Ophthalmic drug delivery is one of the challenging endeavors which is being faced by the pharmaceutical scientist, owing to the anatomy, physiology, and biochemistry of the eye, that renders it impervious to foreign substances. Topical administration of ophthalmic medications is the most common method for treating conditions that affect the exterior parts of the eye. The unique anatomy and physiology of the eye makes it difficult to achieve an effective drug concentration at the target site. Therefore, the major challenge remains to efficiently deliver a drug past the protective ocular barriers accompanied with a minimization of its systemic side effects.Conventional eye drops currently account for more than 90% of the marketed ophthalmic formulations. However, after instillation of an eye drop, only a small amount of the applied drug penetrates the cornea and reaches the intraocular tissues, which is due to the rapid and extensive precorneal loss caused by drainage and high tear fluid turn-over. Tear drainage leads to absorption of the administered dose by the nasolacrimal duct, leading to side effects. As a consequence of the precorneal loss, the ocular bioavailability is usually less than 10%. Furthermore, rapid elimination of the eye drops administered often results in a short duration of action which leads to increase in frequency of administration. A medication is applied to the eye to treat the diseases on the surface of the eye such as conjunctivitis, blepharitis, and keratitis sicca, as well as to provide intraocular treatment through the cornea for diseases such as glaucoma and uveitis. Topical administration of antibacterial medication to the conjunctival sac is usually an effective avenue for treating bacterial conjunctivitis.[2] An ideal topical drug delivery system should possess the following characteristics: 1. Good corneal and conjunctival penetration. 2. Prolonged precorneal residence time. 3. Easy instillation. 4. Appropriate rheological properties.

1. Challenges in trancorneal drug
delivery
Presented by
Bibin Mathew
M.Pharm I.P.(2nd Sem)

2.  Introduction.
 Ocular pharmacokinetics.
 Pathway of the drug after instillation.
 Challenges related to routes of administration.
 Barriers to drug absorption.
 Conventional ocular drug delivery constraints.
 Nasolacrimal drainage.
 Approaches to overcome constraints of conventional dosage form.
 Novel ocular drug delivery.
 Marketed formulations.
 Conclusion.

3.  Medication is applied to the surface of the eye for two purposes:
♦ To treat the surface of eye.
♦ To provide intraocular treatment .
 90% ocular market conventional dosage form.
 5% of applied drug penetrates.
 Major challenge remains to past the protective ocular
barriers.

4.  Good corneal penetration.
 Prolong contact time with corneal tissue.
 Simplicity of instillation for the patient.
 Non irritative and comfortable form.
 Appropriate rheological properties.

5. Ocular pharmacokinetics
Ocular structure with routes of drug kinetics

7. Systemic
administration
Limited penetration,
potential systemic
toxicity
Intraocular implants
Increased risk of retinal
detachment and
intravitreal
hemorrahge.
Intravitreal injections
Increased risk of retinal
detachment hemorrhage
and catracts.
Topical
application
Limited penetration
(5%), rapid tear
washout, poor patient
compliance

8. Flow of lacrimal fluid removes instilled
compounds from the surface of eye.
Excess volume is flown to the
nasolacrimal duct rapidly.
Corneal barrier is formed upon
maturation of epithelial cells
Most apical corneal epithelial cells from
tight junctions that limit the paracellular
drug permeation
These barriers have two parts:
►Blood retina barrier
►Blood-aqueous barrier
►Volume
►Lacrimation
►Tear dilution
►Blinking
BARRIERS
Drug loss from ocular surface: Lacrimal fluid eye barrier:
Blood ocular barriers: Others:

9. CORNELAREA
Drug
interaction
Drug protein
interaction
Instilled dose
Corneal
absorption
Normal tear turn overInduced lacrimation
Conjunctival
absorption

10. Consists of a secretory, distributive and
collection part.
Secretory portion composed of the lacrimal
gland. Tears are spread over the ocular surface
by the eyelids during blinking.
Collecting system consists of the canaliculi,
the lacrimal sac, the nasolacrimal duct, which
has opening in the inferior.
The basal tear flow is of about 1.2 µl/min
(range 0.5–2.2 µl/min). Reflex stimulation
may increase lacrimation a hundred-fold times
Nasolacrimal drainage

11. Attainment of optimal
drug concentration.
Enhance the poor
bioavailability of drugs

12. To increase
bioavailability and
duration of ocular
drugs
Use of DDS which
provide the controlled
and continuous delivery
Maximizing corneal drug
absorption and minimizing
precorneal drug loss

13. 1.Viscosity enhancers
Solution Viscosity Solution Drainage.
 Enhances viscosity of the formulation.
 Slows elimination rate from the precorneal area and enhance contact time.
Generally hydrophilic polymers- e. Methyl cellulose, polyvinyl alcohols,
polyacrylic acids, sodium carboxy methyl cellulose etc.
A minimum viscosity of 20 cSt is needed for optimum corneal absorption.
Approaches to overcome constraints of
conventional dosage form

14. 2. Prodrugs
Prodrugs enhance corneal drug permeability through modification of the
hydrophilic or lipophilicity of the drug.
The method includes modification of chemical structure of the drug molecule,
thus making it selective, site specific and a safe ocular drug delivery system.
 Drugs with increased penetrability through prodrug formulations are
epinehrine, phenylephrine, timolol, pilocarpine.

