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Ocular drug
delivery system

Anatomy and Physiology of Eye 2

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Human eye 3

 Diameter of 23 mm
 Structure comprises of three layers
 Outermost coat : The clear, transparent cornea
and the white, opaque sclera
 Middle layer : The iris anteriorly, the choroid
posteriorly, and the ciliary body at the
intermediate part
 Inner layer : Retina (extension of CNS)

Sclera • The protective outer layer of the eye, referred to as the

“white of the eye” and it maintains the shape of the eye

Cornea
• The front portion of the sclera, is transparent and allows light
to enter the eye
• Powerful refracting surface, providing much of the eye's
focusing power

• Is the second layer of the eye and lies between the sclera

Uvea
and the retina
• The middle coat of the eye is called the uvea (from the Latin
for “grape”) because the eye looks like a reddish-blue
grape when the outer coat has been dissected away

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• The part of the eye that gives it colour 5

Iris • It consists of muscular tissue that responds to surrounding
light, making the pupil opening in the center of the iris,
larger or smaller depending on the brightness of the light

Pupil
• The centre of iris is called the pupil.
• It appears dark because the light passing into the eye is not
reflected back to any great extent

• It is a transparent, biconvex structure, encased in a thin

Lens transparent covering.

• The function of the lens is to refract and focus incoming
light onto the retina

• It is the innermost layer in the eye 6

Retina • It converts images into electrical impulses that
are sent along the optic nerve to the brain
where the images are interpreted

• It is located in the back of the eye, in the center

Macula of the retina
• This area produces the sharpest vision

• It is a mucous membrane that begins at the

edge of the cornea and lines the inside surface
Conjunctiva of the eyelids and sclera
• It lubricates the eye

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Inside of the eyeball 7

Two fluid-filled sections

Vitreous humor Aqueous humor

The larger section at

The smaller section in
the back of the eye
the front that contains
which is filled with a
a clear, water-like
colorless gelatinous
material
mass

Fluid systems in the eye 8

Aqueous Vitreous Lacrimal

humour humour glands
• Secreted • Secreted • Secrete tears
from blood from blood & wash
through through foreign
epithelium of epithelium of bodies.
the ciliary the ciliary • Moistens the
body. body. cornea from
• Secreted in • Diffuse drying out.
posterior through the
chamber vitreous
and body.
transported
to anterior
chamber.

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Aqueous humour 9
The aqueous humour is a clear colourless fluid with a chemical composition rather
similar to that of blood plasma (the blood exclusive of its cells) but lacking the high
protein content of the latter.

Drained away by a
Secreted
Into posterior Into anterior channel at limbus
continuously by Flows through pupil
chamber chamber (junction of cornea
ciliary body
and sclera)

This channel is Connected to blood

It encircles the This is known as Humour moves to
known as canal of vessels in sclera by
cornea intrascleral plexus blood
Schlemm connector channels

Blood goes into Leaves the eyes via

superficial vessels anterior ciliary veins

 The wall of the canal that faces the aqueous humour is very delicate and allows 10 the fluid
to percolate through by virtue of the relatively high pressure of the fluid within the eye.
 Obstruction of this exit causes a sharp rise in the pressure within the eye, a condition that
is known as glaucoma.
 Ultimately the abnormal pressure damages the retina and causes a variable degree of
blindness.
 The normal intraocular pressure is about 15 mm (0.6 inch) of mercury above atmospheric
pressure, so that if the anterior chamber is punctured by a hypodermic needle the
aqueous humour flows out readily.
 Its functions:
 Maintaining the eye reasonably hard
 Provide nutrition for the crystalline lens and also for the cornea, both of which are devoid of
blood vessels; the steady renewal and drainage serve to bring into the eye various nutrient
substances, including glucose and amino acids, and to remove waste products of metabolism.

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Vitreous body 11

 It is a semisolid gel structure that is remarkable for the small amount of solid matter that
it contains.
 The solid material is made up of a form of collagen, vitrosin, and hyaluronic acid (a
mucopolysaccharide).
 Thus, its composition is rather similar to that of the cornea, but the proportion of water
is much greater, about 98 percent or more, compared with about 75 percent for the
cornea.
 The jelly is probably secreted by certain cells of the retina.
 It is devoid of cells
 Embedded in the surface of the vitreous body, however, there is a population of
specialized cells, the hyalocytes of Balazs, which may contribute to the breakdown
and renewal of the hyaluronic acid.
 The vitreous body serves to keep the underlying retina pressed against the choroid.

