The document discusses ocular drug delivery systems (ODDS). It begins with an introduction to ODDS and describes the anatomy and physiology of the eye. It then discusses common eye diseases, factors affecting ocular drug absorption, and barriers to intraocular drug delivery. Methods to overcome these barriers through novel ocular formulations are presented, including ocular inserts, which can enhance drug residence time and bioavailability. Examples of both non-erodible and erodible ocular insert systems are provided. The document concludes with a discussion of how novel formulations can improve ocular drug delivery.

1. 1
OCULAR DRUG
DELIVERY SYSTEM
Submitted By :
Jeevitha K B
M Pharm 1st Sem
Pharmaceutics Dept.
Mallige College of Pharmacy
Submitted To :
Mrs Sheeba F R
Department of Pharmaceutics
Mallige College of Pharmacy

2. Introduction to ODDS
Anatomy and Physiology of Eye
Diseases of Eye
Factors affecting Ocular absorption of drugs
Intra Ocular Barriers
Methods to overcome barriers- Novel Ocular Formulations
Evaluation of ODDS
References
CONTENTS
2

3. Ocular administration of drug is primarily associated with the
need to treat ophthalmic diseases.
• Eg.Glaucoma,Conjunctivitis, etc
Eye is the most easily accessible site for topical
administration of a medication.
Ideal ophthalmic drug delivery must be able to sustain the
drug release and to remain in the vicinity of front of the eye
for prolong period of time.
The most commonly employed ophthalmic dosage forms are
solutions, suspensions, and ointments.
3
INTRODUCTION TO ODDS

4.  The novel approach of drug delivery system in which drug can instilled on the
cull de sac cavity of eye is known as ocular drug delivery system.
 Ocular administration of drug is primarily associated with need to treat the
ophthalmic diseases.
 It is challenging due to the presence of anatomical and physiological barriers.
 These barriers can affect drug entry into the eye following multiple routes of
administration (e.g.. Topical, systemic, and injectable ).
 Topical administration in the form of eye drops is preferred for treating anterior
segment diseases, as it is convenient and provides local delivery of drugs.(poor
drug absorption and low bioavailability)
 To improve the bioavailability of drug novel drug delivery system are also
preferred.
4
OCULAR DRUG DELIVERY SYSTEM

5. 5
COMPOSITION OF EYE:
Water - 98%, Solid -1.8%, Protein - 0.67%,
sugar - 0.65%, NaCl - 0.66%
Other mineral element
sodium, potassium and
ammonia - 0.79%.

6. 6
ANATOMY OF EYE
HUMAN EYE
 Diameter 23mm
 Structure comprises of
three layers
1.Outer layer :
cornea( clear, transparent)
sclera(white, opaque)
2.Middle layer:
iris (anterior)
choroid (posterior)
ciliary body (intermediate)
3.Inner layer: Retina

7.  SCLERA:
 The protective outer layer of the eye
 White colored fibrous membrane surrounding the eyeball
 It maintain the shape of the eye.
 CORNEA:
 The front of the sclera, is transparent, Circular, Bulgy epithelial membrane and
allow light to enter the eye.
 The cornea providing much of the eye’s focusing power.
 Cornea composed of 5 layers
7
Epithelium
Bowman’s Membrane
Stroma
Descemet’s Membrane
Endothelium

8. The cornea has five main layers of cells:
1. Epithelium: The outer layer of the cells that acts as a barrier
against damage and infection
2. Bowman's membrane: A thin, tough membrane
3. Stroma: Consist of collagen fibers and account for 90% of the
cornea’s thickness
4. Descemet's membrane: A thin membrane of collagen and elastic
fiber
5. Endothelium: A layer very delicate cells that cannot regenerate and
are Responsible for maintaining partial corneal dehydration and
transparency
8

9. 9

10. 10
 LACRIMAL GLANDS:
Secrete tears and wash foreign bodies.
 CHOROID: It is the second layer of the eye and lies between the
sclera and retina. It contains the blood vessels that provide
nourishment to the outer layer of the retina.
 RETINA: It is the inner most layer in the eye. It converts image into
electrical impulses that are sent along the optic nerve to the brain
where the images are interpreted.
 MACULA: It is located in the back of the eye in the center of the
retina. This area produces sharpest vision.

