OCULAR DRUG DELIVERY AND PERMEABLITY

PRESENTER:AYAL.T(R1)
MODERATOR: DR.MULUGETA
DR.TEWODROSE

DEPARTMENT OF OPTHALMOLOGY

SPHMMC,2020
 OUTLINE
2

Objective
Introduction
Factors affecting bioavailablity of ocular drugs
Dosages forms and routes of ocular drug delivery
systems
Ocular drug Toxicity
Summary
references
 OBJECTIVE
3

To define pharmacokinetics,pharmacodynamics ‫و‬

pharmacotherapeutics and bioavailability
To describe
 factors affecting ocular drug bioavailability
 Routes of ocular drug delivery
 Drug Toxicity
 Novel drug delivery systems
 Introduction
4
Pharmacology is the study of the interactions of
living organisms with therapeutic substances through
biochemical processes.
A drug can be defined as a chemical substance used in
the treatment,cure,prevention,or diagnosis of disease
or used to enhance physical or mental well-being.
The 2 main branches of pharmacology :
pharmacokinetics and pharmacodynamics.
 Pharmacokinetics
5
Studies how the chemical substances cycle through the biological
system.
Includes the absorption,distribution,metabolism and excretion of the
drug
The drug can be delivered to ocular tissues as
 Locally
o Eye drop
o Ointment
o Periocular injection
o Intraocular injection
 Systemically
o Oral
o Iv
o Im
Pharmacodynamics 6
refers to the biological activity and clinical effects of a
drug.
It is the drug action after pharmacokinetics has
distributed the active agent to the therapeutic site.
Included within the area of pharmacodynamics are
 tissue receptor for the drug
 intracellular changes initiated by binding of the active
drug with the receptor.
Pharmacotherapeutics 7
is the study of how to achieve desirable effects or avoid
or minimize adverse effects or toxicity of the drug.
Pharmacokinetics and dose together determine
bioavailability, or
 concentration of the active drug at the therapeutic site.
The therapeutic dose may vary for any patient and is
related to
 the patient’s age, sex, race,
 other currently prescribed medications
 preexisting medical conditions.
 Bioavailability
8

Is the percentage of a drug that absorbs and reaches

the potential site of action regardless of the route of
administration.
FACTORS
 Anatomy and Physiology of the eye
 Physicochemical properties of the drug molecule
 Formulation factors
 Type of dosage form.
 Route of drug delivery
 Physiological Factors
9

Entry of drugs into ocular tissues is restricted

because of the eye's unique anatomy and physiology.
Several factors such as precorneal clearance,low
corneal permeability, blood-ocular barrier and efflux
pumps limit the ocular bioavailability
Precorneal Factors
10
Topically instilled conventional dosage forms exhibit
a very short precorneal residence time and poor
ocular bioavailability (<5%) because of the
precorneal factors:
 tear turnover and drainage,
 dilution by tear flow,
 reflex blinking and drug-induced lacrimation.
When the drop volume is >30 μL
 nasolacrimal drainage and drainage due to gravity
are major pathways for drug loss
Cornea as a Barrier
11
 12
For topically instilled drugs, the corneal route is a
major route for the absorption.
Steroids,such as dexamethasone,exhibit poor
permeability.
Such poor permeability is probably due to the corneal
epithelium,which possesses very tight intercellular
junctions.
Molecules cross the cornea by simple diffusion via
paracellular or transcellular route.
 13

Unlike the Bowman's layer and corneal epithelium,

stroma is hydrophilic and porous, providing rapid
movement of hydrophilic molecules.
 For macromolecular and lipophilic drugs,it is a
considerable barrier.
With phospholipids as a major constituent, the
endothelium is permeable to lipophilic molecules and
nearly impermeable to ions.
Overall, the molecules
 should have good solubility in both oil and water and
should also be in nonionized form to achieve optimal
corneal absorption.
 14