Mechanism of ocular absorption 12

Non-Corneal Corneal
Absorption Absorption

Outer Epithelium: rate

Penetration across
limiting barrier, with
Sclera & Conjuctiva
pore size 60å,Only
into Intra Ocular
access to small ionic
tissues
& lipophilic molecules

Non-Productive: Trans cellular

because penetrated transport: transport
drug is absorbed by between corneal
general circulation epithelium & stroma.

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13

Pharmacokinetics of ocular drug 14

administration
Tear fluid

Precorneal Epithelial Corneal Stroma

Drug pool surface epithelium epithelium

Aqueous
Nasolacrymal Conjunctiva Metabolism humor
Drainage system

Elimination

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15

Kabs Cornea
Kelm
Precorneal area

Kloss

Kloss = 0.2 – 0.5 min-1

Kabs = 0.01 – 0.001 min-1
apparent
K abs = K abs + Kloss

Factors affecting intraocular BA 16

Inflow & outflow of lacrimal fluids

Efficient naso-lacrimal drainage

Interaction of drug with proteins of lacrimal fluid

Dilution with tears

Corneal barriers

Active ion transport at cornea

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Instilled drug
Drug 17
Diffusion Dissolution
Erosion

pH/ tonicity
Drug in tear film

Absorption
Tear Corneal
turnover Conjunctival
Non-specific/
Irritation induced protein
Drainage binding
lacrimation

Overflow Metabolism
onto lids

18

 Rapid solution drainage by gravity, induced lachrymation, blinking

reflex, and normal tear turnover:

 The normal volume of tears = 7 µl, the non-blinking eye can

accommodate a volume of up to 30 µl without spillage, the drop
volume = 50 µl

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Ophthalmic dosage forms 19

 Ophthalmic preparations are sterile products essentially free

from foreign particles, suitably compounded and packaged
for instillation in to the eye.

 The following dosage forms have been developed to

ophthalmic drugs.

 Some are in common use, some are merely experimental, and

others are no longer used.

Classification of dosage forms 20

Based on Route of
Administration Based on Physical Form

• Topical Soln: Multiple • Aqueous Solution

Dose container With
Preservatives. • Suspension.
• Intra-ocular Soln: For
Surgery, Single dose, • Ointments.
Without preservative. • Gels.
• Ophthalmic Soln
Injections: Intra-ocular • Eye Lotions.
injection, given in eye
tissues, without • Solid Inserts.
preservative.

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SOLUTION
SUSPENTION
EMULSION LIPOSOMES
21
OINTMENT NIOSOMES
INSERT DISCOMES
GELS PHARMACOSOMES

IMPLANTS CONVENTIONAL VESICULAR

HYDROGELS
OCULAR DELIVERY
DENDRIMERS
SYSTEMS
IONTOPORESIS
COLLAGEN SHIELD
CONTROL RELEASE PARTICULATE
POLYMERIC SOLUTIONS MICROPARTICLES
ADVANCED NANOPARTICLES
CONTACT LENSES
CYCLODEXRIN SCLERAL PLUGS
GENE DELIVERY
MICROONEEDLE Si RNA
MICROEMULSIONS STEM CELL

NANO SUSPENSION

Advantages of conventional 22

systems
They are easily administered by the nurse
They are easily administered by the patient himself.
They have quick absorption and effect.
Less visual and systemic side effects.
Increased shelf life.
Better patient compliance.

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Disadvantages of conventional 23

systems
The solution stays at the eye surface for a very short time

Its poor bioavailability.

The instability of the dissolved drug.

The necessity of using preservative.

