protects the ocular
tissues
Divided into the epithelium, stroma, and endothelium
The corneal epithelium is lipoidal in nature
Offers resistance for permeation of topically administered hydrophilic drugs
Corneal epithelium…
Corneal epithelial cells are joined to one another by desmosomes
Tight junctional complexes retards paracellular drug permeation from the tear film
into intercellular spaces of the epithelium as well as inner layers of the cornea
Layers of the Cornea Stroma
Comprises 90% of the corneal thickness
Highly hydrated structure
Barrier to permeation of lipophilic drug molecules
Endothelium
Endothelial junctions are leaky - facilitate the passage of macromolecules between
the aqueous humor and stroma
Drugs should have an amphipathic nature in order to permeate through these layers

Sclera
Consists of collagen fibers and proteoglycans embedded in an extracellular
matrix
Permeability - comparable to that of the corneal stroma
Positively charged molecules exhibit poor permeability presumably due to
their binding to the negatively charged proteoglycan matrix
Permeability of drug molecules across the sclera is inversely proportional
to the molecular radius

– Parenteral Route
Anterior segment: blood–aqueous barrier
Posterior segment: blood–retinal barrier

Blood–aqueous barrier
Tight junctional complexes and prevent the entry of
solutes into the intraocular environment such as the
aqueous humor
Blood–retinal barrier
Restricts the entry of the therapeutic agents from blood
into the posterior segment.
Regulates drug permeation from blood to the retina

● “Smart” hydrogels, or stimuli-sensitive hydrogels, are very
different from inert hydrogels in that they can “sense”
changes in environmental properties such as pH and
temperature and respond by increasing or decreasing their
degree of swelling.
● The stimuli that induce various responses of the hydrogels
systems include physical (temperature) or chemical (pH,
ions) ones.
● There are many mechanisms have been employed to cause
reversible sol-gel phase transition by different stimuli.
STIMULI-SENSITIVE HYDROGELS

STIMULI-SENSITIVE HYDROGELS
● physiological environmental conditions of human body: The
stimuli that induce various responses of the hydrogel
● systems include-
● 1. Physical stimuli like: Change in temperature, electric
fields, light, pressure, sound, and magnetic fields.
● 2. Chemical stimuli like: Change in pH and ion activation
from biological fluid.
● 3. Biological/biochemical (bimolecular) stimuli like:
Change in glucose level
● In ophthalmic drug delivery three types of stimuli-sensitive
hydrogels - temperature sensitive, pH sensitive, and
● ion-sensitive hydrogels are mainly used.

Temperature-sensitive hydrogels
● Temperature-sensitive hydrogels are able to swell or de-swell as a result
of changing in the temperature of the surrounding fluid. For
convenience, temperature-sensitive hydrogels are classified into
negatively thermosensitive, positively thermosensitive, and
thermally reversible gels.
● Negative temperature-sensitive hydrogels have a lower critical
solution temperature (LCST) and contract upon heating above the
LCST. Copolymers of (Nisopropylacrylamide) (PNIAAm) are usually
used for negative temperature release. Hydrogels show an on off drug
release with on at a low temperature and off at high temperature
allowing pulsatile drug release. LCST systems are mainly relevant for
controlled release of drugs, and of proteins in particular.
Thermosensitive polymers may be fixed on liposome membranes; in
that case liposomes exhibit control of their content release.

● Positive temperature-sensitive hydrogel has an
upper critical solution temperature (UCST), such
hydrogel contracts upon cooling below the UCST.
Polymer networks of poly (acrylic acid) (PAA)
and polyacrylamide (PAAm) or poly
(acrylamide-co-butyl methacrylate) have
positive temperature dependence of swelling.

● The most commonly used thermoreversible gels are these prepared from poly
(ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide) (Pluronics
, Tetronics , poloxamer).
● Polymer solution is a free-flowing liquid at ambient temperature and gels at
body temperature, such a system would be easy to administer into desired
body cavity. Depending on the ratio and the distribution along the chain of
the hydrophobic and hydrophilic subunits, several molecular weights are
available, leading to different gelation properties Pluronic F127, which
gives colorless and transparent gels, is the most commonly used in
pharmaceutical technology.
● At concentrations of 20% w/v and higher aqueous solutions of Poloxamer-
407 remain as a liquid at low temperatures [<15°C] and yield a highly
viscous semisolid gel upon instillation into the cul-de-sac. At low
temperatures, the Poloxamer forms micellar subunits in solution, and
swelling gives rise to large micellar subunits and the creation of cross-linked
networks. The result of this phenomenon is a sharp increase in viscosity
upon heating.

