ocular Drug delivery system: Barrier and how to over come

Introduction
 Ocular drug delivery, particularly to the posterior segment, is
one of the most challenging tasks currently facing ocular
drug-delivery scientists.
 The unique anatomy and physiology of the eye renders it a
highly protected organ, and the unique structure restricts
drug entry at the target sit of action.
 Ophthalmic drugs are primarily administered by the topical
route to treat ocular viral and bacterial infections, glaucoma,
inflammations, and immunosuppression.
2

 Most topically instilled drugs do not offer adequate
bioavailability due to wash off of the drugs from the eye by
various mechanism such as lacrimation, tear dilution and tear
turnover
 In addition the human cornea composed of epithelium,
substantia propria, and endothelium hinders drug entry;
consequently, less than 5 % of administered drug enters the eye.
 In order for a drug to reach therapeutic concentrations in the
posterior segment, it has to pass through the anterior segment
barriers, such as the corneal and conjunctival epithelia.
3

 50 % of the normal human tear film is replaced every
2–20 minutes. Such a high rate of tear turnover also
reduces drug residence in the pre-corneal and pre-
conjunctival areas. Therefore, the tear film also acts as
a barrier to topical drug absorption
 Other routes of ocular drug delivery would be by
systemic, intraocular and periocular injections, trans-
scleral and subconjunctival pathways.
4

 Drugs administered topically have a low probability of
reaching the posterior segment in significant amounts, as
they have to pass through the corneal and conjunctival
epithelia, aqueous humor, and lens, to reach the retina.
 Currently, intravitreal bolus injection is the primary mode
of therapy, but repetition of these can lead to retinal
puncture, peeling, and/or detachment.
 Bolus delivery of injections can also lead to higher
concentrations of drugs, which in turn may cause toxicity,
as in the case of gentamycin
8

Barriers in Ocular Drug Delivery
A. Anterior Segment
a) Cornea
i. Bowman’s Layer
ii. Stroma
iii. Descemet’s Membrane
iv. Corneal Endothelium
b) Conjunctiva
B. Posterior Segment
a) Retina
b) Blood–Retinal Barrier
c) Retinal Vessels
d) Retinal Pigment Epithelium
10

A. Anterior Segment
a) Cornea
 The cornea is the outer coat (air–tissue interface) of the
anterior segment. It is one of the few transparent tissues in
the body, and it needs to maintain a high degree of clarity
to transmit light to the retina without causing significant
scattering.
 It is composed of five layers: the columnar epithelium,
Bowman’s layer, stroma, Descemet’s membrane, and
endothelium
11

Fig: Cornea and it’s cellular organization depicting various
barriers to drug transport
12

i. Corneal Epithelium
 It is the outermost layer of the cornea, which contributes more
than half of the corneal resistance. It is composed of five or six
layers of stratified, squamous, non keratinized cells of 50–60
μm total thickness.
 This layer contains 90% of the total cells in the cornea, which
makes it the most lipophilic membrane in the cornea.
 Epithelial cells are tightly bound by cell adhesion proteins to
form tight junctions.
 Tight junctions provide a continuous seal around the epithelial
cells, thereby preventing the entry of polar drug molecules into
the cornea.
13

 Drug molecules traverse the membrane by a number of
mechanisms: paracellular and/or transcellular passive diffusion,
active transport, and carrier-and receptor mediated transport.
 Paracellular diffusion of polar drugs across the cornea is hindered
by epithelial tight junctions. Lipophilic molecules (nonpolar) can
diffuse passively through the lipid membranes of the epithelium
14