Conventional dosage forms 24

Dosage Form Advantages Disadvantages

Solutions Convenience Rapid precorneal elimination, non

sustained action

Suspension Patient compliance, best for drug Drug properties decide

with slow dissolution performance loss of both solutions
and suspended particles
Emulsion Prolonged release of drug from Blurred vision, patient non
vehicle compliance

Ointment Flexibility in drug choice, improved Sticking of eyes lids, blurred vision,
drug stability poor patient compliance

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Ideal characteristics of OCDDS 25

pH should Minimum
Sterile match the protein
ocular pH binding

Isotonic -
Less
e.g.: 1.9%
drainage
boric acid,
tendency
0.9% NaCl

Ocular controlled release systems 26

 Solid or semisolid in nature

 Placed in lower fornix

 Composed of polymeric vehicle containing drug

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27
Comfort

Ease of
Ease of mfg.
handling

Requisites For
Control
Release Ocular
delivery
systems
Reproducibil
Stability ity of release
kinetics

Sterility

Advantages 28

Increase ocular residence, hence, improving bioavailability.

Possibility of providing a prolonged drug release and thus a

better efficacy.
Lower incidence of visual and systemic side effects.

Increased shelf life with respect to aqueous solutions.

Exclusion of preservatives, thus reducing the risk of sensitivity

reactions

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Possibility of targeting internal ocular tissue through non-
corneal routes

Reduction of systemic side effects and thus reduced

adverse effects.

Reduction of the number of administration and thus better

patient compliance.

Administration of an accurate dose in the eye, which is fully

retained at the administration site, thus a better therapy.

Disadvantages 30

Perceived by patient as foreign body.

Movement around the eye.

Occasional loss during sleep or while rubbing eyes.

Interference with vision.

Difficulty in placement & removal.

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• Erodible 31
• Non-
erodible

In situ gelling
Ocular inserts
systems

Iontophoresis Particulates

32

Ocular
inserts

Non
Erodible
erodible

Collagen
Lacrisert Minidisc NODS SODI BODI
shields
Contact
Ocusert
lens

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33

Non-erodible inserts

Ocusert 34

Developed by Alza Corporation

It is a flat, flexible elliptical device
Consists of 3 layers

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35

Two outer layers – made up of

copolymer ethylene vinyl
acetate (EVA)
Inner core of pilocarpine in
alginate

1,4 – Transparent rate controlling membrane

2 – Opaque ring for identification
3 – Pilocarpine reservoir
Retaining ring of EVA
impregnated with TiO2 for
visibility

Eg. Pilo 20/ 40 – pilocarpine ocusert 36

Preprogrammed to release the drug at constant rates for 7 days

Release rates: 20 – 40 mcg/hr

Higher release Making the rate controlling membrane thinner

rates of Pilo 40
is achieved by:
Adding flux enhancer di-(2-ethylhexyl) phthalate

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Advantages 37

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.

Disadvantages 38

Patient discomfort

Placement and removal of insert is

difficult
Removal of insert leading to loss of
the system from eye

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Contact lens 39
 These are structure made up of a covalently cross-linked
hydrophilic or hydrophobic polymer that forms a three-
dimensional network or matrix capable of retaining water,
aqueous solution or solid components

 Classification –
Rigid
Semi-rigid
Elastomeric
Soft hydrophilic
Bio-polymeric

Drug incorporation 40

When a hydrophilic contact lens is soaked

in a drug solution, it absorbs the drug, but
dose not give a delivery as precise.
The drug release from such a system is
very rapid at the beginning and then
declines exponentially with time.
Most of the drug from contact lenses is
released in the first 30 mins

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The release rate can be decreased by incorporating the drug homogeneously

during the manufacture or by adding a hydrophobic component 41

Drug is incorporated as either a solution or suspension of solid particles in

monomer mix.

Polymerization is then carried out

Longer times of release ≈ 180 h

No preservative needed

The problem of discomfort and difficulty in handling and insertion in case of

presoaked lenses can be avoided

42

Erodible inserts

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Soluble inserts 43

They are the oldest class of the ophthalmic inserts.

They don’t need to be removed from their site of application
Pilocarpine containing CMC wafers
PVA discs or rods
Gentamicin sulphate as collagen wafers
Have been developed
But only marketed erodible inserts are Lacrisert, SODI, and Minidisc

Types 44

 Based on natural polymers e.g. collagen.