● Three principal mechanisms have been proposed to explain the
liquid-gel phase transition after an increase in temperature,
including:
● 1. Gradual desolvation of the polymer,
● 2. Increased micellar aggregation, and
● 3. The increased entanglement of the polymeric network.
● Despite all the promising results obtained with thermo
reversible gels, there remains an important drawback
associated with their use; the risk of gelation before
administration by increase in ambient temperature during
packing or storage.

pH-sensitive hydrogels
● These hydrogels respond to changes in pH of the external
environment. These gels have ionic groups (which are
readily ionizable side groups) attached to impart peculiar
characteristics. Some of the pH sensitive polymers used in
hydrogels’ preparations are
● polymethyl methacrylate (PMMA),
● polyacrylamide (PAAm),
● polyacrylic acid (PAA),
● poly dimethylaminoethylmethacrylate (PDEAEMA)
● polyethylene glycol.

● These polymers though in nature are hydrophobic but swells in
water depending upon the pH prevalent in the external
environment. Any change in pH of the biological environment
causes changes in the swelling behavior,
● for example, the hydrogel of caffeine is prepared with polymer
PDEAEMA at pH below 6.6. As the polymer shows high
swellability but when pH changes to higher side, the polymer
showed shrinkage leading to drug release.
● The other pH-sensitive hydrogels are copolymer of PMMA and
polyhydroxyethyl methyl acrylate (PHEMA), which are anionic
copolymers, swell high in neutral or high pH but do not swell in
acidic medium. It was also observed that pH and ionic strength
determines kinetics of swelling of PHEMA and guar gum.

● Cellulose acetate phthalate (CAP) latex, cross linked
acrylic, and derivatives such as carbomer are used.
Cellulose acetate derivatives are the only polymer known to
have a buffer capacity that is low enough to gel effectively
in the cul-de-sac of the eye. The pH change of about 2.8
units after instillation of the native formulation (pH 4.4) into
the tear film leads to an almost instantaneous transformation
of the highly fluid latex into viscous gel.
● But the low pH of the preparation can elicit discomfort in
some patients. The poly acrylic acid and its lightly cross-
linked commercial forms (Polycarbophil and Carbopol)
exhibit the strongest muco-adhesion.

● Ion-sensitive polymers belong to the mainly used in situ
gelling materials for ocular drug delivery. Gelling of the
instilled solution is also triggered by change in ionic
strength. It is assumed that the rate at which electrolytes
from the tear fluid is absorbed by the polymer will depend
on the osmotic gradient across the surface of the gel.
● It is therefore likely that the osmolality of the solution might
have an influence on the rate of the sol-gel transition
occurring in the eye. One example is Gelrite, an anionic
extra cellular polysaccharide, low acetyl Gellan gum
secreted by pseudomonas elodea. Gelrite formulations in
aqueous solutions form a clear gel in the presence of the
mono or divalent cations typically found in the tear fluids.
Ion-sensitive hydrogels

Ion-sensitive hydrogels
● The electrolyte of the tear fluid and especially Na+, Ca++, and Mg++
cations are particularly suited to initiate gelation of the polymer when
instilled as a liquid solution in to the cul-de-sac. Gelrite has been the most
widely studied and seems to be preferred compared to the pH sensitive or
temperature setting systems. The polymeric concentration is much lower
compared to previously described systems.
● Slightly viscous gellan gum solutions in low concentrations (<1%) show
markedly increase in apparent viscosity, when introduced into presence of a
physiological level of cations, without requiring more ions than 10–25% of
those in tear fluid.The precorneal contact times for drugs can thus be
extended up to 20-h. Gellan-containing formulations of pilocarpine HCl
allowed reduction of drug concentration from 2% to 0.5% obtaining the
same bioavailability.