 Molecular size does not play a significant role in the rate of
permeation across epithelium, but the ionization may
decrease the transcellular transport.
 Thus, the lipophilicity of a drug molecule, its ionization
constant, and the pH of the eye drop formulation play
major roles in determining the rate of drug permeation
across the epithelium.
 Permeation enhancers can be used to improve the
permeation of hydrophilic drugs across the cornea.
15

ii. Bowman’s Layer
 This Layer is a modified, acellular part of the stroma. This
layer mostly contains collagen fibrils.
 It separates the epithelium and stroma.
 This layer does not play any role in restricting drug
permeation across cornea.
16

iii. Stroma
 Stroma constitutes a major part of the cornea. Ninety percent of
stroma is made up of water. It also consists of thick collagenous
lamellae parallel to the surface of the cornea. Between the
lamellae, fibroblastic keratocytes are sparsely dispersed.
 Stroma is considered the hydrophilic component of the cornea.
 Lipophilic drugs which enter epithelium, may not readily
partition into the stroma.
 For lipophilic drugs the epithelium can act as depot and stroma
can act as a depot for relatively hydrophilic compounds.
17

iv. Descemet’s Membrane
 This is a thin, collagen-rich layer between the posterior
stroma and endothelium, with thickness of 8–12 μm.
 This layer does not act as a barrier to drug absorption.
v. Corneal Endothelium
 This constitutes a single layer of squamous epithelium.
 The membrane plays a critical role in corneal hydration
and transparency.
 The endothelial cell do not act as a barrier to permeant
molecules due to lack of tight junctions.
18

b) Conjunctiva
 It is a vascularized mucous membrane lining the inner surfaces of
eyelids and the anterior surface of sclera up to the limbus.
 It facilitates lubrication in the eye by generating mucus and helps
with tear film adhesion.
 It contributes to the non-corneal ocular absorption
 Delivery of drugs to posterior segment through the conjunctiva is one
of the potential routes of drug delivery.
 Its surface area is an order of magnitude greater than that of the
cornea, and it is two to three times (depending on the drug) more
permeable than the cornea.
 Since the conjunctiva is highly vascularized, the blood circulation
removes most of the drug before it can enter the inner ocular tissues.
19

 The conjunctiva can be divided into three layers, the outer
epithelium, substantia propias, and submucosa.
 Outer epithelium acts as a permeability barrier that restricts the entry
of particles into the ocular structures as a part of protective function.
 Submucosa contains nerves, lymphatic tissue, and blood vessels. it
provides a loose attachment to the underlying sclera
20

B. Posterior Segment
 The posterior segment is comprised of retina, choroid, vitreous
humor, sclera, and the optic nerve.
 Many sight-threatening diseases that affect the posterior
segment of the eye, with the retina being the primary target, are
increasing in prevalence.
 Therapeutic concentrations of drugs in the retina and vitreous
are needed to treat such diseases as cytomegaloviral (CMV)
retinitis, age-related macular degeneration (ARMD),
proliferative and diabetic vitreoretinopathy, and
endophthalmitis.
21

 The topically drug administered for the treatment of diseases
that affect the posterior segment of the eye, significantly limit
the drug absorption into the retina, choroid and vitreous, due
to lacrimal drainage, cornea barrier and conjunctival
absorption together.
 Drug can be systemically administered to treat disease at the
back of the eye.
 Choroid is richly perfused, with plentiful blood vessels, and
allows easy exchange of molecules.
 Permeation of drug into the retina is limited due to the blood–
aqueous barrier (BAB) and blood–retinal barrier (BRB)
22

Retina
 The retina is a multilayered membrane of neuro-ectodermal
origin that lines the internal space of the posterior segment.
 The following layers comprise a fully developed retina: inner
limiting membrane, optic fiber layer, ganglion cell layer, inner
plexiform layer, inner nuclear layer, outer plexiform layer,
outer nuclear layer, outer limiting membrane, photoreceptor
layer, and the retinal pigment epithelium (RPE).
 In short, a retina can be broadly divided into the neural retina
and the RPE.
23

 The neural retina is involved in signal transduction, leading
to vision. Light enters the retina through the ganglion cell layer
and penetrates all cell layers before reaching the rods and
cones.
 The transduced signal is then relayed out of the retina by
various neuronal cells to the optic nerve. The latter
subsequently conducts the signal to the brain, where it is
registered and an image is formed.
24