 Basedon synthetic or semi-synthetic

polymers

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Corneal collagen sheilds 45

Collagen is the structural protein of bones, tendons, ligaments, and

skin and comprises more than 25% of the total body protein in
mammals
Bloomfield et al . are credited for first suggesting, in 1977 and 1978,
the use of collagen inserts as tear substitutes and as delivery systems
for gentamicin.
These shields produced highest levels of drug when compared to
drops, ointments and conjunctival injections

Derived from bovine collagen

46
Diameter: 14.5 mm

Base curve: 9 mm

Thickness: 0.15-0.19 mm

Sterilized by gamma radiations

Then dehydrated and individually packed

The shield dissolves releasing the drug in tear film maintaining high concentrations on corneal
surface and increasing drug permeation through the cornea into the aqueous humor

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47

The drug is loaded by soaking the shield in the drug solution.

The shields are hydrated by tear fluids & then soften and form a
clear, pliable thin film.

These are designed to slowly dissolve within 12, 24 & 72 hr.

They promote wound healing and used to deliver a variety of

drugs like antibiotics, antifungals, steroids & immunosupressives

Advantages 48

Easy to use in ophthalmologist’s office

Prompt drug release

Maintains high concentration of drug in tear film

No frequent administration

Simple and convenient

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Disadvantages 49

Insertion technique is difficult

Expulsion of shield may occur

Not fully transparent and thus

reduce visual acuity

Release 50
➢ The release of the drug from such system is by penetration of tears into
the inserts, which induces release of the drug by diffusion and forms a gel
layer around the core of the insert, this gellification induces the further
release, but still controlled by diffusion.

➢ The release rate, J, is derived from Fick’s law,

ADKC s
J=
L

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Other factors affecting drug release 51

Penetration of the fluid.

Swelling of the matrix.

Dissolution of the drug and the polymers.

Relaxation of the polymeric chain.

A decreased release rate is obtained by introducing a suitable amount of

hydrophobic polymer capable of diminishing the fluid penetration and thus of
decreasing the release of the drug without modifying the solubility of the insert

Components of soluble inserts 52

Cellulose derivatives – Hydroxypropyl methylcellulose,

Soluble methylcellulose, hydroxyethyl cellulose and hydroxypropyl
synthetic cellulose.
polymers
Others – Polyvinyl alcohol, ethylene vinylacetate co-polymer
Plasticizer – PEG, glycerin, propylene glycol.

Additives Enteric coated polymer – CAP, HPMC phthalate.

Complexing agent – PVP.

Bioadhesives – polyacrylic acids.

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Lacrisert 53

Introduced by Merck, Sharp & Dohme in 1981

Sterile rod-shaped device
Made of HPC for dry eyes syndrome
Free of preservatives
Weight – 5 mg
Diameter – 12.7 mm
Length – 3.5 mm
Dose: 1-2 times a day

Proper insertion of lacrisert 54

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Imbibes water
from 55
Useful in
Inserted into
treatment of
inferior fornix conjunctiva and
keratitis sicca
cornea

Hydrates and
Stabilizes the Forms a
lubricates the
tear film hydrophilic film
cornea

Liquid artificial tears dose: 4 times an hr

Lacrisert dose: 1-2 times a day

Ocular therapeutic system or 56

Minidisc
Contoured disc with a convex front and concave back surface in contact with
the eyeball.

Like a miniature contact lens

Size: 4-5 mm

The symmetric circular design as opposed to the rod shape eliminates the
need to align to a particular geometric axis of the device with the eyelid
margin

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Made up of silicone
prepolymer – α-ω-bis(4- 57
methylacryloxy)-butyl It can be hydrophilic or
polydimethyl siloxane (M2Dx) hydrophobic and can
incorporate both types of
• M = methylacryloxybutyl
drugs
• D = dimethyl siloxane

Gentamicin sulphate
Sulfisoxazole (hydrophobic)
(hydrophilic) + hydrophobic
+ hydrophilic matrix =
matrix = release within 320
release within 170 hrs
hrs

New Ophthalmic Delivery System 58

(NODS)
Originally patented by Smith and Nephew Pharmaceuticals Ltd in 1985

Water-soluble, drug-loaded film approximately 50 mm in length, 6 mm in width

The device consists of a medicated semicircular flag (4 mm x 6 mm, thickness 20 µm,

weight 0.5 g, area 20 m2) which is attached to a paper-covered handle by means of a
short (0.7 mm) and thin (3-4 µm) membrane
All components (flag, membrane, and handle) are made of the same grade of water-
soluble polyvinyl alcohol (PVA)

The devices are individually packaged and sterilized by gamma irradiation.