Ocular Insert
Non erodible inserts
The Ocusert therapeutic system is a flat, flexible, elliptical device
designed to be placed in the inferior cul-de-sac between the sclera
and the eyelid and to release Pilocarpine continuously at a steady
rate for 7 days
Ocusert:

The device consists of 3 layers…..
● Outer layer – ethylene vinyl acetate copolymer layer.
● Inner Core – Pilocarpine gelled with alginate main polymer.
● A retaining ring - of EVA impregnated with titanium dioxide

The ocuserts available in two forms.
● Pilo – 20 (20 microgram / hour)
● Pilo – 40 (40 microgram / hour)
Use: Chronic glaucoma
Advantages
● Increase in ocular residence.
● Drug release at slow and constant rate.
● Increased shelf life compare to aqueous solutions.
● Accurate dosing
● Improved compliance.
● Can administer with inflammed eye.
● Save time of healthcare professional.
● Eliminate systemic side effects.
● Improved patient compliance.

Mechanism of drug release:
 Diffusion
 Osmosis
 Bio-erosion

Erodible Inserts
 The solid inserts absorb the aqueous tear fluid and gradually
erode or disintegrate
 The drug is slowly leached from the hydrophilic matrix
 They quickly lose their solid integrity and are squeezed out of
the eye with eye movement and blinking
 Do not have to be removed at the end of their use
Three types
● LACRISERTS
● SODI
● MINIDISC

Mechanism of inserts: Soluble or Erodible
● In swelling-controlled devices, the active agent is
homogeneously dispersed in a glassy polymer. Since glassy
polymers are essentially drug-impermeable, no diffusion
through the dry matrix occurs. When the insert is placed in the
eye, water from the tear fluid begins to penetrate the matrix,
then swelling and consequently polymer chain relaxation and
drug diffusion take place. The dissolution of the matrix, which
follows the swelling process, depends on polymer structure:
linear amorphous polymers dissolve much faster than cross-
linked or partially crystalline polymers. Thus, some inserts, even
if classified as S, may remain in the eye as empty ‘ghosts’ after
releasing their drug content. Release from these devices
follows in general Fickian ‘square root of time’ kinetics; in some
instances, however, known as case II transport, zero order
kinetics have been observed.

● In truly erodible or E-type devices, the rate of drug
release is controlled by a chemical or enzymatic
hydrolytic reaction that leads to polymer
solubilization, or degradation to smaller, water soluble
molecules.
● These polymers may undergo bulk or surface
hydrolysis. Zero order release kinetics can be
displayed by erodible inserts undergoing surface
hydrolysis, provided that the devices maintain a
constant surface geometry and that the drug is poorly
water soluble.
Mechanism of inserts: Soluble or Erodible

1. LACRISERTS
● Sterile rod shaped device made up of hydroxy propyl cellulose
without any preservative
● For the treatment of dry eye syndromes
● It weighs 5 mg & measures 12.5 mm in diameter with a length of
3.5 mm
● It is inserted into the inferior fornix

2. SODI (Soluble Ocular Drug Inserts)
● Soluble Ocular Drug Inserts
● Small oval wafer
● Made up of water soluble synthetic polymer
● Sterile thin film of oval shape
● Weighs 15-16 mg
● Introduced into the inferior cul-de-sac.
Composition- Acryl amide, vinyl pyrolidone, Ethylacrylate.
Use – glaucoma

● The SODIs are the result of a vast collaborative effort between
eminent Russian chemists and ophthalmologists, and led
eventually (in 1976) to the development of a new soluble
copolymer of acrylamide, N-vinylpyrrolidone and ethyl acrylate
(ratio 0.25 : 0.25 : OS),
● SOD1 in the form of sterile thin films of oval shape (9 x 4.5 mm,
thickness 0.35 mm), weighing 15-16 mg, and color-coded for
different drugs.
● After introduction into the upper conjunctival sac, a SOD1
softens in 10-15 s, conforming to the shape of the eyeball. In the
next 10-15 min the film turns into a polymer clot, which gradually
dissolves within 1 h while releasing the drug. The sensation of
an ‘extraneous body’ in the eye disappears in 5-15 min.
2. SODI

● This dosage form was originally developed for astronauts to
apply it in the state of weightlessness. Drug release from
SODIs does not show vehicle control, and produces a
prolonged-pulse entry of the drug. However, due to the
capacity of the ocular tissues to act as drug reservoirs, a
single SOD1 application has been reported to replace 4-12
drop instillations or 3-6 applications of ointment,
● Drug is released from SODI in a pulsational, uncontrolled
manner, and the dosage form ensures its prolonged effect.
● Active ingredients employed in the course of research on
SODI include neomycin, kanamycin, atropine, pilocarpine,
dexamethasone, sulfapyridine, and tetracaine.
2. SODI