 RPE is a single cell layer that separates the outer
surface of the neural retina from the choroid and
appears as a uniform and continuous layer extending
through the entire retina, playing a vital role in
supporting, and maintaining the viability of the neural
retina.
25

ii. Blood–Retinal Barrier
 The BRB protects the retina and vitreous from the
entry of toxic substances and maintains the
homeostatic control that underpins the physiology of
the retina
 non fenestrated capillaries of retinal circulation and
tight junctions between retinal epithal cells preventing
passage of large molecules from choriocapillaris into
the retina
 .
27

Retinal Vessels
 The intercellular spaces of the retinal endothelium of
retinal vessels were found to be extensively sealed with
zonulae occludens, limiting the permeability of molecules
across the membrane
 Excessive amounts of zonulae occludens in the
intercellular junctions of the retinal endothelium appears
to contribute to the BRB’s barrier
 The retinal endothelium is also referred to as inner blood–
retinal barrier (iBRB).
28

Retinal Pigment Epithelium
 The RPE lies at the interface between the neural retina and
the choroid.
 The microvilli of its apical surface inter digitate with the
outer segments of photoreceptors, whereas its highly
infolded basal membrane interacts with Bruch’s membrane,
serum components that cross the fenestrated chorio
capillaris, and the secretions of the various choroidal cell
types.
 RPE plays a central role in regulating the microenvironment
surrounding the photoreceptors in the distal retina, where
phototransduction takes place.
29

 The outer segments of the rods and cones are
closely associated with the RPE through villous
and pseudopodial attachments.
 It is also responsible for the phagocytosis of the
distal portions of the rods and cones outer segment
 RPE forms the outer blood–retinal barrier (oBRB)
by regulating transport between the neural retina
and the fenestrated capillaries of the choroid
30

 The BRB retards the entry of most water-soluble
molecules into the vitreous, even though several active
carrier-mediated processes are present that regulate the
transport of nutrients and metabolites such as glucose
(via GLUT1 and GLUT3), amino acids, nucleosides
(purine nucleoside transporter) etc., across the retina.
 In addition to these nutrient transporters, several active
ion transporters are also present in order to maintain cell
homeostasis.
31

Physicochemical Properties of Drugs Affecting
Permeability across Ocular Barriers
 Transcellular or paracellular pathway is the main route for
drugs to penetrate across corneal epithelium
 Hydrophilic drugs penetrate primarily through the paracellular
pathway, which involves passive or altered diffusion through
intercellular space
 While lipophilic drugs preferably penetrate through the
transcellular route
32

 Physicochemical properties of a drug, such as
lipophilicity, solubility, charge, molecular size and
shape, and degree of ionization also affect the route and
rate of penetration across ocular barriers.
 Chemical equilibrium between ionized and unionized
drug in eye drop and lacrimal fluid affect penetration of
ionizable drug e.g., weak acid and weak bases
 Unionized species usually penetrates the lipid membrane
more easily e.g, pilocarpine (Free base) and timolo base
penetrate batter than its ionized form.
33

 In some cases, enzymatic transformation of ocular
prodrugs in the corneal epithelium can be utilized for
releasing the active parent drug from the inactive prodrug
 By improving the partition coefficient of hydrophilic
drugs by chemical modifications (by acyl ester prodrug
design), permeation across corneal epithelium will be
improved
 The cornea is an effective barrier to compounds larger
than 10 Å, which cannot cross the membrane at any
significant rate
34

 There is no apparent dependence on corneal
permeability for compounds with small
molecular radius, but for macromolecular
peptides like thyrotropin-releasing hormone
(TRH), p-nitrophenyl beta-cellopentaoside
(PNP), and luteinizing hormone-releasing
hormone (LHRH), dependency on corneal
permeability a increasing with molecular size
35

