A Review paper on Ocular Drug Delivery

1. OCULAR DRUG
DELIVERY SYSTEM
SUBHASISH PRAMANIK
1st YEAR M.PHARM
DEPARTMENT OF PHARMACEUTICS
HIMALAYAN PHARMACY INSTITUTE

2. CONTENT
INTRODUCTION
PARTS OF HUMAN EYE
ADVANTAGES
DISADVANTAGES
PHYSIOLOGICAL LIMITION
FACTORS INFUENCING CORNEAL ABSORPTION
CLASSIFIACTION
OCULAR PHARMACOKINETICS
EVALUATION

3. INTRODUCTION
Ocular medication are administered for the treatment of local infection.
The main problem with conventional dosage forms is eye irritation.
Ocular bioavailability with eye drops is estimated to be 1-5% of applied drug
due to rapid tear turn over.
Topical ocular delivery is ideal because smaller dose required, less toxicity and
rapid onset of action. Topical applied ocular drug have to reach the inner part of
the eye.

4. HUMAN EYE PARTS
1. Sclera- tough sheath around eyeball
2. Choroids- absorbs unused light
3. Cornea- refracts light into eye
4. Cilliary Body- Secretion of aq. Humor
5. Lens- flexible unit
6. Retina- screen where image is formed
7. Conjunctiva- layer of eye
8. Vitreous Compartment
9. Pupil- aperture through which light enters

5. ADVANTAGES DISADVANTAGES
• Possibility of targeting internal ocular tissue
through non-corneal routs.
• Administration of an accurate dose in eye.
• Increasing ocular residence, hence improving
bioavailability.
• Reduction of systemic side effects and thus
reduced adverse effects in case of topical
application.
• Absence of preservative
• Increase in shelf life due to absence of water.
• Perceived by patient as foreign body.
• Insertion technique is difficult & expulsion of
shields may occur not individually fit for each
patient.
• Movement around the eye.
• Occasional loss during sleep or while rubbing
eyes.
• Interference with vision.
• Difficulty in placement & removal

6. PHYSIOLOGICAL LIMITATION OF OCULAR DRUG DELIVERY
Limited
administered
dose
Biphasic
solubility of
drug
Triamellate
structure
Nasolacrimal
drainage
Lacrimal fluid
(dilution)
Corneal penetration
Corneal
contact time
Systemic
absorption
Conjuctival/ Sclera/
Absorption
Ocular tissue (Iris/
retina/ Ciliary/ Body)
Physiological response

7. PHYSIOCHEMICAL FACTORS INFLUENCING CORNEAL
ABSORPTION OF DRUG
Partition coefficient:
• Lipophilicity drugs are absorbed better than hydrophilic drugs across the cornea.
• Two major pathways are used: Partition-controlled process and Diffusion process.
• Distribution coefficient in the range 100-1000.
Molecular size:
• Cellular pores and intercellular spaces may be important for transportation of hydrophilic
compounds.
• Cornea is permeable to mannitol (mol. Wt. 182) but not to insulin and dextran which are
large in size.

8. Charge:
• The corneal epithelial barrier is highly selective for the absorption of positively
charged solutes.
• This is done by attraction between negatively charged corneal epithelial surface and
the positively charged drug molecules.
pKa of the drug:
• pH of the vehicle becomes more or less equal to the lachrimal fluid.
• It is only the pKa of the drug determine the ocular penetrability.
• Ionised compounds are more readily sequestered in the cornea
PHYSIOCHEMICAL FACTORS INFLUENCING
CORNEAL ABSORPTION OF DRUG

9. CLASSIFICATION
IMPROVEMENT IN
BIOAVAILABILITY
• EYE DROPS
• VISCOSITY ENHANCER
• GELS
• in situ GELLING SYSTEM
• PRODRUGS
• BIOADHESIVE POLYMERS
• SPRAYS
• NANOTECHNOLOGY BASED
OCULAR DRUG DELIVERY
MINIDISC
• OCULAR INSERT
IMPROVEMENT IN
CONTROLLED DRUG
DELIVERY
• O/W EMULSION
• LIPOSOMES
• NIOSOMES
• PHARMACOSOMES
• IMPLANT SYSTEM