● Based on natural polymers, for example, collagen.
● Based on synthetic or semi-synthetic polymers.
● The therapeutic agent is absorbed by soaking the insert in a
solution containing the drug, and drying and rehydrating it before
use in the eye. The amount of drug contained will depend upon the
capacity of the binding agent, concentration of the drug solution into
which the insert is soaked, and the duration of soaking.
● The soluble ophthalmic inserts are easily processed by
conventional methods – slow evaporating extrusion, compression
or injection molding. The release of the drug takes place when
tears penetrate into the insert. This induces drug release by
diffusion and forms a layer of gel around the core of the insert. This
gelification causes further release of the drug, but it is still
controlled by diffusion. The release rate, J, is derived from Fick's
law, which yields the following expression
2. SODI

Advantages:
● Single SODI appliction: repaces 4-12 eye drops
instiation. Or 3-6 applications of ointments.
● Once a day treatment of Glaucoma.
● In 10-15 Sec softens; In 10-15 min turns in viscous
liquid; After 30-60 min becomes a polymeric solution.
API: Neomycin, kanamycin, atropine, pilocarpine,
dexamethasone, sulfapyridine, and tetracaine
2. SODI

3.MINIDISC
Countered disc with a convex front and a concave back
surface in contact with eye ball.
Diameter – 4 to 5 mm
Composition
Soluble copolymers consisting of actylamide, N-vinyl
pyrrolidone and ethyl acetate
-Silicone based prepolymer-alpha-w-dis (4-
methacryloxy)-butyl poly di methyl siloxane. (M2DX)
 M-Methyl acryloxy butyl functionalities.
 D – Di methyl siloxane functionalities.
 Pilocarpine, chloramphenicol
Drug release: upto 170hrs.

Contact lenses - Challenges
● Incorporation of sufficient amounts of the drug into the lens
matrix;
● sustaining the drug release for the desired time frame at a
controlled rate;
● Good optical clarity;
● Patient comfort during prolonged wear; and biocompatibility.
● Prolonged wear of contact lens is associated with risk of
infection such as microbial keratitis and dry eye syndrome.
● Wearing of contact lenses is contraindicated in various
inflammatory conditions of anterior segment such as anterior
uveitis, vernal conjunctivitis, microbial keratitis and dry eye
syndrome, limiting the applicability of this delivery system.

The routes of drug delivery by contact lens
● Drug- loded contact lenses are
worn on the cornea to achieve
topical administration for the
management of ocular diseases.
● As shown in Fig.2, a human tear
film contains approximately 6–7 μl
of fluid to form a thickness of 7–10
μm.
● When contact lenses are not worn,
the tear film covers the cornea,
however, after the insertion of a
contact lens the tear film is divided
into the PLTF and the POLTF.

● The PLTF is located on the anterior side of the contact lens,
which has direct exposure to air, while the POLTF is located
between the cornea and the posterior segment of the contact
lens .
● Therapeutic agents in contact lenses are released into both the
PLTF and the POLTF. The drug released from the contact lens
into the POLTF can be subsequently delivered into the cornea or
radially diffuse outwards into the outer tears, and the periodic
lens motion can enhance the radial transport.
● The drug delivered into the cornea can reach the anterior
segment for the management of ocular diseases through the
corneal route. Reversely, drug released from the contact lens
into the PLTF is dominantly absorbed into the conjunctiva,
further entering the posterior segment and systemic circulation,
or drained by the canaliculus.
The routes of drug delivery by contact lens

The process of manufacturing contact lens
by different methods
● a. lathe-cut method; b. spin casting method; c. injection molding method.
● CL: Contact lens; HIGH THEM: High temperature.

Soaking in Drug Solutions
● The traditional method is to soak the preformed contact lens in drug
solution so that the drug is adsorbed into the polymeric lenses. Drug
loading is achieved be either being dissolved in the aqueous phase of the
contact lens, or being physically adsorbed on the polymer matrix.
● Due to the drug concentration difference between the soaking solution and
aqueous phase of contact lens, molecular diffusion is the main driving
force for drug delivery into contact lenses, and is subsequently also the
mechanism of drug release from the contact lens.
● Although soaking of preformed contact lenses in drug solution is an easy
way to incorporate the drug, this approach suffers from various limitations
including low drug loading and fast diffusion of the drug from the lenses.
● Drug upload and release by the soaking method is related to certain
factors such as drug concentration in the soaking solution, the molecular
weight of the drug, the lens thickness, the type and water content of the
lens.