11. Common disease affecting the anterior segment of the eye
• Dry eye syndrome
• Glaucoma
• Allergic conjunctivitis
• Anterior uveitis
• Cataract
Prominent disease affecting the posterior segment of the eye
• Age Related Macular Degeneration (AMD)
• Diabetic retinopathy Macular Edema(DME)
• Proliferative Vitreo Retinopathy (PVR)
• Posterior Uveitis
• Cytomegalovirus(CMV) 11
DISEASES OF EYE

12. FACTORS AFFECTING OCULAR ABSORPTION OF DRUGS
12
1. Lacrimal Fluid
2. Nasolacrimal drainage
3. Molecular size
4. Partition Coefficient
5. Protein Binding
6. Charge
 Lacrimal Fluid
• When the eye drops are instilled in the cul-de-sac, the drug solution gets
diluted with the lacrimal fluid.
• This coupled with continuous tear flow decreases the volume and
concentration of drug reaching the target sites.

13.  Nasolacrimal Drainage
• This drainage system is also responsible for reducing the contact
time of the drug solution with the corneal surface
 Molecular size
• Small size particles like mannitol (mol.wt 182) can easily pass
through an intact cornea when compared to large sized particles
like insulin and dextran
 Partition Coefficient
• Corneal membrane being lipophilic is highly permeable to lipophilic drugs
while hydrophilic drugs experience greater resistance from the epithelium for
penetration. It has been observed that drugs permeate through the epithelium
of the cornea via the following two major pathways,
(a) Movement of drug molecules through transcellular route which is a partition
controlled pathway.
(b) Passage of molecules through the intercellular spaces.
13

14. 14
Protein Binding
• Upon instillation of the drug solution, proteins in the lacrimal fluid
bind with the drug molecules.
• Only free or unbound drug molecules are able to undergo corneal
permeation.
• In the cornea, free drug molecules undergo drug protein interaction
which produces a lag time thus preventing the penetration of drugs
in the anterior chamber.
• Such protein-drug interactions have found to decrease the
pharmacological activity of the drug.
Charge
• Surface of the corneal epithelium is negatively charged and
hence it favours the absorption of positively charged drug
molecules.

15. • After the drug has been topically instilled into the precorneal area of the
eye in the form of the eye drops, it get removed by the following
mechanisms which can act alone or in combination
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INTRA OCULAR BARRIERS

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ANTERIOR
SEGMENT
DEUG DELIVERY
BARRIERS:
CORNEAL
BARRIERS
EPITHELIAL
TIGHT JUNCTION
BARRIERS
NON-CORNEAL
BARRIERS
CONJUCTIVAL
BARRIERS
PRE CORNEAL
BARRIERS
REFLEX BLINKING
TEAR TURN OVER
NASOLACRIMAL DRAINAGE
METABOLISM IN OCULAR
TISSUE
POSTERIOR
SEGMENT
DRUG DELIVERY
BARRIERS
BLOOD
AQUEOUS
BARRIER
BLOOD RETINAL
BARRIERS
BARRIERS

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EPITHELIAL TIGHT JUNCTION BARRIERS
Corneal epithelium is the primary barrier
Stratified corneal epithelium consists of a basal layer of columnar
cells, two or three layers of wing cells and one or two outer layers
of squamous cells.
Superficial cells are surrounded by the intercellular tight junction
(zonula occludens).
There are four tight junction Proteins, zo-1, Cingulin, zo-2 and
Occluden
Corneal Epithelium – Resist absorption of Hydrophilic drugs
Stroma- Barrier to Lipophilic drugs

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 Conjunctival Barriers
 Non-corneal route by passes the cornea and involves movement
across conjunctiva and sclera.
• Drug upon reaching beyond the cornea is absorbed by small
capillaries and is transferred to the systemic circulation.
• This route is important especially for large and hydrophilic
molecules such as peptides, proteins and si RNA (small or short
interfering RNA).E.g. Gentamycin, Timolol maleate etc.,
• The conjunctiva is more permeable than cornea especially for
hydrophilic molecules due to much lower expression of tight
junction proteins relative to corneal epithelium.
Non-corneal Barriers

19. 19
REFLEX BLINKING
• A normal eyedropper delivers 25-56µL of the topical
formulation.(average volume 39µL)
• However, an eye can transiently hold up to 30 µl, and the rest
is lost either by nasolacrimal drainage or reflex blinking (5-7
blinks/ min), significantly decrease the overall drug available
for therapeutic action.
Pre Corneal Barriers

