This document summarizes barriers to ocular drug delivery and methods to overcome them. The major barriers include ocular surface barriers like the cornea, ocular wall barriers like the sclera, retinal barriers, the vitreous body, lachrymal fluid, and properties of the drug itself like solubility and molecular weight. Methods to enhance delivery include microneedles, ultrasound, iontophoresis, periocular routes, and intravitreal injections. Various ophthalmic formulations are also discussed like eye drops, gels, ointments, and inserts that utilize approaches like prodrugs, penetration enhancers, and nanoparticle carriers to improve ocular bioavailability.

1. Barriers and methods to
overcome barriers of
ocular drug delivery
system
By
G.Tarun Kumar
10201S0301
1st year M.Pharmacy
[pharmaceutics]
Bapatla college of
pharmacy

2.  Barriers of ocular drug delivery
 Methods to overcome intraocular
barriers
 Approaches to improve ocular
bioavailability
 Ophthalmic formulations

3. Barriers of Drug permeation
 1.Ocular surface barriers
 2.Ocular wall barriers
 3.Retinal barriers
 4.Viterous body
 5.The lachrymal fluid
 6.Solubility of the drug
 7.lipophilisity of the drug
 8.Mol.wt and size of the drug

4.  1.Occular surface barriers:
 The corneal and conjuctival superficial layers
form the ocular surface i.e.,in contact with the
tear film
 These create a defence barrier against
permeation from undesired molecules
 Corneal surface 5%, Conjuntival surface 95%
 Out of corneal five layers only the outermost
squamous epithelial layer forms a barrier

5.  2.Ocular wall barriers :
Sclera&Choroid
 Sclera
o It contain stroma made of bundles of collagen
and fibroblasts covered by vascular episclera
-occupies 80%of eye globe
thickness is 0.3 to 1.0mm
 Choroid
beneath sclera – highly vascular tissue
thickness is 0.25mm

7. 3.RETINAL BARRIERS

8. • 4.Vitreous body
It occupies a vol about 4.5 ml and is the largest single structure in the eye
Drugs are rapidly eliminated from the vitreous by first order kinetics
• 5.The lachrymal fluid
It is an aqueous fluid which maintain Isotonicity and contain
proteins[lysozyme]and lipids
After topical application increase in lachrymal flow dilution of dose
dimnished drug absorption Lowers drug concentration
Rapid clearence of precorneal area by lacremation and nasolachrymal
drainage and spillage decrease in Bioavailability

9.  5. Solubility of the drug
Solubility is dependent on the pKa of the drug and pH of the
solution
-Usually unionised drugs permeate rapidly than ionised drug
As the corneal epithelium bears negetive charge cationic species
penetrate fast
 6.Lipophilisity of the drug
Outermost corneal epethlium is tend to permeate lipophilic drugs
where as inner stromal layer of cornea permeate hydrophobic drugs
Partition coefficient value ranging from 2-4 is found to be optimum
 7.Molecular weight and size of Drug
M.wt less than 500 daltons can permeate readily in corneal
epithilium
Conjunctva has larger paracellular pore diameter thus allow
permeation of larger molecules such as small and medium size
peptides[5000-10000d]
Permeation through sclera is by aquous pores
Sclera permeability is half of conjunctiva but much higher than

10. Methods to overcome Intraocular Barriers
1. Microneedle drug delivery
2. Ultrasound mediated Drug Delivery
3. Iontophorosis
4. Periocuar route DDS
5. Intravitreal injection

11. 1.Microneedle
 It is an non invasive method to deliver drugs to intraocular regions
 Researchers have developed drug coated microneedles with a
length of 500-750 μm
 Drug to be delivered can be coated on a solid metal
 On administration coated molecules dissolve rapidly and
subsequently microneedles are removed from the tissue
 Similarly intrascleral hollow microneedles have also developed .
This delivery system is able to deliver microparticles,nanoparticles
and drugs in a solution with minimal invasion