Soaking in Drug Solutions
● Drugs with a low molecular weight, between 300 and 500 Da, are
released from the contact lens over a few minutes to a few hours . High
molecular weight drugs such as hyaluronic acid have difficulties
penetrating the aqueous channels of contact lens and only remain on
the surface
● Such presoaked lenses allow limited, slow release of the drug into the
post-lens lacrimal fluid. Soft contact lenses made from poly-
hydroxymethacrylate (pHEMA) hydrogels release the majority of their
drug content in one day.

Cyclodextrin-based contact lens
A. Copolymerization of acrylic/vinyl CDs derivatives
B. Grafting of CDs to preformed polymer networks
C. Directing cross-linking of CDs

● Molecularly imprinted contact lenses exhibited a more prolonged drug release when
compared with lenses soaked in drug solution. Molecularly imprinted contact lenses
of ketotifen (diffusion coefficient: 5.57 ± 0.31 × 10 cm2 /s) showed a diffusion
coefficient that was nine-times lower than nonimprinted lenses (50.2 ± 4.8 × 10 cm2
/s).
Molecularly imprinted polymeric hydrogels

Conjugation of nanoparticles or drug
molecules to contact lens surface
● Another approach to prepare contact lens drug delivery systems is to immobilize the
drug or drug-loaded nanocarriers such as liposomes and nanoparticles on the
surface of commercial soft contact lenses.
● This can be achieved by surface functionalization of contact lenses to attach the
drug or nanocarriers. Surface immobilization of levofloxacin liposomes on
NeutrAvidin-coated Hioxifilcon-B contact lenses resulted in slower release than drug
soaked lenses.
● However, most of the drug (70%) was released within the first 5 h, with 30%
remaining drug release occurring over the next 6 days. Thus, the drawback of this
approach is the relatively rapid detachment or disintegration of liposomes in the
contact lenses.
● The lipid layer may also impede O2 and CO2 permeability.

● Recent research from the
Massachusetts Eye & Ear
Infirmary (Needham, MA, USA)
demonstrated that near zeroorder,
4-week release of ciprofloxacin
and fluorescein is feasible from a
drug-polymer film (poly[lactide-co-
glycolide] [PLGA] 65:35) coated
with a hydrogel (pHEMA) contact
lens.
● In vitro release studies showed
that the drug release rate can be
reduced by using highmolecular-
weight polymers or increasing the
polymer-to-drug ratios.
Drug-polymer films integrated with contact
lenses

Liposome-loaded contact lenses
● In this method, drug-loded nanoparticles,
liposomes or surfactant are added to the
polymerizing medium of hydrogel matrix
followed by polymerization to form contact
lenses dispersed with drug carriers.
● The overall drug release can be regulated by
controlling the release of the drug from the
various carriers, followed by the lens matrix to
the post-lens tear film.
● Contact lenses created with dispersion of
lidocaine loaded liposomes or nano-particles
showed nonlinear release of drug for 7 days,
with an initial 15–20% burst release over the
first few hours followed by near zero-order
release for the remaining 7 days.

Scleral lens delivery systems
● The scleral lenses were first approved by the FDA in 1994 for the management of
ectasia and irregular astigmatism. Scleral lenses are large diameter lenses which
rest over the sclera, unlike the conventional contact lenses which rest on the cornea.
● These lenses are fitted to not touch the cornea and there is a space created
between the cornea and the lens. These lenses are inserted in the eyes after filling
with sterile isotonic fluid.
● A scleral lens rests on the sclera and creates a space over the cornea and limbus,
acting as a reservoir for tear fluid between the inner surface of the scleral lens and
the cornea to form an expanded tear film.
● This expanded tear film over the cornea acts as a liquid bandage in corneal surface
irregularities.
● The scleral lens allowed improved retention of topically applied drug on the corneal
surface in the expanded tear film, that is, the tear film or artificially introduced tears
retained between the corneal surface and the scleral lens.
● The drug may be added to the scleral lens, which acts as a reservoir for sustained
release of the drug, or administered externally as an eye drop, which is retained in
the expanded precorneal tear film.
● The topical delivery of Avastin for the treatment of corneal neovascularization using
scleral lens delivery system showed promising results in a clinical study with five
patients.