20.  NASOLACRIMAL DRAINAGE
• When medication is instilled into
the cul-de-sac, the constant tear
volume increase, which initiated
rapid reflex blinking.
• To maintain constant tear volume,
most of the drugs flows into
lacrimal drainage system into
nasolacrimal duct with in 5 mins.
20

21. 21
 Such drainage continues until the normal resident tear volume of 7-10 µl is attained.
 Due to this almost 80% of the instilled dose is lost thereby decreasing the contact
time of the drug with the precorneal surface and hence its ocular bioavailability.
 Once the normal resident tear volume is attained, drug concentration in the
precorneal area further decreases rapidly due to absorption by cornea and
conjunctiva and also due to rapid tear turnover.
 It has been found that nasolacrimal drainage is the major route through which the
drug is eliminated almost immediately following ocular administration due to which
only negligible quantity of the drug reaches the desired tissues.
 Other demerit with nasolacrimal drainage is that the drug may get absorbed through
the nasal mucosa, reach the systemic circulation and may precipitate undesirable
adverse effects.

22. 22
 So, the rate of nasolacrimal drainage is directly proportional to the
volume of the instilled drug solution.
 When smaller volumes of ophthalmic drugs were instilled, nasolacrimal
drainage was found to be less thereby increasing the intraocular
bioavailability of the drug.
 Hence it has been proposed that a reduction in the volume of drug
solution instilled by an eye dropper from 50-70 µl to almost 5-10 µl would
significantly increase the ocular bioavailability of the drug.

23. 23
TEAR TURNOVER
• A significant impediment to topical ocular drug delivery is tear
turnover.
• Following topical administration an increase in the volume of cul-de-
sac occurs that leads to reflex blinking and increased tear secretion
eventually resulting in rapid drug loss from the precorneal area.
• Loss of the solution occur due to tear turnover and nasolacrimal
drainage until the tear volume in the conjunctiva cul-de-sac returns
to normal range (7-9 µL)

24. 24
METABOLISM IN OCULAR TISSUES:
• Drug containing aromatic hydrocarbons are metabolized in the
pigmented epithelium and ciliary body to their corresponding
epoxides and phenols, or further metabolized by other enzymes
present in the eye.
• Poor absorption of peptide drugs and insulin is due to the
extensive metabolism during conjunctival permeation in albino
rabbits.

25. 25
Blood aqueous barriers
• The Endothelium of the Iris / Ciliary blood vessels and non
pigmented ciliary epithelium.
• Both the cell layers express tight junction complexes and
prevent the entry of the solutes into the intra ocular
environment.
Blood retinal barriers
• Retinal Capillary endothelial cells (inner)
• Retinal pigment epithelial cells ( outer) restrict the entry of the
therapeutic agents from the blood into posterior segment
POSTERIOR SEGMENT DRUG DELIVERY BARRIERS

26. Conventional ocular drug delivery systems are very
inefficient, so attempts are made to design Novel Ocular
Drug Delivery System which improve the
• Drug-cornea Contact time
• Increase the corneal permeability
• Increased site specificity
26
METHODS TO OVERCOME INTRA OCULAR BARRIERS –
NOVEL OCULAR FORMULATIONS

27. 27
METHODS TO OVERCOME BARRIERS
ALTERNATIVE DRUG DELIVERY ROUTES
NOVEL DRUG DELIVERY SYSTEM

28. 28
ALTERNATIVE DRUG DELIVERY ROUTES
a) INTRAVITREAL INJECTIONS
b) SUB CONJUNCTIVAL INJECTIONS
c) RETROBULBAR ROUTE
d) PERIBULBAR ROUTE
e) INTRACAMERAL ROUTE

29. 29
CONVENTIONAL OCULAR DOSAGE FORMS

30. 30
 ADVANTAGES
Novel ocular drug delivery systems have been developed with an
aim to provide the following advantages.
1. Accurate and constant rate of drug delivery.
2. Provide sustained and controlled delivery of drugs.
3. Increase the intraocular bioavailability by prolonging the
residence time of the drug in the precorneal space.
4. Specifically targets the desired ocular tissues, thus preventing
systemic drug delivery.
5. Overcomes the barriers to efficient delivery like lacrimation,
nasolacrimal drainage, conjunctival uptake etc.
6. Improve patient compliance and therapeutic efficacy of drugs.
NOVEL OCULAR DOSAGE FORMS