12. 2.Ultrasound mediated Drug delivery
• It includes application of ultrasound waves across
cornea to enhance drug permeability
• Delivery of hydrophilic molecules – sod.flourosceine
at an ultrasound frequency of 880KHz with 5 min
duration reported 10 fold enhancement in corneal
permeation with minor changes in epithelium
Delivery of beta blockers such
as Atenelol,timolol and
beraxalol was attempted

13. 3.Iontophoresis
 Ocular iontophoresis is an non invasive method to deliver drugs to
both anterior and posterior segments
 It is a method of transferring ionised drugs through membrane with
low electric current
 Ocular iontophoresis is classified into transcorneal and
corneoscleral or trans-scleral iontophoresis
 Drugs moved across the membrane by 2 mechanisms include
migration and electro-osmosis
 Trans scleral delivery allows drug transfer to posterior segment
 Disadvantages
 No sustained half life
 Requires repeated administration
 Mild pain in some cases
 Low patient compliance becuause of frequent
administration that may needed

14. 4.PERIOCULAR ROUTE
 It has been considered as most promising and
efficient route for administering drugs to posterior
eye segment
 Periocular refers to region surrounding the eye
Drug solution placed in close
proximity to sclera, which
results in high retinal and vitreal
concentration
It has an advantage like
improved drug absorption over
systemically and topically and
more safety towards posterior
segment of eye

15. 5.Intravitreal injection
Short term complications include :retinal
detachment,endophthalmitis
Intravitreal hemorrage
Disadvantages :Injection display first order kinetics
Short half life
Pain caused due to repeated injections
Increased intraocular pressure &intraocular
bleeding
•This involves injection of drug
solution into vitreous by using
30G needle which improve drug
absorption
•Offers high drug
concentrations in vitreous
and retina

16. A. Viscosity enhancers
viscosity increasing polymers are usually added to ophthalmicdrug
solutions to increase vehicle viscosity
 This leads to improved precorneal residence time &grater trans-corneal
penetration
 Polymers used: poly vinyl alcohol, poly vinyl pyrrolidone, Methyl
cellulose , HPMC , HEC ,HPC
Out of the polymers PVA is more effective due to its adhesive properties
and its capability to increase thickness of precorneal tear film
B. Prodrug
Generally prodrugs are used for the drugs having low corneal permeability
Prodrugs are used to increase corneal permeability by changing
hydrophilicity/lipophilicity of the drug
After corneal penetration the prodrug is chemically or enzymatically
metobalised into its parent compound

17.  Enzyme systems identified include:Esterases , ketone reductases and
steroid 6-hydroxylase
 Prodrugs examples include anti viral medications :Genciclovir , Acyclovir
C. Penetration enhancers
 The transportation across the cornea can be maximized by increasing the
permeability of corneal epithelial membrane
 It can be maximized by modifying the integrity of corneal epithelium by
permeation enhancers which leads to increased bioavailability
 Penetration enhancers include: cetylpyridinium chloride , lasalocid ,
benzalkonium chloride , parabens , tween 20 , bile acids , bile salts , azone
 Other drug formulations that can enhance drug bioavailability are:
Eye ointments Nanosuspension
Lioposomes Microemulsions
Niosomes Insitu forming gels
Nanoparticles

18. Ophthalmic formulations
1. Eye drops
2. Ophthalmic solutions
3. Microemulsions
4. In situ gels
5. Eye ointments
6. Contact lenses coated with drugs
7. Liposomes
8. Niosomes and Discosomes
9. Ocuserts

19.  Eye drops are in the form of water and oil
solitions,emulsions or suspensions of one or
more active ingredients and may contain
preservatives if stored in multidose packaging
 These are sterile and isotonic dosage forms
 The optimum pH for eye drops should be equal
to pH of tear fluid which is about 7.4
 If pH value gets outside the range , it is
intolerated to the eye which leads to decrease
in drug bioavalibility