Non-biodegradable polymeric implants
● These implants can entrap drug either by dispersion throughout
a polymer matrix or storage inside a reservoir surrounded by a
release controlling non-biodegradable polymer membrane.
● Drug release from non-biodegradable matrix systems is
governed by diffusion and an initial burst is often observed.
● On the other hand, reservoir systems release the drug either
through permeable non-biodegradable membranes or ia a small
orifice in an impermeable membrane.
● Both of these systems have shown near zero order drug release
of effective concentrations over extended periods of time.
● Polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA) and silicon
are the most commonly used non-biodegradable polymers for
ocular implants.

● Silicon and EVA are hydrophobic in nature and are mainly used
as membranes with limited permeability in reservoir based
systems. On the other hand, PVA is more hydrophilic and
therefore permeable to a broader range of drugs. Often a
combination of PVA with either EVA or silicon is utilized to
optimize drug release from the implant.
● Vitrasert, approved by the FDA in 1996, is a non-biodegradable
implant containing 4.5 mgof ganciclovir for the treatment of CMV
retinitis. It contains the drug in form of a pellet coated with two
layers of nonbiodegradable polymers. The inner coating is PVA,
with the outer impermeable coating of EVA on three sides and
an additional PVA layer on the remaining side. Drug permeates
via the permeable PVA coated side at a rate of approximately 24
μg/day and the implant has shown clinical suppression of
disease symptoms over five to eight months.

● Vitrasert is sutured to the pars plana region of the sclera.
Common complications with the use of this implant include
endophthalmitis, cataract formation, intraocular pressure
increase and risk of retinal detachment.
● In general, non-biodegradable polymers are preferred for implant
fabrication to deliver therapeutics to the posterior segment as
they release the drug in a more controlled manner over
extended periods of time, while also offering easier removal in
case of adverse reactions. Fabrication of refillable non-
biodegradable implants might therefore be advantageous in
terms of patient compliance and overall treatment costs.

Biodegradable polymeric implants
● These implants are made from biodegradable polymers entrapping the drug either throughout a
polymer matrix or in form of a reservoir with biodegradable polymer coating. From matrix
systems the drug is released through a combination of diffusion and polymer degradation.
● In reservoir based implants drug is mainly released through a pore in the otherwise impermeable
membrane with the biodegradable polymer coating degrading relatively slow compared to the
drug release out of the system. With matrix biodegradable systems, there is generally an initial
burst and then a fairly constant release rate over time, with a final burst observed in reservoir
systems. Drug release can vary depending on the surface area, rate of polymer degradation,
polymer swelling, molecular weight and nature of the drug molecule.
● Polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA),
polycaprolactones (PCL), polyanhydrides (PA) and polyortho esters (POE) are commonly used
biodegradable polymers for ophthalmic drug delivery, with PLGA being the most widely studied.
These polymers are all aliphatic esters which are degraded in the body by water and/or enzymes
with their degradation products being metabolized into CO2 and water.

● Ozurdex, the first biodegradable intravitreal implant approved by the
FDA, is a cylindrical implant comprising dexamethasone dispersed in a
PLGA matrix based on the NOVADUR® technology (Allergan). It
contains 700 μg of dexamethasone and has proven to be clinically
effective for up to sixmonths in the treatment of diabetic macular edema
and non-infectious uveitis. It is injected into the vitreous via a 22-gauge
needle and exhibits fast drug release over the first twomonths due to
diffusion of the drug and degradation of the polymer after which solely
polymer degradation is responsible for the slower drug release over the
following four months.

Stimuli-responsive implants
● Implants made from stimuli-responsive polymers exhibit abrupt
changes in structure, solubility, charge, volume and
hydrophobic– hydrophilic balance in response to physical or
chemical changes in the environment and can be utilized to tune
drug release rates.

Iontophoresis
● Iontophoresis is a noninvasive technique for ocular drug delivery, and therefore
avoids the complications of a surgical implantation or frequent and high dose of
intravitreal injections. The drug is applied with a weak direct current (DC) that drives
charged molecules across the sclera and into the choroid, retina, and vitreous. A
ground electrode of the opposite charge is placed elsewhere on the body to
complete the circuit.
● The drug serves as the conductor of the current through the tissue. In the rabbit
iontophoresis of DEX phosphate, DEX levels in the cornea after a single
transcorneal iontophoresis for 1 min (1 mA) were up to 30 fold higher compared to
those obtained after frequent eye-drops instillation.

Reference
● https://www.mdpi.com/2288328
● https://doi.org/10.1016/j.jconrel.2018.05.
020

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