10.  EYE DROPS:
 Drugs which are active at eye or eye surface are widely administered in the form of Solutions,
Emulsion and Suspension. Generally eye drops are used only for anterior segment disorders as
adequate drug concentrations are not reached in the posterior tissues using this drug delivery
method.
 Less than 5 Percent of the dose is absorbed after topical administration into the eye. The dose
is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood
vessels.
 Ocular absorption is limited by the corneal epithelium, and it is only moderately increased by
prolonged ocular contact.
 VISCOSITY ENHANCER:
 In order to improve bioavailability must be increase the viscosity of the formulation. The
viscosity enhancers are used such as cellulose, polyalcohol and polyacrylic acid.
 Sodium carboxy methyl cellulose is one of the most important mucoadhesion polymer having
more adhesive strength. Polysaccharide such as xanthan gum is found to increase the
viscosity.

11.  GELS:
 Gel formation is an extreme case of viscosity enhancer. Cellulose acetate phthalate dispersion
constituted a micro-reservoir system of high viscosity. Poloxamer 407 is used as ophthalmic
vehicle for pilocarpine delivery and found that the gel formation enhance the activity of
pilocarpine.
 The high viscosity of gel, however results in blurring of vision and malted eyelids which
substantially reduce patient acceptability.
 IN situ GELLING SYSTEM:
 In-situ hydrogels refer to the polymeric solutions which undergo sol-gel phase transition to form
viscoelastic gel in response to environmental stimuli.
 For ocular delivery, it have been focused towards development of thermo sensitive gels which
respond to changes in temperature. Several thermo gelling polymers have been reported for
ocular delivery which includes Poloxamer, polycaprolactone, polyethylene glycol etc.
 These thermo sensitive gels demonstrated promising results for enhancing ocular bioavailability
for both anterior and posterior segment.

12.  PRODRUGS:
 Prodrugs enhance corneal drug permeability through modification of the hydrophilic or
Lipophilicity of drug. Several ophthalmic drugs have been investigated for Prodrug
derivatisation.
 BIOADHESIVE POLYMERS:
 The bioadhesive polymers adhere to the mucin coat covering the conjunctiva and the corneal
surfaces of the eye. So it increase the residence time of the drug eye conjunctiva. The synthetic
polymer such as polycarbiphil, polyacrylic acid and hyaluronic acid are used. Xanthan and
carrageenan are also described a bioadhesive polysaccharides.
 SPRAYS:
 Sprays are not commonly used. Some practitioners use mydriatics or cycloplegics alone or in
combination in the form of eye spray. These sprays are used in the eye for dilating the pupil or
for cycloplegics examination.

13.  NANOTECHNOLOGY BASED OCULAR DRUG DELIVERY:
 Nanotechnology based ophthalmic formulations are one of the approaches which is currently
being pursued for both anterior, as well as posterior segment drug delivery. Nanotechnology
based systems with an appropriate particle size can be designed to ensure low irritation,
adequate bioavailability and ocular tissue compatibility. Several Nano-carriers have been
developed for ocular drug delivery such as nanoparticles, Nano-suspension, Nano-micelles etc.
 OCULAR INSERT:
Ophthalmic inserts are defined as sterile preparations, with a solid or semisolid consistency,
compose of polymeric support. It increase the contact time between the preparation and the
conjunctival tissue.
 Advantages:
1) Ease of handling and insertion; 2) Lack of expulsion during wear
3) Stability; 4) Sterility
5) Comfort: Poor-patient compliance. A properly designed ocular insert will minimize the
sensation caused by its insertion and wear.