 The ion can be actively transported across the corneal
epithelium and endothelium. The corneal epithelium
contains ionic channels that are selective for cations over
anions and also contains an outwardly rectifying anion
channel in the apical membrane and highly conductive
potassium channel in the basal cells
 Sodium penetrates from the tears into the epithelium via
passive diffusion, but it is actively transported from
epithelium to stroma
36

Conventional ocular formulations for ocular drug
delivery
 Conventional drug delivery systems like solution
suspension, gel and ointment are no longer sufficient to
fulfill the present day requirements of providing a constant
rate delivery and for a prolonged time.
37

39
Dosages form Advantages Disadvantages
Ointment Flexibility in drug choice
Improved drug stability.
Longer contact time
Inhibition of dilution by tear
Resistance to nasolacrimal
drainage
Sticking of eyes lids.
Blurred vision.
Poor patient compliance
Matting of eyelids
No true sustained effect
Drug choice limited by
partition coefficient
Gel Longer contact time
Blurred vision but less then
ointment.
comfortable
Matting of eyelids after use
No rate control on diffusion
Advantages and disadvantages of ocular gel and ointment

Requisites of Controlled ocular delivery system
I. To overcome the side effects of pulsed dosing (Frequent dosing
and high concentration) produced by conventional systems
II. To provide sustained and controlled drug delivery
III. To increase the ocular bioavailability of drug by increasing
corneal contact time.
IV. To provide targeting within the ocular globe
V. To circumvent the protective barriers like drainage, lacrimation
and diversion of exogenous chemicals into the systemic
circulation by the conjunctive
VI. To provide comfort and compliance to the patient and yet improve
the therapeutic performance of the drug over conventional
systems
VII. To provide the better housing of the delivery system in the eye so
as the loss to other tissues beside cornea is prevented
41

Ideal characteristics of ophthalmic drug delivery system
I. Good corneal penetration.
II. Maximizing ocular drug absorption through prolong
contact time with corneal tissue.
III. Simplicity of instillation for the patient.
IV. Reduced frequency of administration.
V. Patient compliance.
VI. Lower toxicity and side effects.
42

VII. Minimize precorneal drug loss.
VIII. Nonirritative and comfortable form (viscous solution
should not provoke lachrymal secretion and reflex
blinking).
IX. Should not cause blurred vision.
X. Relatively non greasy.
XI. Appropriate rheological properties and
concentrations of the viscous system.
43

Various formulation approaches to improving the
availability of drugs in ocular system
 A major challenge in ocular therapeutics is the improvement of
ocular bioavailability from less than 1–3% to at least 15–20%
 Two major approaches are being undertaken:
I. Approach to prolong the contact time of drug with corneal
surface and conjunctival region
II. Approach to enhance corneal permeability either by mild or
transient structural alteration of corneal epithelium or by
modification of chemical structure of the drug molecules.
44

Contact time of drug with corneal surface and conjunctival
region can be prolonged by following way:
 Addition of water-soluble, natural, synthetic, or semi-synthetic
viscolizers.
 Use of drug carrier systems such as nanoparticles, microspheres,
liposomes, etc., which would remain in the cul-de-sac for a
longer period of time, thus giving a sustained action.
 Utilization of the mucoadhesive property of polymers to
improve the ocular absorption of poorly-absorbed drugs.
45

Recent formulations for ocular delivery
I. Polymeric Solution
 Viscosity-increasing polymers are usually added to ophthalmic drug
solutions on the premise that an increased vehicle viscosity should
correspond to a slower elimination from the preocular area, which lead
to improved precorneal residence time and hence a greater transcorneal
penetration of the drug into the anterior chamber.
 It has minimal effects in humans in terms of improvement in
bioavailability.
 The polymers used include polyvinyl alcohol (PVA), polyvinyl
pyrrolidone (PVP), methylcellulose, hydroxyethyl cellulose,
hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose
46