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Soluble 59
Paper handle Handle film membrane
Medicated
flag

The flag is
touched onto The membrane Rapidly Which swells
Delivering the
the surface of proceeds to releasing the and dissolves in
drug
the lower dissolve flag the lacrimal fluid
conjunctival sac

60

 Both soluble (pilocarpine) and insoluble drugs

(tropicamide) can be incorporated
 Both classes of drugs show increase in
bioavailability
 PilocarpineNODS showed 8-fold increase in the
BA as compared to conventional eye drops

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Soluble Ocular Drug Insert (SODI) 61

Developed by Soviet scientists for cosmonauts who could not

use eye drops in weightless conditions
Sterile thin oval wafers

Weight 15-16 mg

Made up of acrylamide, N-vinylpyrrolidone and ethylacrylate

(ratio 0.25: 0.25: 0.5)
A single dose of SODI replaces 4-12 drops or 3-6 applications of
ointment

62
Location • Inferior cul-de-sac

10-15 secs • Wetted by tear film

• Softens and assumes the curved configuration

10-15 mins • Film turns into a viscous polymer mass

30-60 mins • Becomes a polymer solution

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Bioadhesive Ophthalmic Drug 63

Inserts (BODI)
The main problem encountered with conventional ophthalmic inserts is their site
of application and the risk of expulsion from the site.

To overcome this drawback, a new type of ophthalmic insert incorporating a

water-soluble bioadhesive component in its formulation has been developed to
decrease the risk of expulsion and ensure prolonged residence in the eye,
combined with controlled drug release
These inserts, named BODI, are totally eliminated so that they do not need to be
removed, thus limiting manipulations to insertion only

64

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65

Preparation and evaluation of

ocular inserts

Solvent
66
casting

Method of
preparation
of ocular
inserts

Printing Melt
technology extrusion

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Solvent casting method 67

Polymer and plasticizer is dissolved in

a volatile solvent

Dissolve the drug in this mixture

Pour into moulds and allow

controlled evaporation of the solvent

Peel, process further if required, and

package

Sterilize by gamma sterilization

process

Melt extrusion technique 68

Blend drug with plasticizer and polymer

Load it into a melt extruder

Maintain the temperature above the glass

transition temperature of the polymer

Extrude the mass and cut it into desired

sizes

Process further if required, package and

sterilize by gamma sterilization process

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Printing technology 69

 Increasingly gaining popularity because of its flexibility and cost-

effectiveness

• Drug-loaded inks are deposited to

Ink-jet printers yield accurately dosed units of
pharmaceutical ingredients

Flexographic • Drug loaded-substrate was coated

printing with a polymeric thin film

70

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Evaluation of inserts 71

1. Thickness
2. Weight variation
3. Surface pH
4. Content uniformity
5. Folding endurance
6. Mechanical strength
7. Tensile strength
8. Ex vivo bioadhesion strength
9. Swelling index
10. In vitro drug release
11. Eye irritancy tests
12. Sterility testing

Thickness of insert 72

 Measured by using a gauge like vernier caliper or a dial caliper at 5

different places on the same film and average is determined

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Weight variation test 73

Cut 5 sections
The deviation of
from the same
individual
patch from
Weigh them Weigh them weights from
different places
together individually the average
or get 5
should be less
separate films of
than 5%
the same batch

Surface pH 74

Prepare a Measure
solution of the pH on
2% w/v the surface
Prepare an Place an Allow it to
agar in of the
agar plate insert on it swell
simulated swollen
tear fluid insert using
pH 7.4 a pH meter

Simulated tear fluid pH 7.4

Sodium chloride 0.67 g
Sodium bicarbonate 0.2 g
Calcium chloride 0.008 g
Purified water qs to 100 g

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Drug content uniformity 75

Take 5 individual inserts

Ground them and disperse them in a

suitable solvent

Allow the drug to solubilize

Filter the solution

Analyse spectrophotometrically

Folding endurance 76

 The folding endurance is determined by folding the film repeatedly

at 180° angle of the plane at the same place until it breaks
 The film exhibiting folding endurance value of 300 or more is
considered to have excellent flexibility

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Mechanical strength 77

Films are attached by screws between two plates

with a cylindrical hole of required diameter

The plate is stabilized to avoid movements using

pins, which are placed centrally beneath the
punch

The measurement starts after the probe is in

contact with the sample surface (triggering force)

