OCULAR DRUG DELIVERY

PRESENTED BYTARUN POKHARIYAL

M.PHARM. (PHARMACEUTICS)
JAIPUR NATIONAL UNIVERSITY
(JAIPUR)
1

CONTENTS

o IN TRO D U CTIO N
o EYE:AN ATO M Y & PH YSIO LO G Y
o ABSO RPTIO N O F D RU G IN EYE
o PH ARM ACO KIN ETIC
o CO N TRO LLED O CU LAR D RU G SYSTEM S
o O CU LAR D RU G D ELIVERY D EVICES
o O TH ER D ELIVERY D EVICES
o RETRO M ETABO LIC D RU G D ESIG N
o EVALU ATIO N
o AD VAN CED D ELIVERY SYSTEM
o FU TU RE TREN D S
o CO N CLU SIO N
o REFEREN CES

INTRODUCTION

Drug administration through eyes is just

for effect in eyes

To reduce the systemic absorption of
drug is primary goal
The normal volume of tears = 7 ul
the blinking eye can accommodate a
volume of up to 30 ul without spillage
the drop volume = 50 ul

ADVANTAGES1. Accurate dosing.

2. Absence of
preservative
3. Increase in shelf life
due to absence of
water.
4.Best of drug with
slow dissolution
eg.suspension
5.Flexibilty in drug
choice
7.Rapid action
8. Self medication is
easy
9.Decrease side effects
to other organs

disadvantages
1. Perceived by
patient as foreign
body.
2. Movement around
the eye.
3. Occasional loss
during sleep or while
rubbing eyes.
4. Interference with
vision.
5. Difficulty in
placement &
removal.
6.Patient non
compliance
7. Blurred vision
8. Irritation in eyes
9.Not suitable for
running people
4

EYE :A N ATO M Y A N D PH YSIO LO G Y

Diameter 23mm

1. Sclera,
2. Choroids,
3. Cornea,

Outer-Epithelium(lipophilic),
Middle-Stroma(hydrophilic),
Inner-Endothelium(lipophilic).

4. Cilliary BodySecretion of aq.

humor,
5. Lens,
6. Retina,
7. Conjuctiva,
8. Vitreous
Compartment,
9. Lacrimal
gland.

The sclera: The protective outer layer of the

eye
The cornea: The front portion of the sclera.
transparent and allows light to enter the eye.
Diameter-11.7mm and thickness -0.5-0.7mm
The choroid the second layer.
lies between the sclera and the retina.
contains the blood vessels & provide
nourishment to the outer layers of the
retina.
The iris gives it color.
consists of muscular tissue that
responds to surrounding light,
6

 The

lens transparent, biconvex

structure, function-refract and focus
incoming light onto the retina.

The retina is innermost layer in the

eye. converts images into electrical

impulses that are sent along the
optic nerve to the brain where the
images are interpreted.

The macula located in the back of

the eye, in the center of the retina.

This area produces the sharpest
vision.
7

The inside of the eyeball is divided by

the lens into two fluid-filled sections.
The larger section at the back of the

eye is filled with a colorless gelatinous

mass called the vitreous humor.

The

smaller section in the front

contains a clear, water-like material
called aqueous humor.

The

conjunctiva
is
a
mucous
membrane that begins at the edge of
the cornea and lines the inside surface
of the eyelids and sclera,
serves to lubricate the eye.
8

OPTHALMIC DISORDERS

COJUCNCTIVITIS- inflammation of

conjuctiva
DRY EYE SYNDROME-inadequate wetting
of ocular surface
GLAUCOMA IRITIS-pain and inflammation
ROSACEA
BLEPHARITIS-inflammation of lid margin
CHALAZIA-meibomian cysts of eylid
KERATITIS
9

ABSORPTION OF DRUG IN EYE

10

NonCorneal
Absorptio
n

Corneal
Absorptio
n

Penetration across Sclera & Conjuctiva into Intra Ocular tissues

Non-Productive: because penetrated drug is absorbed by general circulation

Outer Epithelium: rate limiting barrier, with

pore size 60,Only access to small ionic &
lipohilic molecules
Trans cellular transport: transport between
corneal epithelium & stroma.

11

OCULAR

ABSORPTION

Corneal
Absorption
Depend upon physicochemical
properties of drug

Only access to small ionic & lipophilic molecules

Non-Corneal
Absorption
Penetration across Sclera & Conjunctiva into
Intra Ocular tissues

Non-Productive: because penetrated drug is

absorbed by general circulation.