II. Phase transition systems (In situ gel)
 These are liquid dosages forms which shifted to the gel or solid
phase when instilled in the cul-de-sac
 These solution are liquid in the container and thus can be
easily instilled as eye drops, but as it gets in contact with tear
turn in to gel
 Results of that an increased contact time of drug formulation in
precorneal region leads to an increased bioavailability, due to
slower drainage from the cornea and increased the duration of
therapeutic effect
 These systems can be triggered by pH, temperature, ion
activation and lysozymes upon contact with tear fluid
47

 Poloxamer 407 & Lutrol FC-127 are normally used as polymer,
whose viscosity increases when its temperature raised to 37 ºC
 Celluloses acetate phthalate (CAP) too coagulates when its
native pH of 4.5 is raised by tear fluid to pH 7.4.
 The concentration of sodium ion in tear, 2.6 g/L was
particularly suited to cause gelation of material such as gellan
gum, alginic acid etc., when topically instilled into the
conjunctival sac.
 These polymers are serve as good sustained release material for
ophthalmic use but surface active properties and low pH of
CAP, however limits their use.
 It has excellent ocular tolerance, low toxicity per os and it can
be formulated as isotonic neutral solution
49

III. Mucoadhesive/ bioadhesive dosage forms
 These dosages form containing polymers which will
attach, via noncovalent bonds, to mucin at the cornea
and conjunctival surface
 They are retained in the cul-de-sac through adhesive
bound established with the mucins and the epithelium
thus increasing the corneal contact time.
 The corneal contact time is rate limited by dissolution
of polymer with cross linked mucoadhesives
 The adhesion often detaches itself from the rate
controlling drug delivery device and caused a premature
release of drug.
50

 Mucoadhesive polymers are usually macromolecular
hydrocolloids with numerous hydrophilic functional groups
such as carboxyl hydroxyl-, amide and sulphate, capable of
establishing electrostatic and hydrophobic interactions and
hydrogen bonding with the underlying surface.
 A good bioadhesive should exhibit a near zero contact angle to
allow maximal contact time with the mucin coat
 The flexibility in chain of polymer is required, to diffuse and
penetrate into the mucin layer. The entanglement with mucin
coat increases the adhesive strength of polymer
51

 Bioadhesiveness also increases with increase in
molecular weight to a critical value.
 pH and ionic strength of dosage form also affect the
bioadhesion performance; e.g., polycarbophil exhibit
strongest bioadhesion at an acidic pH.
 The bioadhesive dosage form showed more
bioavailability of the drug as compared to conventional
dosage forms
52

IV. Ocular penetration enhancers
 The transport characteristics across the cornea can be maximized by
increasing the permeability of the corneal epithelial membrane.
 The stratified corneal epithelial cell layer is a ‘tight’ ion-transporting
tissue, because of the high resistance of 12 to 16 kΩcm2 being
exhibited by the paracellular pathway.
 This approach consists of increasing transiently the permeability
characteristics of the cornea with appropriate substances, known as
penetration enhancers or absorption promoters.
 It bears a strict analogy to techniques aimed at facilitating drug
penetration through the skin and other epithelia such as the corneal,
buccal, nasal etc.
53

 There are two possible modes of
action of the absorption
promoters:
 Surface active absorption
enhancers are believed to
increase the permeability of the
cell membranes,
 Calcium chelators act mainly on
the tight junctions.
 However, most enhancers have
been shown to affect both the cell
membranes and the tight junctions
54
Fig: Schematic illustration of the
transcellular and paracellular modes of
action of penetration enhancers.