31. Ocular inserts are defined as sterile, thin, multi
layered, drug-impregnated, solid or semisolid
consistency devices placed into the cul-de-sac or
conjunctival sac, whose size and shape are especially
designed for ophthalmic application.
This helps in enhancing drug residence time in the
precorneal space and thus increase ocular
bioavailability.
31
OPHTHALMIC INSERTS

32. 32
IDEAL CHARACTERISTICS
An ideal controlled release ophthalmic insert should possess
the following properties.
1. It should not cause any discomfort
2. It should be easy to handle and insert
3. It should not interfere with vision and exchange of oxygen
4. It should exhibit reproducible release kinetics
5. It should offer ease in sterilization
6. It should be stable and easy to manufacture.

33. 33
MERITS
• Accurate dosing
• Prolongs drug contact time  increase ocular bioavailability
• Release drug at constant rate
• No nasolacrimal drainage  no systemic absorption reduction in
undesirable effects
• Reduced frequency of use
• Targeted to internal ocular tissue
• More shelf life
DEMERITS
• Poor patient acceptance as it is difficult to apply
• Device interfere with Vision
• Expensive

34. 34
CLASSIFICATION
1.NON ERODIBLE INSERTS:
A) Ocusert
B) Hydrophilic Contact lens
2. ERODIBLE INSERTS:
A) Lacriserts
B) SODI
C) NODDS
D)Corneal Collagen Shields

35. 35
OCUSERTS
 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.
 The device consists of three layers…
I. Outer layer: ethylene vinyl acetate copolymer layer.
II. Inner layer: pilocarpine gelled with alginate main polymer
III.A retaining ring: of EVA impregnated with titanium di oxide .

36. 36
Merits Demerits
• Controlled Rate Of Drug Delivery
• Difficult In Handing And Insertion
• Expelled From The Eye
• They Must Removed After Dosing
Period

37. 37
HYDROPHILIC CONTACT LENSES
• These are circular shaped structures.
• Dyes may be added during polymerization.
• Drug incorporation depends on whether their structure is hydrophilic
or hydrophobic.
Drug release depends upon :
• Amount of drug
• Soaking time.
• Drug concentration in soaking solution.
 ADVANTAGES:
• No preservation.
• Size and shape
 DISADVANTAGES:
• Handling and cleaning
• Expensive

38. 38
ERODIBLE INSERTS
The solid inserts absorbs the aqueous tear fluid and gradually erode or
disintegrate.
The drug is slowly leached from the hydrophilic matrix.
These do not have to removed at the end of their use from the body
tissues.
They are classifies as four types:
1. Lacriserts
2. SODI ( soluble ocular drug inserts)
3. New Ophthalmic Drug Delivery System (NODDS)
4. Corneal Collagen Shields

39. 39
LACRISERT
Lacrisert is a non-medicated, sterile, rod-shaped erodible
insert which is made from hydroxypropyl cellulose.
It is devoid of any preservative and is useful in the treatment
of dry eye syndrome.
It is placed in the inferior fornix, where it gets hydrated to form
a hydrophilic film, which in turn hydrates the cornea.

40. 40
Soluble Ocular Drug Insert (SODI)
It is a sterile, small, oval-shaped wafer weighing 15-16 mg
which is composed of polyacrylamide
It is inserted in the inferior cul-de-sac, where it undergoes
hydration, softens in 10-15 sec and acquires the shape of
globe of the eye.
The film converts into a viscous polymer mass after 10-15
min and eventually into a polymer solution within the next 30-
60 min.
It enables once-a-day therapy for treating trachoma and
glaucoma.

41. 41
New Ophthalmic Drug Delivery System (NODDS)
It is a sterile, preservative-free system that helps to
deliver a film loaded with water soluble drug to the eye. It is
about 5 cm in length and 6 mm in breadth.
Each NODDS is basically composed of three films, all of
which are made up of polyvinyl alcohol (PVA) but differ in
terms of concentration.
(i) Medicated Flag: It is a circular-shaped film whose 40%
weight is composed of drug.
(ii) Membrane Film: It is a thin, water-soluble film which helps
to attach the medicated flag to the handle film.
(iii) Handle Film: It is a thicker, water soluble film that is
provided with a paper backing for strength.

42. 42
CORNEAL COLLAGEN SHIELDS
 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 with thickness 0.15-0.19 mm.
 Sterilized by gamma irradiation.
 Disadvantages
 1. It is not optically clear.
 2. The collagen shield causes some discomfort.
 Clinical uses
 1. Wound healing.
 2. Treatment of dry eye.