20. 2.Ophthalmic solutions
 These are sterile , aqueous solutions used for cleansing and rinsing
eyeballs
 They may contain excipitents for regulating osmotic pressure , pH and
viscosity of preparations
 They may also contain preservatives if stored in multiuse packaging
3.Microemulsions
 Microemulsion is stable dispersion of water and oil facilited by
combination of surfactant and co-surfactant in a manner to reduce
interfacial tension
 These are thermodynamically stable dosage forms having droplet size
of [-100nm] and clear appearence
 These are inexpensive and easy to sterilize and stabilize, provides
possibility to intorduce large amounts of active ingredient
 The mech of action involves the adsorption of nanodrops constituting
a reservoir of drug and inner phase of microemulsion on corneal
surface
 Active ingredients includes : Diflupendrate , cyclosporine A ,
Flubriprofen

21. 4.In situ gels
[sol-to-gel systems]
 The droppable gels are liquid upon instillation and undergo a phase
transition from sol-to-gel to form a viscoelastic gel in ocular region
 The change in the dosage form is triggered by factors like pH , temp and
presence of electrolytes
 Polymers used are gellan gum , poloxamer and cellose acetate pthalate
 Active ingredients include Ciprofloxacin , Flucanazole , Pilocarpine
5.Eye ointments
 Ointments are semisolid dosage forms for external use , consisting solid or
semisolid hrdrocarbon base having melting or softning point close to human
temp
 After application it decomposes into small drops which stay for a longer
period in conjunctival sac , thus increasing drug’s bioavailability
 These are safe and well tolerated with certain disadvantages of blurred
vision and irritating effects . Thus these are preferred at night time.

22. • In this type ,drug is coated on a contact lens and is
released after applying the drug over the eyeball
for a longer period of time
• Polymer used in the production of lenses is cross linked poly[2-hydroxy ethyl
methacrylate] with small amount of ethelene glycol dimethylacrylate
• Drugs include: Timolol , ciprofloxacin , dexamethasone , cyclosporine
7.Liposomes
• Liposomes are made of phospholipids which are microscopic vesicles containing
one or more concentric lipid bilayers separated by water or aqueous buffer
compartments
• These are biocompatable , biodegradable , amphiphilic
and nontoxic in nature
• They have the ability to have intimate contact with
corneal & conjunctival surfaces
Desirable for drugs that are poorly absorbed , low partition
Coefficient and poor solubility
6.Contact lenses coated with
drugs

23. • Positively charged liposomes are preferentially captured at negatively charged corneal
surface
• Disadvantages
• Production is very expensive and very difficult technological preparation
• The effectiveness depends on many factors: encapsulation efficiency , size and charge of
liposomes , stability of liposomes in conjunctival and corneal surfaces
8.Niosomes and Discosomes
• Niosomes are non ionic surfactants capable of encapsulating both hydrophilic and
lipophilic compounds
• Biocompatable,biodegradable and non imunogenic carriers that extend time period
• Releases the drug which is independent of
pH and temperature
Discosomes are modified form of niosomes
• Larger in size , varies from 12-16 nm
• Discosomes differ from niosomes by using
different non ionic surfactants Solulan C24
a derivative of lanolin
• Due to their size they cannot penetrate the
general circulation
Disc shape ensure better fitting into conjunctival
sac Drugs include Genciclovir , cyclopentolate
timolol

24. 9. Ocuserts
 Ocuserts [ocular inserts] are defined as sterile
preparations , multilayered, solid or semisolid
devices placed in cul-de-sac or conjunctival sac
and whose size and shape are designed especially
for ophthalmic application
 Deliveres at constant rate by diffusion mechanism
 Ocuserts increase corneal contact time , prolongs
duration of action , improve bioavailability , reduces
the frequency of administration and thus acheive
patient compliance
 Ocusert® , pilocarpine ocular therapeutic system is the
firstproduct by Alza incorporationUSA from this catogary
Generally all types of ocuserts consist of 3 components namely :
1.A central drug reservoir
2.Rate controlling membrane
3.An outer annular ring meant for easy handling

25. Classification of ocular inserts
1. Insoluble ocular inserts : a. Diffusional inserts
b. Osmotic inserts
c. Hydrophilic contact lenses
2. Soluble ocular inserts : a. Natural polymeric inserts
b. Synthetic insert
3. Bio erodable inserts : a. Soluble ocular drug inserts
[SODI]
b. Lacrisert
c. Minidiscs
d. Collagen shields