 The entry of molecules through the paracellular pathway is
primarily restricted by tight junctions
 Tight-junction permeability has been shown to depend on a
number of factors, including:
 Degree of maturation of epithelia;
 Response to physiological requirements;
 Change in environmental conditions such as osmolarity and ionic
strength;
 Presence of drugs, vitamins, and hormones.
Among these, a few agents play a central role, e.g., the
concentration of calcium
55

 Maintenance of the tight junction requires an unknown
appropriate level of Ca 2+ bound to or in the vicinity of the
plasma membrane.
 The chelation of Ca 2+ can lead to the disruption of these tight
junctions
 Drugs that disrupt the organization of the actin network, such
as Calcium Chelators (EDTA) (ethylenediaminetetraacetic
acid) and cytochalasin B, may also cause an increase in
corneal permeability.
56

 Surfactant enhancers have been suggested to increase drug and
peptide permeability through the cell membranes or via the
transcellular pathway
 Epithelial cells are surrounded by an outer cell membrane
composed of a phospholipid bilayer with the protein molecules
embedded in the lipid membrane.
 At low concentrations, these surfactants are incorporated into the
lipid bilayer, forming polar defects which change the physical
properties of the cell membranes.
 When the lipid bilayer is saturated, mixed micelles begin to
form, resulting in the removal of phospholipids from the cell
membranes and hence leading to membrane solubilization.
57

 Many surfactants increase the paracellular penetration of drugs by
disrupting the tight junctions ; e.g., sodium caprate and sodium
dodecyl sulfate.
 Inclusion of these agents such as cetylpyridinium chloride,
ionophore such as lasalocid, benzalkonium chloride, Parabens,
Tween 20, saponins, Brij 35, Brij 78, Brij 98,
ethylenediaminetetraacetic acid, bile salts,[and bile acids (such as
sodium cholate, sodium taurocholate, sodium glycodeoxycholate,
sodium taurodeoxycholate, taurocholic acid, chenodeoxycholic
acid, and ursodeoxycholic acid), capric acid, azone, fusidic acid,
hexamethylene lauramide, saponins, hexamethylene octanamide,
and decylmethyl sulfoxide in different formulations have shown
a significant enhancement in corneal drug absorption.
58

Prodrug
 The principle of prodrug is to enhance corneal drug permeability through
modification of the hydrophilicity (or lipophilicity) of the drug.
 Within the cornea or after corneal penetration, the prodrug is either
chemically or enzymatically metabolized to the active parent compound.
 Thus, the ideal prodrug should not only have increased lipophilicity and a
high partition coefficient, but it must also have high enzyme susceptibility.
 Enzyme systems identified in ocular tissues include esterases, ketone
reductase, and steroid 6-hydroxylase.
59

 Prodrug is considered as a new drug entity; so,
extensive pharmacokinetic and pharmacologic
information is required for proper design
 E.g., Fourfold higher transcorneal permeability of L-
aspartate acyclovir compared to acyclovir
60

Ophthalmic Inserts
 Inserts are defined as sterile solid or semisolid preparations, with
a thin, flexible and multilayered structure, for insertion in the
conjunctival sac.
 The main objective of the ophthalmic inserts is to increase the
contact time between the preparation and the conjunctival tissue to
ensure a sustained release of drug
61

Advantages:
 Increasing contact time and improving bioavailability.
 Providing a prolong drug release and thus a better efficacy.
 Reduction of adverse effects.
 Reduction of the number administrations and thus better patient
compliance.
 Administration of an accurate dose in the eye and thus a better
therapy
 Ease of handling and insertion.
 Non-interference with vision and oxygen permeability
 Exclusion of preservatives.
 Increased shelf life with comparison to aqueous solutions due to
absence of water.
62

Limited popularity of ocular inserts has been
attributed to psychological factors, such as:
I. Reluctance of patients to abandon the traditional
liquid and semisolid medications
II. To occasional therapeutic failures (e.g.,
unnoticed expulsions from the eye, membrane
rupture, etc.).
63

Classification of Ophthalmic Inserts
I. Non erodible inserts
A. Reservoir systems:
a. Diffusional inserts, e.g. Ocusert,
b. Osmotic inserts
B. Matrix systems: Contact lens
II. Erodible inserts
i. Lacriserts
ii. Soluble ocular drug inserts (SODI)
iii. Mindisc
64