Scleral barrier Conjuctival barrier

 Barrier to diffusion of
macromolecules
 Permeablity decreases
rapidly at high molecular
weight.
 Poses tight junctions that
prevent penetration of molecules
 Intercellular spaces wider than
the cornea
 More permeable to larger
molecules
Due to the Presence of blood and
lymphatic vessles>>>>
drug absorbed across conj.taken
into systemic circulation
 Blood-Ocular Barrier
15
is a major barrier to drug entry into the eye after
systemic administration.
 blood-aqueous barrier (BAB)
 blood-retinal barrier(BRB).
 16
 BAB protects the anterior segment.
The nonpigmented cell layer of ciliary epithelium and
endothelial cells of iridial blood vessels, together
constitute the BAB.
 Both cellular layers express tight intercellular junctions.
Is not considered a complete barrier like BRB
 because of the fenestrated capillaries on the ciliary
processes.
*drugs in the AH,especially small and lipophilic ones,
can easily enter the circulation and be removed from
anterior chamber.
 Retinal barrier
17
 Diffusion barrier to
macromolecules
 Inner and outer plexiform layers
provides highest resistance to
diffusion for those molecules
 BRB is present in the posterior
segment
prevents the entry of the drug
molecules from blood circulation
into the retina.
divided into
 inner BRB
 outer BRB.
 Physicochemical Properties
18
Transport of drug across anatomical barriers such as
the cornea, blood-ocular barrier, and sclera depends
on its physicochemical properties:
 Solubility and pKa,
 lipophilicity),
 molecular weight and molecular size
 Formulation factors
o preservatives,antioxidants,viscosity
enhancers,surfactants,penetration enhancers,and
mucoadhesives.
 Solubility and pKa
19
Aqueous solubility depends on both pH of the solution
and pKa of the drug molecule.
Acidic drugs having lower pKa are soluble at higher pH.
Basic drugs with higher pKa are soluble at lower pH.
Therefore, the pKa of the drug and the pH of
formulation can affect absorption.
the pH of the formulation can affect the corneal
penetration of drugs by altering the amount of un-
ionized drug.
 20
It should be present more in the un-ionized form to have
appropriate permeability across cellular layers.
Many eye medications are alkaloids, or weak bases.
 tropicamide, cyclopentolate, atropine, and epinephrine
 exist in both charged and uncharged form

(tear pH 7.4)
Therefore the drug penetration can be increased by
raising the pH of the water phase,
 thereby increasing the proportion of drug molecules in the
more lipid-soluble, uncharged form.
21
Molecular Weight and Size
22
Corneal epithelium has a paracellular pore diameter
of 2 nm because of tight junctions
 hence it hinders the permeation of drugs with
molecular weight >500 Dalton (Da).
Permeability studies done on isolated stroma
suggest that the transport across stroma is molecular
weight and size dependent.
The endothelium of cornea is not a rate-limiting
membrane with respect to molecular weight and
molecular size
 23
Conjunctival membrane is leakier in comparison to
cornea or sclera.
The paracellular pore size for epithelium
 3 nm in bulbar conjunctiva
 4.9 nm in the palpebral conjunctiva,
which is larger than corneal epithelium.
Therefore,conjunctiva allows permeation of small
peptides and oligonucleotides.
 24
Sclera is predominantly composed of collagen fibers
like cornea.
The space between the fibers and cells in sclera is filled
with aqueous media,
 which eases paracellular movement of hydrophilic
compounds.
Studies clearly show that the scleral permeability
depends on the molecular radius and is independent of
the distribution coefficient
Osmolarity 25
A solution with equivalent osmolarity to 0.9% NaCl is
considered isotonic to tear fluid.
If the tonicity of a solution deviates significantly from
normal, it may cause discomfort or irritation.
 lead to reflex tearing and blinking,causing drug loss.
 It is necessary to adjust the osmolarity of ophthalmic
solutions to that of tears.
Surfactants 26
Surfactants are amphiphilic molecules having both
hydrophilic and hydrophobic groups.
They are added to the formulation for various
reasons.
 increase the aqueous solubility of drugs.
 act as a preservative since the molecules possess
antibacterial activity.
 can increase bioavailability by increasing
permeation across the cornea.
 27
Viscosity : adding methylcellulose and polyvinyl
alcohol increases drug penetration by increasing
contact time with the cornea
Lipid solublity:higher lipid solublity>>>>more
penetration
 Bcose of lipid reach environment of epithelial cell
membrane
 Epithelium/endothelium>>>>>lipophilic
 Stroma>>>>hydrophilic
 Tissue binding of medication
28

Tear and surface proteins, as well as ocular melanin,

may bind topical or systemic medication,
 making the drug unavailable or creating a slow
release reservoir.
 May alter the lag time, or onset of action, of a
medication as well as the peak effect and duration of
action,
 it can cause a delayed local toxicity despite
discontinuation of the medication.
 Dosage Forms
29

Solutions
Suspensions
Ointments
Hydrogels
 Solutions
30
Solutions are the most accepted and preferred
ophthalmic dosage form.
Two main advantages
 high patient compliance
 self-administration.
The drug is available in the solution form and is
ready for absorption.
The drug needs to exhibit high aqueous solubility to
produce a high concentration gradient.
 Suspensions 
31