Outer Epithelium: rate limiting

barrier

Minor pathway

Trans
cellular
transport:
transport between corneal
epithelium & stroma

Important

e.g. pilocarpine

e.g. inulin

for

drug

with

low

corneal

permeability

12

FATE OF OPHTHALMIC DRUG DELIVERY

SYSTEMS

13

DRUG ELIMINATION FROM LACRIMAL FLUID

14

STRUCTURE OF THE TEAR FILM IN

THE HUMAN EYE

15

Also
responsibl
e for
serious
side
effects

THE NASOLACHRYMAL DRAINAGE

SYSTEM
16

TRANSCORNEAL PENETRATION

EFFECTED MAINLY BY:1.CORNEAL BARRIER

2. PROPERTIES OF DRUG

Transcellular
pathway
Paracellular
pathway

SECTION THROUGH THE CORNEA.

17

Small molecules eg
glycerol
m.w.92 are able to
penetrate

Contain very
hydrophilic
Tissue, mol.size of
500 microm
Can diffuse in stroma

Schematic of corneal structure and its cellular

organization of various transport-limiting 18

Physiochemical properties of drug: Hydrophilic drugs penetrate through

paracellular pathway
Lipophilic drugs penetrate through
transcellular pathway
Drugs topically applied passive
diffusion
Transport of lysine NA-K-ATPase
pump involved- carrier mediated
transport.
Drug loaded nanoparticles- endocytic
pathway.
19

 Lipophilicity
Solubility
Molecular size & shape
Charge
Degree of ionization

Chemical equilibrium between ionized

and unionized in eye drop and in
lacrimal fluid effect the penetration
of ionizable drug.
Eg -pilocarpine (free base ) and timolol
base penetrate better than its
ionized form.

20

NON CORNEAL ABSORPTION

CONJUCTIVA ABSORPTION- for hydrophilic

& mol. Size of 20000-40000 eg. insulin

SCLERA through perivascular space
through aq. Media of gel
more permeable than
cornea
mol.weight 229-1056 eg.
Sucrose,inulin
RETINA
BLOOD RETINAL BARRIER
21

CONJUNCTIVAL ABSORPTION
22

BLOOD RETINAL BARRIER

23

PHARMACOKINETICS OF O.D. ADMINISTRATION

24

TEAR
FLUID

PRECORNEA
L
DRUG
POOL

NASOLACRIM
AL DRAINAGE
SYSTEM

EPITHELIA
L SAC

CORNEAL
EPITHELIU
M

STROMA
EPITHELIA
L

METABOLIS
M
CONJUCTIVA
AQUEOU
S
HUMOR
ELIMINATION
25

26

27

28

29

CONTROLLED DRUG DELIVERY

REQUISITES OF CDDS
a. To overcome the side effects of pulse dosing
b. Provide sustained and controlled drug delivery
c. To increase ocular bioavailability
d. To provide targeting within the ocular globe
e. To circumvent the protective barriers
f. Patient compliance
g. Improved therapeutic effect

30

APPROACHES

TO PROLONG THE CONTACT TIME OF DRUG

WITH CORNEAL SURFACE

ENHANCE CORNEAL PERMEABILITY

31

WAYS TO GET THE AIM..

POLYMERIC SOLUTION
PHASE TRANSITION SYSTEM
MUCOADHESIVE/ BIOADHESIVE

SYSTEM
COLLAGEN SHIELDS
PSEUDOLATICES
OCULAR PENETRATION ENHANCER
OCULAR IONTOPHORESIS
OCULAR DD DEVICES
32

POLYMERIC SOLUTION:- eg. Methyl cellulose,

PVA,HPC,PVP.
Increase the corneal penetration.
PHASE TRANSITION SYSTEMS:-liquid dosage
form eg. Lutrol FC-127
poloxamer 407,
gallen gum : forms in gel in presence of sod.
ions
2.6 gm/L sodium ions ions in tears
cellulose acetate pthalate coagulates when
pH increased 4.5 to 7.4

33

USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY

Mucoadhesives adhered to cornea

Types1. Naturally Occurring Mucoadhesives- Lectins,

Fibronectins
2. Synthetic
Mucoadhesives-PVA,Carbopol,
carboxy
methyl
cellulose,
cross-linked
polyacrylic acid
. Drugs incarporated in to this are pilocarpine,

lidocaine, benzocaine and prednisolone acetate.