Non Erodible Inserts :
Ocusert
 It is a multilayered structure consisting of a drug
containing core surrounded on each side by a layer
of copolymer membranes through which the drug
diffuses at a constant rate.
 The rate of drug diffusion is controlled by:
The polymer composition
The membrane thickness
The solubility of the drug
65

 The Ocusert pilocarpine ocular therapeutic system,
developed by Alza Corporation, 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.
 This product was the first rate controlled, rate specified
pharmaceutical ocular formulation for which the strength
is indicated on the label by the rate(s) of drug delivery in
vivo, rather than by the amount of contained drug.
66

 The constant drug concentration in ocular tissues
markedly improves the selectivity of action of
pilocarpine.
 The ocuserts available in two forms . Ocusert® Pilo-20
and Pilo-40 Ocular system
 The former delivers the drug at a rate of 20 µg/h for 7
days, and the latter at a rate of 40 µg/h for 7 days
67

Ocusert device consists of 3 layers…..
I. Outer layer - A rate controller ethylene vinyl acetate
(EVA) copolymer membrane.
II. Inner Core - Pilocarpine gelled with alginate main
polymer
III. A retaining ring - of EVA impregnated with titanium
dioxide
68

Advantages:
 Reduced local side effects and toxicity.
 Around the clock control of intraocular pressure (IOP)
in glaucoma patients is fully maintained..
 Improved compliance.
Disadvantages:
 Retention in the eye for the full 7days.
 Periodical check of unit.
 Replacement of contaminated unit
 Expensive.
69

Contact lenses
 Contact lenses can be a way of providing extended release of
drugs into the eye by prolong the ocular residence time of the
drugs
 Contact lenses can absorb water-soluble drugs when soaked in
drug solutions and these drug saturated contact lenses are placed
in the eye for releasing the drug for a long period of time and also
minimizing clearance and sorption through the conjunctiva.
 Their ability to be a drug reservoir strongly depends on the water
content and thickness of the lens, the molecular weight of the
drug, the concentration of the drug loading solution and the time
of the lens remains in it 71

Types of contact lenses:
1. Hard contact lenses
 Made of rigid plastic resin polymethylmethacrylate
 Impermeable to oxygen and moisture
2. Soft contact lenses
 Made of hydrophilic transparent plastic, hydroxyethyl
methacrylate
 Contain 30 – 80% water so are permeable to oxygen
 Have two types: daily wear and extended wear 7272
72

3. Rigid gas permeable (RGP)
 Take the advantages of both soft and hard lenses, they are
hydrophobic and oxygen permeable.
Advantages of hard contact lenses and RGP lenses:
 Strength durability
 Resistant to absorption of medications and environmental
contaminants
 Visual acuity
Disadvantages:
 Require adjustment period of the wearer
 More easily dislodged from the eye 73

Advantages of soft contact lenses:
 Worn for longer periods
 Do not dislodge easily
Disadvantages:
Have a shorter life span and the wearer must ensure that the
lenses do not dry
E.g., In humans, the Bionite lens which was made from
hydrophilic polymer (2-hydroxy ethyl methacrylate) has
been shown to produce a greater penetration of
fluorescein. [
74
"soft" lens | "hard" lens

Erodible ocular 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.
 Advantage: being entirely erodible or soluble so that they do not
need to be removed from their site of application at the end of
their use.
 Three types :
I. Lacriserts
II. Soluble ocular drug inserts (SODI)
III. Minidisc 75

Lacriserts
 It is a sterile ophthalmic insert used in the treatment of dry
eye syndrome and is usually recommended for patients to
obtain symptomatic relief with artificial tear solution
 The insert is composed in a rod shaped device made up of
hydroxylpropyl cellulose without any preservative, since it is
essentially anhydrous
 It weighs 5 mg and measures 1.27 mm in diameter with a
length of 3.5 mm.
 It is inserted into the inferior fornix.
76