15.  Dipivefrine prodrug of epinephrine has 17 times better ability to penetrate
across the cornea. Thus is because dipivefrine is 600times more lipophilic
(at pH 7.2) than epinephrine.
 Phenylephrine hydrochloride prodrug of phenylephrine raised the amount
of phenylephrine in the aqueous humor by 6-8 times and improved
mydriatic activity four fold.

16. Poor aqueous stability
Post aqueous solubility
Eye irritation

17.  Polymereric mucoadhesive vehicle retained in the eye due to non-
covalent bonding with conjuctival mucine.
 Mucine is capable of picking of 40-80 times of weight of water.
Thus prolongs the residence time of drug in the conjuctival sac.
 Mucoadhesives contain the dosage form which remains adhered to
cornea until the polymer is degraded or mucus replaces itself.

18. Types-
1) 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.
Mucoadhesives

19. Objectives
 To reduce the frequency of administration
 To provide controlled, continuous drug delivery
 To prolong the pre ocular retention
 To avoid or minimize the initial drug concentration peak in the
aqueous humor.
 To avoid periods of under-dosing that may occur between eye
drop instillation.
Novel ocular drug delivery system

20. Novel ocular drug delivery system
Advantages
Sustained and/or controlled drug release.
Site-specific targeting .
Protect the drug from chemical or enzymatic hydrolysis.
Increasing contact time and thus improving bioavailability.
Better patient compliance.

21. Vesicle composed of phospholipid bilayer enclosing
aqueous compartment in alternate fashion
Types :1.MLV
2.ULV
Polar drugs are incorporated in aqueous compartment while lipophilic drugs
are intercalated into the liposome membrane
Phospholipids used- Phosphotidylcholine, Phosphotidic acid, Sphingomyline,
Phosphotidyleserine,Cardiolipine.
LIPOSOMES

22.  Behaviour of liposomes as an ocular drug delivery system is due to their
surface charge.
 Degree of association of liposomes with corneal surface decreased in
order
MLV+ > SUV+ > MLV- > SUV- >MLV > SUV
 Eg: Ocular formulation of Acetazolamide using liposome.
Percentage entrapment efficency was 29.27, 41.06, and
49.58 % for negatively, neutral and positively charged
liposomes.
Portion of drug released after 9h was 13.36,33.8 and 26.7%
for negatively, neutral and positively charged liposomes.
LIPOSOMES

23. ADVANTAGES DISADVANTAGES
 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.
 Short shelf life.
 They need many modification
for drug delivery to special
organs.
 Cost
 Limited drug capacity
 Sterilization problems
LIPOSOMES

24. Niosomes are non-ionic surfactant based multilamellar(>0.05µm),small
unilamellar(0.025-0.05µm) or large unilamellar vesicles(>0.1µm).
Structural components used:
• Surfactants (dialkyl polyoxy ethylene ether non ionic surfactant)
• Cholesterol.
Niosomes

25.  No difficulty of insertion.
 No tissue irritation and damage.
 Provide patient compliance.
 Biocompatible and have minimum side effects..
 Prevent the metabolism of drugs from the enzymes
 Prolong and sustained release of drug.

28.  Developed by Alza Corporation
 Oval flexible ocular insert,
 Release Rate: 20-40mg/hr
for 7day
 Consist of-

Part Material
Drug Reservoir Pilocarpine
Carrier material Alginic acid
Rate controller Ethylene vinyl acetate
copolymer
Energy Source Conc. Of Pilocarpine
Delivery Portal Copolymer membrane
Ocusert
Implantable systems

29. 2. Contact lenses:
Presoaked Hydrophilic lens
Drug Release : within 1st 30 Min.
Alternate approach : incorporate drug either as solution or suspension of
solid monomer mixture.
 Release rate is up to : 180 hr.
3. Diffusional Inserts :
Central reservoir of drug enclosed in Semi permeable or micro porous
membrane for diffusion of drug.
Diffusion is controlled by lacrimal fluid penetrating through it.
It prevents continues decrease in release rate due to barrier.
Contact lens

30. 4.Lacrisert:
 Sterile, Rod Shaped device.
 Composition: HPC without preservative.
 Weight:5mg,
 Dimension:Diameter:12.5mm, Length:3.5mm
 Use:-Dry eye treatment, Keratitis Sicca.
5.SODI: Soluble Ocular Drug Insert.
 Small water soluble developed for Cosmonauts who could not use their
eye drop in liquid condition.
 Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.
 Weight 15-16 mg.
 Softens in 10-15 sec
 In 10-15 min. turns in viscous liquid.
 After 30-60min. Becomes Polymeric Solution.