14.  Mechanism of ocular drug absorption:
 Topical delivery into the cul-de-sac is most common route of ocular drug delivery. Absorption
from this site either corneal or non-corneal. The non-corneal route of absorption involves
penetration across the sclera and conjunctiva into the intraocular tissues. The non-corneal route
of administration may be significant for drug molecules with poor corneal permeability.
 Classification of ocular insert:
Based on solubility ocular insert are classified as following
1. Insolubility inserts: a) Diffusional system; b) Osmotic system; c) Contact lens
2. Soluble inserts.
3. Bioerodible insert
1. Insolubility inserts:
 Diffusion is controlled by Lacrimal Fluid penetrating through it. It prevents continues decrease
in release rate due to barrier. It follows Zero Order Kinetics. Diffusional systems and Osmotic
systems include a reservoir in contact with the inner surface for rate Controlling and Supplying
drug.
 The contact lens have to remove after use for their insolubility.

15. 2. Soluble inserts:
 The soluble insert have greater advantage of being entirely soluble so that they do not need to
be removed from their site of application. The therapeutic agents are preferably absorbed by
soaking the insert in a solution containing the drug, drying and re-hydrating it before use on
the eye.
 The amount of drug loaded will depend upon the amount of binding agent, upon the
concentration of the drug solution into which the composite is soaked, as well as the duration
of soaking.
 Components of soluble inserts containing synthetic polymers:
a. Soluble synthetic polymers: Methyl cellulose, Hydroxyethyl cellulose, Polyvinyl alcohol.
b. Plasticizers: Polyethylene glycol, glycerine, propylene glycol
c. Complexing agent: Polyvinyl pyrrolidone
d. Bioadhesive: Polyacrylic acids.

16. 3. Bioerodible ophthalmic inserts:
 The bioerodible inserts are composed of metrical homogeneous dispersion of a drug with
or without a hydrophobic coating. They are made of the so-called bioerodible polymers.
The release of the drug from such a system is the consequence of the contact of the device
with the tear fluid inducing a superficial bio erosion of the matrix.
 O/W EMULSION:
 This type of emulsion is useful for delivery water insoluble drug which is solubilised in the
internal oil phase. Phospholipids are use as polymer. Antioxidant are used to improve their
shelf life.
 LIPOSOMES:
 A liposome is a spherical vesicle having at least one lipid bilayer. Liposomes are
favourable for lipophilic drug not for hydrophilic drugs. It have affinity for, and are able to
bind to, ocular surfaces and release content at optimal rates.
 Polar drugs are incorporated in aqueous compartment while lipophilic drugs are
intercalated into the liposome membrane. It easily coating with bioadhesive polymers and
prolong the precorneal retention. It is Biodegradable, Non-toxic in nature.

17.  NIOSOMES:
 A Niosome is a non-ionic surfactant-based Vesicle. Niosomes are formed mostly by non-ionic
surfactant and cholesterol incorporation as an excipient.
 Niosomes are osmotically active and chemically stable as compared to liposomes and can entrap
both hydrophobic and hydrophilic drugs.
 Discoidalniosomes (discomes) timolol maleate have been reported for controlled ocular
administration of water soluble drugs because the vesicles act as depot to drug release slowly.
The disc shape provides for better fit in the cul-de-sac of the eye.
 PHARMACOSOMES:
 These vesicles formed by the amphiphilic drugs. The free carboxylic group or an active hydrogen
atom (-OH, -NH2) can be esterified to the hydroxylic group of lipid molecule, thus generating an
amphiphilic Prodrug.
 These are converted to pharmacosomes on dilution with water. It show greater stability,
controlled release profile and facilitated transport across the cornea. It also help to decrease drug
metabolism.

18. IMPLANT SYSTEM:
Intraocular implants are specifically designed to provide localized controlled
drug release over a extended period. These devices help in circumventing
multiple intraocular injections and associated complications. These system is
implant by making incision through minor surgery at pars plana. It show the
sustained release profile. It is reduced side effects and ability to circumvent
blood retina barrier. Ocular implants are available as biodegradable and non-
biodegradable drug releasing devices. Non-biodegradable implants offer long-
lasting release by achieving near zero order release kinetics.