The movement of probe occurs at constant fixed

speed until the film detaches

The applied force and displacement (penetration

depth) should be recorded along with the room
temperature and relative humidity

Tensile strength 78

Measurement of elongation is generally done to predict the

ductility of polymers

The percent elongation indicates the stretch ability of

material without being broken, whereas elongation at break
means the point until which the film can be stretched when
it is torn (or broken) by the applied probe Measured using a
texture analyser

With the exertion of stress to a sample, strain generates, and

the sample elongations will become more predominant as
the amount of stress applied increases

After reaching a certain point, the sample breaks; this point

of breakage is referred to as percent elongation break

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Ex vivo bioadhesion strength 79

 Measured using a modified balance

Swelling index 80

 The piece of films is weighed (W1) and it is subjected to immersion in

simulated physiological fluid for a predetermined time.
 After the predetermined time, the sample is taken out, wiped off to
remove excessive water on the surface and weighed (W2).
 The calculation is done by using the following formula, which is
expressed in %

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In vitro drug release 81

 Can be done using Franz diffusion cell or using USP dissolution

apparatus V (Paddle over disc), VI (Rotating cylinder), or VII
(Reciprocating holder)

Eye irritancy test 82

 Carried out on 12 adult albino rabbits weighing ab0ut 2.5-3.5 kg of

either sex
 They are maintained under 12h light and dark cycle
 Fed green vegetables and water
 Ocular inserts are placed in the cul-de-sac of one eye and other
eye serves as control
 Check for redness and excessive lacrymation.

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Sterility testing 83

 Incubate portions of the film in:

(a) Fluid Thioglycollate medium / Alternate Thioglycollate medium at 30°C
to 35°C, and
(b) Soyabean casein digest medium at 20°C to 25°C
 For not less than seven days
 No growth of microorganisms should occur

84

Mucoadhesive drug delivery

systems

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Mucoadhesive in ocular drug 85

delivery
 The capacity of polymer to adhere to mucin coat forms the basis of
mucoadhesion.
 These system significantly prolong the drug residence time since
clearance is controlled by rate of mucus turn over.
 Mucoadhesive polymers are usually macromolecular hydrocolloids
which establishes electrostatic, hydrophobic interaction & hydrogen
bonding with the underlying surface.
 It should exhibit a near zero contact angle to allow maximum
contact with the mucin.

 Mucin covers the external surface of the

globe of the eye 86
 Secreted by goblet cells of conjunctiva
 It forms the part of precorneal tear film that
continuously bathes the cornea and Air
conjunctiva
 The tear film consists of 3 main components:
 Lipid portion secreted by mebimain glands Superficial lipid layer
 Mucin secreted by goblet cells
 Aqueous portion (salt solution) secreted by
lachrymal glands Aqueous layer

Adsorbed mucin layer

Corneal epithelium

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Mechanism of mucoadhesion 87

• The polymer undergoes swelling in

water,
• Entanglement of the polymer
chains with mucin on the epithelial
surface.
• The un-ionized carboxylic acid
residues on the polymer form
hydrogen bonds with the mucin.
• The water-swellable yet water-
insoluble systems are preferred

Ocular Mucoadhesive polymers 88

Hydroxy Propyl Cellulose

Non-ionics

Chitosan, Dextran
Polycationics

Polyacrylic acid derivatives

Polyanionics
(carbopols, polycarbophils &
CMC)

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89

Particulates as drug delivery

carriers

Liposomes 90

 Biodegradable, Non-toxic in nature.

 Vesicle composed of lipid membrane enclosed in an aqueous volume.
 Formed when matrix of phospholipids is agitated in aqueous medium to
disperse two phase.
 Polar drugs are incorporated in aqueous compartment while lipophilic drugs
are intercalated into the liposome membrane
 Phospholipids used are : Phophotidylcholine, Phophotidic acid,
Sphingomyline, Phosphotidyleserine, Cardiolipine

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91
•Can be used for both hydrophilic
and hydrophobic drug.
Advantages •The size, charge and other
characteristics can be altered
according to the drug

•Instability issues.
Disadvantages
•Cost

Degradation and Drug Release Of Liposomes 92

1. Endocytosis

2. Fusion

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Niosomes 93

 Limitations of liposomes
 Chemical instability - Oxidative degradation of phospholipids
 Cost
 Purity of natural phospholipids
 Niosomes have been developed as they are chemically
stable compared to liposomes and can entrap both
hydrophilic and hydrophobic drugs.
 They are nontoxic and do not require special handling
techniques

Nanoparticles 94

 For water insoluble drugs.