These formulations contain finely divided particles

suspended uniformly in aqueous vehicle.
Suspensions provide some advantages
 particles reside in the cul-de-sac for a longer time,
thereby prolonging contact time and providing
sustained release
o Disadvantages :
 Particles suspended in the vehicle have a natural
tendency to settle.
 Oswald ripening.
 Ointments
32
are semisolid formulations in which the drug is dispersed in a base.
Incorporate both hydrophilic and hydrophobic drugs with
appropriate ointment bases.
Since molecules are dispersed within the ointment base,
 stability of the drug is improved relative to solution or suspension
 can maintain the applied dose on the surface of the cornea for more
than 2 hours.
Disadvantage
 visual disturbance
 it is not very patient compliant
 Hydrogels
33
Hydrogels are aqueous-based ointments, composed
of polymers that can absorb water and swell.
Such polymers,
 At low concentrations, increase solution viscosity.
 At higher concentrations, they form gels.
Another type of hydrogel is the in situ gelling
system
 Here the hydrogel is formulated as a solution.
Hydrogels can provide a sustained release, and the
rate of release depends on the interaction between
the drug and the polymer
Routes of Drug Delivery
34
 Topical Route

35
is the most common route to deliver ocular
medications for treating both surface and intraocular
conditions.
often preferred over other routes for the management
of various pathological diseases affecting the anterior
chamber
 cornea,conjunctiva, sclera, anterior uvea.
 36

Three main reasons account for this route:

 (a) convenience for administration,
 (b) higher ratio of ocular to systemic drug level,
 (c) cost affordability.
Solutions,emulsions,suspensions,ointments,and rate-
control release systems (devices) are commonly used
dosage forms administered by the topical route.
 37
topical application complications
 blurring of vision,
 nonproductive absorption,
 transient precorneal residence time,
 instilled solution drainage.
As a result,the extent of drug absorption is limited to
5% at best.
38
 39

Measures to increase topical

absorption
 Wait 5-10 min b/n drops
 Compress lacrimal sac
 Keep lids closed for 5 min after
instillation
Color Codes of Topical Ocular Medication
40
 Systemic Route

41

have poor access to the aqueous and vitreous.

Ocular bioavailability of systemically administered
drugs depends on
 the concentration gradient between serum and
ocular tissues
 blood-ocular barrier characteristics.
Limitations of this route for drug delivery include
BOB and systemic toxicity.
 42
Drugs with higher lipid solubilities more readily
penetrate the blood–ocular barrier.
The ability of systemically administered drugs to gain
access to the eye is also influenced
 by the degree to which they are bound to plasma
proteins.
Only the unbound form can cross the blood–ocular
barrier.
E.g Sulfonamides
 43
Because bolus administration of a drug exceeds the
binding capacity of plasma proteins and leads to
higher intraocular drug levels than can be achieved
by a slow intravenous drip,
 this approach is used for the administration of
antibiotics in order to attain high peak intraocular
levels.
INJECTABLE ROUTE OF DRUG DELIVERY
44
 Intraocular Injection
45

The intraocular injection of drugs instantly delivers

effective concentrations at the target site.
Although it may reduce systemic adverse effects,
ocular adverse effects may be more pronounced.
To avoid infection, strict adherence to standard
aseptic technique is required for the preparation
and injection of intraocular medication.

 intracameral
 intravitreal.
 Intracameral Injection
46

Up to 100 μL volume can be injected in humans by

this route.
are used in cataract surgery as well as for the
management of diseases afflicting the anterior
segment.
 fails to deliver significant amounts to the posterior
segment.
May be the last resort in controlling severe ocular
infections
 Intravitreal Injection
47
Drug access into the vitreous is necessary to treat
various retinal diseases.
 endophthalmitis
 various vitroretinopathies.
is more suitable for drugs with high molecular weight
(>500 Da) and long half-life.
Adverse effects
 retinal detachment from repeated injections,
 retinal hemorrhage,
 endophthalmitis,
 cataracts, and other retinal toxicities
 48
Intravitreal implantation is another advanced
surgical technique in which implants can be placed
inside the vitreous to deliver constant drug levels over
longer periods.
These implants can be conveniently replaced every 6
months,
 unlike intravitreal injections administered 2 or 3
times a week.
 Periocular Injection
49