34

MUCOADHESIVE / BIOADHESIVE DOSAGE

FORM:Polymer adhere to the mucin
These may be polymeric solution or
microparticle suspension

Muco polymers mainly macromolecular

hydrocoloids with hydrophilic groups
eg.carboxyl,hydroxyl,amide
35

Mechanism of mucoadhesion
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 waterinsoluble systems are preferred

36

D egree of m ucoadhesive of polym ers

polymer

origin

charge

Solubility in

Poly acrylic acid

Natural

Anionic

Insoluble

Excellent

Carbomer

Synthetic

Anionic

Insoluble

+++

Hyaluronans

Natural

Anionic

Soluble

+++

Chitosan

Natural

Cationic

Soluble

good

Sodium CMC

Natural

anionic

Soluble

++(+)

Poly (galacturronic)

Natural

Anionic

Insoluble

++

Sodium alginate

Natural

anionic

Soluble

++(+)

Methyl cellulose

Natural

nonionic

Soluble

Pectin

Natural

anionic

Soluble

++(+)

PVA

Synthetic

Nonionic

Soluble

PVP

Synthetic

Nonionic

Soluble

PEG

Synthetic

Nonionic

Insoluble

+(+)

HPMC

Natural

Nonionic

Soluble

Poloxamer

Synthetic

Nonionic

Soluble

+(+)

Xyloglucan

Natural

anionic

Soluble

Xanthan gum

natural

nonionic

Insoluble

poor

Water

Mucoadhesiv capacity

acid

37

Factors: Dissolution of polymer

Chain flexibility
mol. Weight
pH and ionic strength
COLLAGEN SHIELDS:It is main constituent of food grade gelatin
Comprise 25% of total body protein in
mammels
Drug delivery by collagen shield
38

The corneal collagen shield

A disposable, short-term therapeutic bandage lens for the

cornea.
It conforms to the shape of the eye, protects the corneal
surface, and provides lubrication as it dissolves.
The shields are derived from bovine collagen and are 14.5
mm in diameter.
Sterilized by gamma irradiation.
Disadvantages
1. It is not optically clear.
2. The collagen shield causes some discomfort.
Clinical uses
3. Wound healing.
4. Treatment of dry eye.

39

PSEUDOLATICES :-polymeric colloidal

dispersion and film forming agent
OCULAR PENETRATION ENHANCER :-topical
applied peptide and protiens.
Eg. Actin filament inhibitor
surfactants
bile salt
chelators
organic compounds

OCULAR IONTOPHORESIS:40

NANOPARTICULATE DRUG DELIVERY

Size:10-1000nm

Types- 1.nanospheres , 2.nanocapsules

Drug is Dispersed, Encapsulated, or Adsorbed

Particulate systems in nanoparticulate drug deliery- 1,Topical system e.g.

chloramphenicol (suspended), 2.local injectable system e.g. 5FU

Polymer used are Biodegradable.

41
e.g. polyalkylacrylates

Advantages of nanoparticles
Sustained drug release and prolonged therapeutic

activity
Site-specific targeting
Higher cellular permeability
Protect the drug from chemical or enzymatic
hydrolysis
Efficient in crossing membrane barriers -blood retinal
barrier
Act as an inert carrier for ophthalmic drugs

42

Preparation of Nanoparticles

Solvent evaporation method

43

OCULAR DRUG DELIVERY DEVICES

MATRIX
TYPE DRU
G
DELIVERY
SYSTEM

Hydroph
ilic
soft contact
lenses
Soluble
ocular inser
s
Scleral
buckling
materials

CAPSULAR
TYPE DRUG
DELIVERY
SYSTEM
Ocuserts

IMPLANTABLE
DRUG
DELIVERY
PUMPS
Osmotic
minipumps
Implantable
infusion
systems

44

HYDROPHILIC SOFT CONTACT LANSES

Bionite was developed in griffin lab.
Soflens was developed by Bausch &Lomb.

contact lanses made from hefilcon-A

Copolymer(80% 2-hydroxy ethyl methacry
-late and 20% N-vinyl-2-pyrollidone)
16 mm in diameter
0.3 mm thick
45

OCULAR INSERTS

Classification of
ocular inserts
Insoluble
inserts
Diffusion
based(Ocuser
t)
Osmotic based

Soft(presoaked) contact
lenses

Bioerodible
inserts
e.g. Lacrisert,
Minidisc.