 Size:10-1000nm
 Drug is Dispersed, Encapsulated, or Adsorbed
 Produced by polymerization, high pressure or high shear
homogenization, probe sonication, etc.
 Polymer used are biodegradable.
 E.g. :- Nanoparticle of Pilocarpine enhances Mitotic
response by 20-23%.

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95

Penetration enhancers

Ocular penetration enhancer 96

 Typically classical penetration enhancers have a nonspecific action on

biological membranes.
 They work by reversibly or permanently damaging membranes; therefore,
their safety is questionable.
 Newer penetration enhancers that have been introduced in ocular drug
delivery recently with the aim of solving these problems are cyclodextrins,
1-Dodecylazacycloheptan-2-one, Saponin, α-aminoacid, PZ-peptide, etc.
 It is not possible to increase bioavailability indefinitely by use of penetration
enhancement alone.
 Other approaches such as increased residence time and inhibition of
metabolizing enzymes should be used in conjunction with penetration
enhancement

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97

Phase transition systems

PHASE TRANSITION SYSTEM 98

 These system when instilled into the cul-de-sec shift from liquid form
to gel or solid phase.
POLYMERS MECHANISM

Lutrol FC – 127 and Viscosity increased when their

Poloxamer 407 temperature raised to eye
temperature.

Cellulose acetate Coagulates when its native pH 4.5

phthalate latex raised by tear fluid to pH 7.4

Gelrite Forms clear gel in the presence of

cations

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99
 These systems are prepared from polymers that exhibit
reversible liquid-gel phase transition.
 They are instilled as drops into the eye and undergo a
sol‐gel transition in the cul-de-sac.
 This system shows various advantages like:
1. Improved Patient Compliance
2. Reduce Dose Frequency
3. Increase Bioavailability
4. Sustain And Controlled Delivery

100
Three methods have been employed to cause phase transition on
the surface: change in temperature, pH, and electrolyte
composition.

In-situ hydrogels provide such ‘sensor’ properties and can undergo

reversible sol-gel phase transitions upon changes in the
environmental condition.

Ideally, an in-situ gelling system should be a low viscous, free flowing

liquid to allow for reproducible administration to the eye as drops,
and the gel formed following phase transition should be strong
enough to with stand the shear forces in the cul-de-sac and
demonstrated long residence times in the eye.

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101

 Classification of in situ gelling systems along with polymers used:

Sr. no. Stimuli Polymers

1 Temperature Chitosan, Pluronics, HPMC

2 pH Carbopol, Cellulose
acetate phthalate, PEG
3 Ion activated Alginate, gellan, gelrite,
hyaluronic acid

Thermo-reversible hydrogels 102

Gelling of solution is triggered by change in temperature.

SR can be providing by the use of temperature sensitive polymers that change

from solution to gel at the temperature of the eye i.e. 37ºC.

These preparations are liquid at room temperature (20ºC-25ºC) and become

gel at body temperature (35ºC-37ºC) due to change in temperature.

These temperature sensitive gels are classified into three types i.e., negative
temperature sensitive, positively thermo sensitive and thermally reversible gels.

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103

104
Negative temperature-sensitive hydrogels have a lower
critical solution temperature (LCST) and contract upon
heating above the LCST eg. Copolymers of (N-
isopropylacrylamide).
A positive temperature-sensitive hydrogel has an upper
critical solution temperature (UCST), such hydrogel
contracts upon cooling below the UCST eg. Polyacrylic
acid and polyacrylamide.
Common polymers used are poloxamers, cellulose
derivatives like HPMC and MC, Chitosan, Xyloglucan etc

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pH sensitive hydrogels 105

Gelling of the solution is triggered by a change in the pH.

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.

106
Mechanism of gelling: All the pH-sensitive polymers
contain pendant acidic or basic groups that
either accept or release protons in response to
changes in environmental pH.
The polymers with a large number of ionizable
groups are known as polyelectrolytes.