it is the most efficient and least invasive route of

drug delivery.
The dose is usually injected in close proximity to
sclera for delivery to the posterior eye segment.
Lack of efficacy,convenience,and safety are a few
drawbacks of the periocular route
 due to which it is yet not considered a firstline
treatment.
 still serves as an additive to topical drug therapy
 Subconjunctival Injection
50
Drug injection beneath the conjunctiva
 is a less invasive localized delivery technique for the
posterior segment.
It is easier and safer to deliver subconjunctival
injections as compared to sub-Tenon
With forceps at the superior or inferior temporal
conjunctiva,
 a tent can be formed for administration of
approx.200 to 300 μL of a drug solution into the
subconjunctival area.
 51
After applying the injection,the resultant tent is
massaged through the closed lids to spread the fluid
uniformly.
Routinely, subconjunctival injections of antibiotics
are used to treat severe intraocular and corneal
infections.
 Sub-Tenon Injection
52
The sub-Tenon or episcleral space is a void b/n the
Tenon's capsule and sclera.
Due to the avascular nature of sclera, drugs will stay
in episcleral space for a longer period of time followed
by Sub-Tenon injection.

It is considered to be the most promising route of

targeting posterior segment.
 53
In sub-Tenon injections, the needle tip passes
through the conjunctiva and Tenon's capsule in the
inferior cul-de sac, entirely out of view.
Carries a higher risk of globe penetration
 the closer proximity to the interior of the eye
 the fact that it is a ―blind injection
 Retrobulbar Injection
54

Injections through the lower eyelid into muscles

surrounding the eye are frequently used for:
 administration of anesthetic agents or
 for corticosteroid therapy in severe inflammation to
the posterior segment
involves deposition of drug solution into retrobulbar
space within the muscle cone and
 is the most preferred route of drug administration for
macular region.
 55
Injection is administered in the quadrant b/n the inferior
and the lateral rectus muscles
 directed posteriorly until orbital septum resists its
penetration;
 the needle is directed towards the apex of orbit and
penetrated until it meets the resistance of intermuscular
septum
Following penetration through this structure,the needle
reaches the retrobulbar space,which can take 2 to 3 mL
of solution
In order to ensure homeostasis and uniform anesthetic
effect,pressure should be applied on the globe.
 Peribulbar Injection
56
The injection is administered in the inferior lateral
quadrant of the orbit using a 26-gauge half-inch
disposable needle.
To ensure that the needle is in the proper peribulbar
space,
 the eversion of the lower lid when the hub of the
needle touches the eyelid skin should be checked.
A total of 8 to 10 mL of anesthetic solution (mixture)
can be injected in both sites
Even though safer,the peribulbar route is less effective
than the retrobulbar route in anesthetizing the globe
 Toxicity
57

refers to the adverse effects of either medications or

environmental chemicals, including poisoning.
Toxicity may be influenced by pharmacokinetics
and/or pharmacodynamics.
Topical absorption avoids the first pass metabolism of
the liver and increases systemic bioavailability.
 The systemic toxicity may be more than expected
relative to the total topical dose.
 58
Drug metabolism and excretion are less developed in
neonates and infants than in adults.
 drug doses and dosing schedules must be adjusted
appropriately in pediatric populations to avoid toxicity.
Pharmacologic principles apply differently to elderly
patients-
 the pharmacotherapeutic effects and toxicity of
medication may be altered simply by the aging
process,independent of drug dosage.
the selection of a specific therapeutic agent should be
guided by the general health, age, and concomitant
medication taken by the individual patient.
 59

Local toxicity of topical drugs is more common than

is systemic toxicity.
Local toxicity
 May be a type I immunoglobulin E (IgE)–mediated
hypersensitivity reaction or
 May represent a delayed reaction to either the
medication or the preservatives.
 NOVEL DRUG DELIVERY SYSTEMS
60

Reading assignment
 SUMMARY
61
Pharmacokinetics is absorption,distribution,metabolism
and excretion of the drug
Pharmacodynamics:
Bioavailability: percentage of a drug that absorbs and
reaches the potential site of action regardless of the route of
administration
 Affected by physiological factors and physiochemical
properties of the drug
Routes of drug delivery system:
topical,periocular,intraocular and systemic
Novel drug delivery systems and drug carriers have been
investigated to increase ocular bioavailability
 REFERENCE
62

AAO.FUNDAMENTAL 2018/19
DUANS 2012 ed
ALBERT JACOB’S 2008
RYAN RETINA,5TH Ed
INTERNET SOURCES
 63

Thank you