Soluble inserts
e.g. SODI,
BioCor-12,24,72.
46

Desired criteria for ocular inserts

* Ease of handling and insertion

* Lack of expulsion during wear
* Reproducibility of release kinetics
*
*
*
*

(Zero-order drug delivery)

Applicability to variety of drugs
Non-interference with vision and
oxygen permeability.
Sterility.
Ease of manufacture
47

48

A) Insoluble inserts-

Diffusional Inserts :
Central reservoir of drug
enclosed in Semi permeable or
microporous
membrane for
diffusion of drug.
Diffusion is controlled by
Lacrimal
Fluid
penetrating
through it.
Release follows : Zero Order
Kinetics.

e.g. Ocusert:

20-40g/hr for 7day

Annular ring : Impregnated with Ti0

2 : For Visibility
49

SOLUBLE OCULAR INSERTS:Eg. Poly vinyl alcohol inserts

Soluble opthalmic drug insert
Polypeptide devices
SODI thin elastic oval plate Made from
polymer and
Copolymer of polyacrylamide ,
ethylacrylate and vinylpyrollidone
MOA:-
Advantages of SODI
Single SODI application : replaces 4-12 eye drops Instillation, or
3-6 application of Ointments.
50
Once a day treatment of Glaucoma.

C) Biodegradable inserts

1.Lacrisert:
Sterile, Rod Shaped device.
Composition: HPC.
Weight:5mg,
Dimension:Diameter:12.5mm, Length:3.5mm
Use:-Dry eye treatment.

2.Minidisc:
It is made up of counter disc with Convex front & Concave back surface in contact

with eye ball.

4-5mm in diameter.
Composition : Silicon based polymer.
Drug release upto170 hr.

51

LIPOSOMES

Vesicle composed of phospholipid bilayer

enclosing aqueous compartment in alternate
fashion.
Biodegradable, Non-toxic in nature.
Types :1.MLV

2.ULV-SUV(upto 100 nm)

LUV(more than 100 nm)

Polar drugs are incorporated in aqeous
compartment
while
lipophilic
drugs
are
intercalated into the liposome membrane
Phospholipids
usedPhophotidylcholine,
52
Phophotidic
acid,
Sphingomyline,

ADVANTAGES
Drugs delivered intact to
various body tissues.
Liposomes can be used for
both hydrophilic and
hydrophobic drug.
Possibility of targeting and
decrease drug toxicity.
The size, charge and other
characteristics can be altered
according to drug and desired
tissue.

DISADVANTAGES OF
LIPOSOMES
.
They need many modification for
drug delivery to special organs.
Cost .

53

Preparation Of Liposomes

Reverse phase evaporation method

54

Degradation and Drug Release Of Liposomes

1. Endocytosis

2. Fusion

55

SCLAREL BUCKLING MATERIALS:Eg. Gelatin film & solid silicon rubber

impregnated with antibiotic
OCUSERT AND RELATED DEVICES:A true controlled and continuous release
and zero order kinetic fashion achieved
by ocusert
First marketed by ALZA corporation
pilocarpine ocusert improved the
noncompliance problem

56

Two types of ocuserts

Ocusert pilo- 20 20 g/h for 7 days
Ocusert pilo- 40- 40 g/h for 7 days
IMPLANTABLE SILICON RUBBER
DEVICES:For hydrophobic drugs

BCNU(1,3-bis(2-chloroethyl)-1-nitrosourea)
consist two sheets of silicon rubber
(0.13mm thick)
57

OSMOTIC MINIPUMP
Generic osmotic minipump(ALZET) is a
useful implantable system.
Pumping duration 2 weeks
IMPLANTABLE INFUSION SYSTEM
Infusaid - device permit long term
infusion via refilling in animals
Pumping force generated by an
expending fluid
(Flurocarbon at liq. Gas equilibrium) at
body temp.
58

Registered

Active

name

substances

vitrasert

Ganciclovir

Millimeter

Clinical use

retisert

Flucinolone

Tablet 3mmx 2mmx

Clinical use

acetonide

5mm

Flucinolone

Cylindrical tube 3.5

acetonide

mm in length and

Medidur

Implant size

Marketing
status

Phase 3

0.37 mm in diameter
Posurdex

Dexamethasone

Microsized implant

Phase 3

Ozurdex

Dexamethasone

intravitreal implant)

Clinical use

0.7 mg

59

OTHER DELIVERY SYSTEMS

Ocufit currently developed. Made by

silicone elastomer.
Diameter-1.9 mm & length is 25-30 mm
Lacrisert- made up of cellulose

used to treat dry eye patients.