Swelling of hydrogel increases as the external pH

increases in the case of weakly acidic (anionic)
groups, but decreases if polymer contains weakly
basic (cationic) groups

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107

Common polymers used are CAP and carbomer

(Carbopol)

Ion-sensitive hydrogels 108

Gelling of solution is triggered by cations present in the

present in the eye tear fluid like Na+, Ca++ and Mg++.

Generally anionic polymers are used in the formation of ion

sensitive drug delivery system.

This system based on the mechanism of ionic interaction of

ions of polymer and divalent ions of tear fluid.

When anionic polymers come in contact with cationic ions

they convert into gel viscosity of solution increases to an
extent.

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109

Common polymers used are alginates,

gelrite, gellan etc.

Drug release from these hydrogels 110

is controlled by:
• Enhanced drug diffusion due
Swelling to polymer swelling

• Drug diffuses from non-

Diffusion degraded polymer

Chemical • Drug release due to polymer

control degradation and erosion

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Evaluation of in-situ gelling systems 111

Consistency and firmness of gel by texture analyser

Clarity and pH

Gelling capacity – Time of forming gel by 2 ml of simulated tear fluid

Drug content

Rheology – By Brookfield or cone and plate viscometers

In vitro diffusion – by Franz diffusion cells

Isotonicity – Formulations are mixed with few drops of blood and observed under
microscope at 45X magnification
Ocular irritancy test – Draize test on rabbits

112

Ocular iontophoresis

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Ocular iontophoresis 113

To overcome the inherent shortcomings of available ophthalmic treatments such

as low ocular bioavailability, limited depth of drug penetration, high dosing
frequency, and injection-related complications, researchers have investigated a
wide variety of drug delivery approaches over the application for vitreal drug
delivery was reported.
David Maurice played a pivotal role in advancing the use of iontophoresis to
enhance ocular drug delivery but techniques for ophthalmic iontophoresis have
taken decades to evolve.

Although scientists, engineers, and ophthalmologists have experimented with a

broad variety of ocular iontophoresis devices and drugs, no product has been
approved, nor have there been data published from carefully controlled clinical
trials addressing the efficacy and safety of this delivery method.

114
The process of iontophoresis involves applying an electrical
current to an ionizable substance to increase its mobility across a
surface, a concept which dates back to the 18th century
It is based on physical principles of electroosmosis (opposites
attract) and electrorepulsion (likes repel)

It employs low voltage (10V or less) to supply a continuous direct

current of 0.5 mA/cm2

It increases transport of ionizable substances through ocular tissue

by application of external electric current

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Laws of physics 115

Ohm’s law •V = IR
Coulomb’s
law •Q = IT
Faraday’s
law •D = IT/ZF

Iontophoretic devices 116

 Basic components:
1. A power source – battery or on-line unit with voltage
regulator
2. A miliampere meter to measure current
3. Rheostat – controls the amount of current flowing
through the system
4. 2 electrodes
 Mostly platinum – releases almost no ions, undergoes
degradation at slow rate and is non-toxic

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117

Circuit 118

Ground electrode
Eye cup (diameter No direct contact connected to
≈ 1cm) with eye surface other end of
power supply

Placed over Submerged in

Attached to ear
cornea solution

Via wet gauze

Metal electrode
Filled with drug (0.9% saline) to
connected to DC
solution get good
power supply
connection

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Drug 119

Drug solution should have minimum extraneous ions

Drugs with pKa values < 6 or > 8 are excellent candidates because they will
ionise at physiological eye pH

Salt form is preferred it can dissociate

In the rabbit iontophoresis of dexamathasone phosphate, its 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

Eyegate Pharmaceutical, Inc. 120

(Waltham, MA, U.S.) has begun to
enroll for a pivotal Phase III study
of EGP-437 for the treatment of
dry eye syndrome
EGP-437 is a DEX phosphate for
delivery using the EyeGate II®
Delivery System.

The EyeGate II® Delivery System

has been studied in many subjects
and completed Phase II studies for
the treatment of dry eye and
anterior uveitis

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Limitations 121

 Iontophoresis is limited to:

1. Drugs of a small size
2. Drugs having an ionic nature
3. Drugs with low molecular weight
4. Small burns over areas where the current was applied
were, not unsurprisingly, commonly described

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