SODI (Soluble ocular drug inserts)
 Small oval wafer.
 Sterile thin film of oval shape.
 Weighs 15-16 mg.
 The system soften in 10-15 sec after introduction into the
upper conjunctival sac, gradually dissolves within 1 h,
with concomitant release of the incorporated drug.
 Use – glaucoma.
 Advantage – Single application (once a day)
77

Minidisc
 It is miniaturized contact lens, with a convex front and a concave
back surface.
 Diameter – 4 to 5 mm.
 This small size and shape allowed an easy placement of the device
under the upper or lower lid without compromising vision, comfort
or oxygen permeability
 Composition
 Silicone based prepolymer-alpha-w-dis (4-metha cryloxy)-butyl poly di
methyl siloxane. (M2DX)
 M-Methyl a cryloxy butyl functionalities.
 D – Di methyl siloxane functionalities.
 Pilocarpine, chloramphenicol. 78

Advantages of vesicular systems for ocular delivery
 No difficulty of insertion as in the case of ocular inserts.
 No tissue irritation and damage as caused by penetration enhancers.
 Provide patient compliance as there is no difficulty of insertion as
observed in the case of inserts.
 The vesicular carriers are biocompatible and have minimum side
effects.
 Degradation products formed after the release of drugs are
biocompatible.
 They prevent the metabolism of drugs from the enzymes present at
tear/corneal epithelium interface.
 Provide a prolong and sustained release of drug.
80

LIPOSOMES
 Liposomes are biocompatible and biodegradable lipid
vesicles made up of natural lipids and about 25 –10 000 nm
in diameter.
 They are having an intimate contact with the corneal and
conjunctival surfaces which is desirable for drugs that are
poorly absorbed, the drugs with low partition coefficient,
poor solubility or those with medium to high molecular
weights and thus increases the probability of ocular drug
absorption.
 Vesicle composed of phospholipids bilayer enclosing
aqueous compartment in alternate fashion. 81

Advantages of liposomes over other delivery systems in ODD:
 Controls the rate of release of encapsulated drug
 It is Biodegradable, Non-toxic in nature.
 Non irritant and do not obscure vision
 Protect the drugs from the metabolic enzymes present at the tear
 Ability to form intimate contact with the corneal and conjunctival
surface thereby increase in the possibility of ocular drug absorption
 Manipulation can be done regard to permeability and encapsulation
Disadvantages
 Costly
 Stability problem and oxidative degradation.
 Requires special packaging and storing facility.
82

Niosomes
 The major limitations of liposomes are chemical instability, oxidative
degradation of phospholipids, cost and purity of natural phospholipids.
 To avoid this niosomes are developed as they are chemically stable as
compared to liposomes and can entrap both hydrophobic and
hydrophilic drugs.
 Niosomes are non-ionic surfactant based multilamellar (>0.05µm),
small unilamellar (0.025-0.05µm) or large unilamellar vesicles
(>0.1µm) in which an aqueous solution of solute(s) is entirely enclosed
by a membrane resulted from organization of surfactant
macromolecules as bilayers
 They are non toxic and do not require special handling techniques. 83

 Discosomes are giant niosomes (about 20 um size) containing
poly-24- oxyethylene cholesteryl ether or otherwise known as
Solulan
Implants:
 For chronic ocular diseases like cytomegalovirus (CMV)
retinitis, implants are effective drug delivery system.
 Earlier non biodegradable polymers were used but they needed
surgical procedures for insertion and removal.
 Presently biodegradable polymers such as Poly Lactic Acid
(PLA) aresafe and effective to deliver drugs in the vitreous cavity
and show no toxic signs 84

Particulates (nanoparticles and microparticles):
 The maximum size limit for microparticles for
ophthalmic administration is about 5-10 mm above
which a scratching feeling in the eye can result upon
ocular instillation.
 That is why microspheres and nanoparticle sare
promising drug carriers for ophthalmic application.
 Nanoparticles are prepared using bioadhesive polymers
to provide sustained effect to the entrapped drugs
85

ocular Drug delivery system: Barrier and how to over come

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