Minidisc ocular therapeutic system
New opthalmic delivery system
60

RETROMETABOLIC DRUG DESIGN

METABOLISM

CDS1

CDSn
M1
METABOLISM

M2

CDS

Mn
RETROMETABOLIC DESIGN

I1
I2
METABOLISM

Mi

SD
RETROMETABOLIC DRUG DESIGN

61

EVALUATION

1. Gelling capacity
2. Rheological properties
3. In vitro drug release
4. Texture analysis
5. Isotonicity evaluation
6. Drug polymer interaction study
7. Thermal analysis
8. Antibacterial activity
9. Occular irritancy test
10.Accelereted stability study
62

11. Thickness of ocular film

12.Drug content uniformity
13.Uniformity of weight
14.% moisture content
15. % moisture loss
16. Sterility testing
17.Growth promotion test

63

ADVANCED DELIVERY SYSTEM

1. Cell encapsulation
2. Gene therepy
3. Stem cell therepy
4. Protein ad peptide therepy
5. Sclaral plug therepy
6. Si RNA therepy
7. Oligonucleotide therepy
8. Aptamer
9. Ribozyme therepy

64

FUTURE TRENDS

The sustained and controlled release technologies

are being proposed and the possible benefits of
using liposomes, nanoparticles and inserts will be
at store in future.
Targeted drug delivery with modifications of
conventional, advanced and novel ocular drug
deliveries has potential as future drug delivery for
eye.
It is possible to the give effective ocular drug
delivery to any part of the eye.
65

Currentand future drugs in clinicaltrials foranteriorDDSs.

Active ingredient

Brand name

Dosage form

Release-controlling excipient

Target Indication

Developmental stage

Azithromycin

AzaSite

Eye-drops

Polycarbophil

Bacterial conjunctivitis

Launched

Bromfenac

-------

Eye-drops

Polycarbophil

Post cataract surgery

P1/2

Timolol maleate

Rysmon TG

Eye-drops

Methylcellulose

Glaucoma

Launched

Betaxolol

Betoptic S

Eye-drops

Amberlite IRP-69

Glaucoma

Launched

Tobramycin/Dexamethasone

TobraDex ST

Eye-drops

Xanthan gum

Blepharitis

Launched

Ketotifen

--------

Soft contact lens

----------

Allergic conjunctivitis

P3

(ISV-303)

Latanoprost

Puctal plug
--------

Bimatoprost

Glaucoma

P2

------

Puctal plug

--------

Glaucoma

P2

Iontophoresis

-------

Dry eye

P3

Anterior uveitis

P2

--------

Dexamethasone phosphate
(EGP-437)

EyeGate II

66

Currentand future drugs in clinicaltrials forposteriorDDSs.

Active ingredient

Brand name

Dosage form

Release-controlling excipient

Target Indication

Developmental stage

Ganciclovir

Vitrasert

IVT, implant

EVA/PVA

CMV retinitis

Launched

Fluocinolone acetonide

Retisert

IVT, implant

Silicone/PVA

Posterior uveitis

Launched

Fluocinolone acetonide

Iluvien

IVT, implant

Polyimide/PVA

DME

P3

Wet AMD

P2

Dexamethasone

Ozurdex

IVT, implant

poly(lactide-co-glycolide),

Posterior uveitis

Launched

Triamcinolone acetonide

I-vation TA

IVT, implant

PMMA/EVA

diabetic macular edema,

P2

Visudyne

IV, injection

Liposome

Wet AMD

Launched

Difluprednate

Durezol

Eye-drops

Emulsion

DME

Off-label

Triamcinolone acetonide

------

IVT, injection

Oil

branch retinal vein occlusion,

P1

Verteporfin

(IBI-20089)

67

CONCLUSION

Very few advanced ocular drug delivery

systems have been commercialized.

The performance of these new products,

however, is still far from being perfect.

More clinical studies are necessary to provide

further information and insights into these

advanced ocular drug delivery systems.
68

REFERENCES
1.

Targeted and controlled drug delivery system by Vyas

S.P. and Khar K. R.,
published by CBS Publishers and
distributors, first edition 2002

2.

http://www.jgtps.com journal of global trend in

pharmaceutical sciences Patel vishal & Y.K. Agrawal current
status and advanced approaches in ocular drug delivery
system

3.

Kumari A, Sharma PK and Garg VK: Ocular inserts

Advancement in
therapy of eye diseases. Journal Advance
Pharmaceutical Technology Research 2010; 3: 87-96.

4.

Rathore K.S. review on in situ gelling ophthalmic drug

delivery system International
journal of
pharmacy and
pharmaceutical sciences

5.

V. Shankar , A.K. Chandrasekharan , S. durga. design and

evaluation of diclofenac sodium ophthalmic inserts. Acta

69

THANK YOU

The eyes are the mirror of the

soul
Take care of your eyes
with gentleness.
70