19.  OCULAR PHARMACOKINETICS :
The drug pharmacokinetics from the eye follows the following paths
• Trans corneal permeation from the lacrimal fluid into the anterior chamber.
• Non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea.
• Drug distribution from the blood stream via blood-aqueous barrier into the anterior
chamber.
• Elimination of drug from the anterior chamber by the aqueous humor turnover to the
trabecular meshwork and sclemm's canal.
• Drug elimination from the aqueous humor into the systemic circulation across the
blood-aqueous barrier.
• Drug distribution from the blood into the posterior eye across the blood-retina barrier.
• Intra vitreal drug administration.
• Drug elimination from the vitreous via E.g. posterior route across the blood-retina
barrier.
• Drug elimination from the vitreous via anterior route to the posterior chamber

20. EVALUATION
 % MOISTURE LOSS: The percentage moisture loss is carries out to check integrity of the
film at dry condition. Ocular inserts are weighing and keep in a desiccators containing
anhydrous calcium chloride. After 3 days, the ocular inserts are taken out and reweigh, the
percentage moisture loss is calculated using the formula:
% Moisture Loss = [Initial weight ─ Final weight/Initial weight] ×100
 % MOISTURE ABSORPTION: The percentage moisture absorption test is carried out to
check physical stability or integrity of ocular inserts. Ocular inserts are weigh and place in a
desiccators containing 100 ml of saturated solution of aluminium chloride and 79.5% humidity
is maintain. After three days the ocular inserts are taken out and reweigh. The percentage
moisture absorption is calculated using the formula:
% Moisture Absorption = [Final weight ─ Initial weight/Initial weight] ×100

21.  SWELLING INDEX:
Swelling index of the polymer depends on the concentration of the polymer, ionic strength and the
presence of water. To determine the swelling index of prepared ocular inserts, initial weight of index
is taken and then placed in agar gel plate (2% agar) and incubated at 37 ˚ C ± 2˚C. For five hours,
insert is removed from plate after every 1 hour, surface water is removed with help of filter paper
and insert is reweighed. Percentage hydration or % swelling index is calculated.
% Swelling Index = (Wt. ─ Wo/Wo) ×100
Wt. = Weight of swollen insert after time t ; Wo = Weigh of original insert at zero time
 DRUG CONTENT UNIFORMITY:
To check the uniformity of the drug in the cast film inserts are cut at different places in the cast films and each
film is place in vials containing 5 ml of pH 7.4 phosphate buffer and shaken to extract the drug from patch. 1
ml from above resulting solution is taken and dilute. The solution is analyzed by spectrophotometer using pH
7.4 phosphate buffer as blank.

22.  In-vitro diffusion method:
To simulate the actual physiological conditions prevailing in the eye an in-vitro dissolution is
use in the present work. In-vitro release studies are carries out using bi-chamber donor-receiver
compartment model design using commercial semi-permeable membrane of transparent and
regenerated cellulose type (sigma dialysis membrane). It is tie at one end of the open cylinder,
which acts as the donor compartment. The ocular insert is place inside the donor compartment.
The semi permeable membrane is use to simulate ocular in vivo condition like corneal
epithelial barrier in order to simulate the tear volume, 0.7 m1 of distilled water is place and
maintain at the same level throughout the study in the donor compartment. The entire surface of
the membrane is in contact with reservoir compartment, which contains 25ml of pH 7.4
phosphate buffers and stirs continuously using a magnetic stirrer. Samples of 1ml are
withdrawn from the receptor compartment at periodic intervals and replace with equal volume
of distilled water. The drug content is analyse at 246 nm against reference standard using pH
7.4 phosphate buffer as blank on a UV/visible spectrophotometer.

23. CONCLUTION
 Ocular drug delivery system provide as well as systemic delivery drug.
 Controlled ocular drug delivery system increase the efficacy of the drug by reducing it
wastage and by enhancing absorption by increasing contact time for drug.
 They improve patient compliance by reducing the frequency of dosing and adverse effect.
 The use of inserts, which are solid devices to be placed in the cul-the-sac or on the cornea
represents one of the possibilities to reach increased residence time

24. THANK YOU