43. Another approach to increase intra ocular bioavailability of
drug was to incorporate suitable penetration enhancers like
preservatives(benzalkonium chloride), bile salts, chelating
agents, surfactants etc.
Usage of benzalkonium chloride and Chlorhexidine gluconate
increased the penetration of fluorescein in a normal eye
 Medicaments containing penetration enhancers cause
endothelial degeneration.
43
PENETRATION ENHANCERS

44.  Bioadhesion is defined as a phenomenon in which two materials, at least one of
which is of biological origin, are held together for prolong period of time by means
of interfacial forces.
 An attachment between an artificial material and a biological surface, which could
be an epithelial tissue, mucous membrane or a tissue surface is known as
adhesive attachment.
 The external surface of the globe of eye is covered by a thin film of glycoprotein
called as mucin.
 This layer is secreted by the goblet cells and it lines the cornea and conjunctiva.
 Thus mucin is a part of the corneal tear film and is capable of absorbing almost
40-80 times its weight of water.
 These mucoadhesive agents bind with the corneal-conjunctival mucin via non-
covalent bonds.
 Cationic and anionic polymers exhibit better mucoadhesive activity than non-
ionic polymers.
44
MUCOADHESIVES

45. 45
GELS
OPHTHALMIC DRUGS
ADVANTAGES DISADVANTAGES
Ease Administration
Inexpensiveness
Increase Drug corneal
surface contact
Long duration of action
Reduced dosing frequency
Blurred Vision
Matted eyelid after use
Reduced patient Compliance

46. 46
NANOPARTICLES
Drug containing nanoparticles upon administration in suspension form accumulate
at the site of administration from which it gets released either via diffusion,
chemical reaction, etc.
This helps in increasing the drug-corneal surface contact and thus
ocular bioavailability.
The first commercial nanoparticle formulation for ocular delivery was Pipolex. It
was composed of pilocarpine-loaded nanoparticles made from
poly(methylmethacrylate acrylic acid) copolymer.
These nanoparticles were found to increase the drug activity.

47. 47
LIPOSOMES
Liposomes are microscopic sealed structures in which the central aqueous
compartment is enclosed by one or more membrane-like phospholipid bilayers
Liposomes are amphiphilic in nature, hence both hydrophilic and lipophilic drugs
can be incorporated in them.
Liposomes were first used to deliver idoxuridine suspension to rabbits to treat
herpes simplex keratitis which exhibited greater therapeutic efficacy than its
aqueous solution.
MERITS
Deliver drug at constant rate
Protect from metabolizing enzyme
Biodegradable and Non toxic
DEMERITS
Have shorter shelf life
Limited loading capacity
Difficulty in Sterilization of
liposomal formulation

48. 48
HYDROPHILIC HEAD
HYDROPHOBIC TAIL
AQUEOUS INTERIOR

49. 49
INTRAVITREAL IMPLANTS
Systemic administration of drug for treatment of chronic intraocular
infection is associated with undesirable adverse effects.
Intravitreal implants or Depot devices release drug at zero order rates
and Prolong rate of drug release and decrease dosing frequency
Examples of commercially available ocular insert is VITRASET used
in treatment of Cytomegalovirus retinitis

50. 50

51. UNIFORMITY OF THICKNESS
UNIFORMITY OF WEIGHT
DRUG CONTENT UNIFORMITY
DETERMINATION OF SURFACE PH
PERCENT MOISTURE ABSORPTION
PERCENT MOISTURE LOSS
SWELLING INDEX
FOLDING ENDURANCE
51
EVALUATION OF ODDS

52.  Controlled and Novel Drug Delivery By N.K.Jain
 Novel Drug Delivery System by Y.W. Chein
 Drug Delivery and Targeting (Anya .M. Hillery)
 Occular Drug Delivery System by Pankaj Verma (Slideshare)
52
REFERENCES

53. 53
QUESTIONS
1) Explain the Barriers associated with ocular drug delivery.
2) Add a note on Ocuserts and soft contact lens.
3) Explain any two methods to overcome the corneal barrier.
4) Write a note on bioerodible ocular inserts.
5) Advantages and disadvantages of ocular drug delivery system.
6) Discuss the design and development of ocuserts.

54. 54
THANK YOU….