31.  Poor patient compliance
 Need of surgery
 Difficulty in self insertion.

32. Visulex system
OcuPhor

33. Process in which direct current drives ions into cells or tissues.
Positive charge, they are driven into the tissues at the anode; if
negative charge, at the cathode.
Fast, painless, safe, and results in the delivery of a high
concentration of the drug to a specific site.
Ocular iontophoresis has gained significant interest recently due
to its non-invasive nature of delivery to both anterior and posterior
segment.
Iontophoresis

34. CYCLODEXTRINS
Cyclodextrins (CDs) forming inclusion complexes with many
guest molecules.
Aqueous solubility of hydrophobic drugs can be enhanced
without changing their molecular structure.
They increase corneal permeation of drugs and increase ocular
bioavailability of poorly water soluble drugs.

35.  Insignificant dissociation of the administered complex
within the residence time in the precorneal fluid to release
the free drug into the tear film and at the corneal surface.
 Precorneal fluid was found to be too low to cause any
significant dissociation of the administered complex.

36. Ophthalmic Solution Corresponding
Commercial Product
Concentration of
Active Ingredient
Uses
Adrenergic
Epinephrine bitartrate Epitrate Opthalmic
Solution (Ayerst)
2% Chronic open angle
glaucoma
Naphazoline HCl Naphcon Forte (Alcon) 0.1% Topical ocular
vasoconstricter
Anesthetic
Proparcaine HCl Ophthaine Opthalmic
Solution (Squibb)
0.5%
Rapid acting local
anestheticTetracaine HCl Anacel Sterile
Opthalmic Solution
(Professional
Pharmacel)
0.5%
Antibacterial
Chloramphenicol Ophthochlor Opthalmic
Solution (Parked avis)
0.5% Used for superficial
infections of eye due to
susceptible
microorganism
Gentamicin Sulfate Garamycin Opthalmic
Solution (Schering)
0.3%
Marketed formulations

37. Anticholinergic
Atropine Sulfate Isopto Atropine
Opthalmic Solution
(Alcon)
0.125 to 4%
Used to produce
mydriasis and
cycloplegiaHomatropine HBr Isopto Homatropine
Opthalmic Solution
(Alcon)
2 and 5%
Anti-inflammatory
Dexamethasone
sodium phosphate
opothalmic solution
Decadron Phosphate
(Merck
Sharp&Dohme)
0.1%
Combats
inflammation due to
mechanical,chemical
or immunologic
causes
Prednisolone sodium
phosphate
Metreton Opthalmic
(Schering)
0.55%
Cholinergic
Pilocarpine HCl Carbine Opthalmic
(Alcon)
0.25 to 10% Used as a miotic in
treating glaucoma.
Marketed formulations

38. Ophthalmic
ointment
Commercial
product
Concentration of
active ingredient
Category
Atropine sulfate Atropine sulphate
ophthalmic
ointment
0.5 and 1.0% Parasympatholytic
Dexamethasone
sodium phosphate
Decadron phosphate
ophthalmic
ointment (Merk
Sharp &Dohme)
0.05% Antiinflammatory
Idoxuridine
Opthalmic ointment
Stoxil Opthalmic
ointment (Smith
kline )
0.5% Antiviral
Sulfisoxazole
diolamine
Gantrisin Opthalmic
Ointment (Roche)
4% Antibacterial
Marketed formulations

39. Drug Product Uses
Timolol maleate Timoptic-XE (MERCK &
CO. Inc)
Non-selective beta-
adrenergic
receptor blocking agent
Azithromycin AzaSite (InSite Vision) Antibacterial
Pilocarpine
hydrochloride
Pilopine HS Alcon
Laboratories
Lidocaine hydrochloride Akten Ocular surface anesthesia
Ganciclovir Virgan Acute herpetic
keratitis
Interleukin-2 (IL-2) Cytoryn Activates the
systemic antitumor immunity
Marketed formulations of In-situ drug delivery

40. 1.Optrex Actimist Eye Spray (Optima-Pharma, Germany)
Ingrediants- Soy Lecithin, Sodium Chloride, Ethanol, Phenoxyethanol,
Pro-Vitamin B5 (Dexpanthenol), Vitamin A Palmitate, Vitamin E, Purified
Water.
Use- Repair and restore dry, irritated eyes.
Working:

41. 2.Dry eyes mist (Boots pharmaceuticals)
Use:
 Soothes and relieves dry eyes.
 Moisturises eyes and lids.
Ingrediants:
Liposomate isoflavonoids, Sodium hyaluronate, Camomile extract, N
hydroxymethylglycinate, Isotonic buffer solution.
Marketed Products of liposomes

42.  Although eye drops represent 90% of all opthalmic dosage forms, there is
significant effort directed towards new drug delivery systems.
 Most formulation efforts aim at maximizing ocular drug absorption
through prolongation of the drug residence time .
 Newer concepts of introducing vesicular, prodrugs, in situ gel inserts,
iontophoresis, viscosity and permeation enhancers have been explored.
 Among the novel delivery vesicular and in situ systems emerged to be
most exploited sections in ocular drug delivery.
 However for future prespective in depth knowledge about the
physicochemical characteristics of the drug molecule and expected
interaction and implication of entrapping has to be studied .