26.  1. Insoluble ocular inserts
 a. Diffusional inserts
 The release of drug from the inserts is based on diffusional release mechanism
 Drug release is controlled by the lachrymal fluid permeating through the membrane
and when sufficient internal pressure was developed , then only drug comes out of
the reservoir
 b. Osmotic inserts
 The osmotic inserts consist of a central part surrounded by a peripheral part and are
of two types
Type 1 Type 2
•Central part is composed of single
reservoir of drug with osmotic solute
dispersed throughout a polymeric matrix
•The peripheral part comprise a covering
film made of an insoluble semi
permeable membrane
•The osmotic pressure against the
polymer matrix causes its rupture form
apertures from where drug releases
•Central part is composed of two distinct
compartments , the drug and osmotic
solute in two separate compartments
•Drug reservoir is surrounded by elastic
impermeable membrane and osmotic
layer is by semi permeable membrane
•Osmotic pressure that stretches the
elastic membrane and contracts the
compartments , so drug release from
aperture

27.  C. Hydrophilic contact lenses
 These are covalently cross linked hydrophilic or hydrophobic
polymers that forms a 3 dimensional matrix capable of
retaining water , aqueous solution or solid components
 Provide extended release of drugs into the eye
 There are two types of contact lenses : Hard contact lenses and Soft contact
lences
 Soft lenses are used to aid corneal wound healing in patients with infections
and corneal ulcers . They treat corneal erosions and epithelial defects after
corneal transplantation
 2 . Soluble ocular inserts
 Soluble inserts offer the advantage of being entirely soluble so that they need
not to be removed from their site of application
 Simple design and easily processed by conventional methods
 Controlled by diffusion mechanism
a) Natural polymeric inserts : collagen type
b) Synthetic polymeric inserts : cellulose derivatives

28. 3. Bio erodible ocular inserts
• These are formed by bio erodible polymers
• Ex. Cross linked gelatin derivatives , polyester derivatives
• They can modulate their erosion rate by modifying the final structure during
synthesis and by addition of anionic or cationic surfactants
• A. Soluble ophthalmic drug insert [SODI]
• It is a small oval wafer developed by soviet scientists for cosmonauts who could not
use eye drops in weightless conditions
• It is a thin film made from acrylamide , N-vinylpyrrolidone and ethylacrylate
• B. Lacrisert
• Sterile rod shaped device made of HPC without any preservatives
• Weight is 5mg , diameter 12.7mm , length 3.5mm
• Used in treatment of keratitis , inserted into inferior fornix by a special applicator
• Imbibes water from cornea and conjunctiva , forms hydrophilic film which stabilizes
the tear film and hydrates and lubricates the cornea .

29.  C. Minidiscs
 Minidiscs are profiled , convex outside , concave from
the side of contact with eye surface , d is 4-5 mm
which are similar to contact lenses
 Main copolymers are ᾳ-ῳ-bis[4-methacryloxy]-butyl poly[dimethylsiloxane]
and poly [hydroxyethyl methacylate]
 This dosage form is either hydrophilic or hydrophobic which enables
extended time period of release of water soluble and poorly soluble drugs
 D. Collagen shield
 Collagen is the structural protein of bones , tendons , ligaments and skin
and comprises more than 25% of total body protein in mammals
 Produces higher drug concentration in cornea and aqueous
humour when compared with eye drops and contact lenses
 Collagen shields are fabricated with foetal calf skin tissue
and originally developed as a corneal bandage

30. • Adavntages
• Increased ocular residence, hence prolonged drug activity and
higher bioavailability
• Releasing drugs at slow and constant rate
• Accurate dosing
• Reduction of systemic absorption
• Better patient compliance , targeting internal ocular tissues
through conjunctival and scleral routes
• Disadvantages
• A capital disadvantage of ocular inserts is their solidity which
results in inconvenience in patients
• Unwanted migration of inserts to upper fornix
• Interference with vision
• Difficult in placement of ocular inserts