ocular drug delivery system

1. By- Dr. Neeraj Agarwal

2. INTRODUCTION
 Ocular administration of drug is primarily associated
with the need to treat ophthalmic diseases.
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.

3. FACTORS AFFECTING
INTRAOCULAR BIOAVAILABILITY:
 1. Inflow & outflow of lacrimal fluids.
 2. Efficient naso-lacrimal drainage.
 3. Interaction of drug with lacrimal fluid.
 4. dilution with tears.
 5. Corneal barriers.
 6. Active ion transport at cornea.

4. OCULAR ABSORPPTION
PATHWAY
4

5. BARRIERS IN OCULAR ABSORPTIONPrecorneal Constraints
It include –
• Solution drainage
• Lacrimation
• Tear dilution
• Tear turnover
• Conjunctival
absorption
Corneal constraints
• Cornea as rate limiting
barrier
• Anatomy of cornea
1.Outer-
Epithelium(lipophilic),
2.Middle-
Stroma(hydrophilic),
3.Inner-
Endothelium(lipophilic)
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6. Cornea
 Epithelium- only non ionized drug penetrate
 Stroma- only ionized drug can pass
so drug must have capacity to exist in both ionized and
nonionized form for a better penetration
Eg- homatropine (proposed by KINSEY)
Eg- Fluorescein is a negative charged ion so can not
penetrate the intact epithelium and this property forms the
basis of fluorescein dye test

8. SURFACE ACTIVE AGENT
 Agents that reduce surface tenson, increase corneal
wetting and therefore present more drug for absorption.
 Eg.- Benzalkonium Chloride used as preservative also act
as wetting agent.

9. PRO DRUG FORM
 Prodrug is more Lipophilic so more absorbed by
epithelium and afterthat converted into another form.
 Eg.- Dipivefrine(alpha adrenergic agonist antiglaucoma
drug) is lipophilic prodrug which hydrolysed by esterases
into adrenaline

10. OCULAR DELIVERY
SYSTEMS
CONVENTIONAL VESICULAR
CONTROL
RELEASE
PARTICULATE
IMPLANTS
INSERTS
DENDRIMERS
IONTOPORESIS
COLLAGEN SHIELD
POLYMERIC
SOLUTIONS
CONTACT LENSES
MICROONEEDLE
MICROSUSPENSION
NANOSUSPENSION
ADVANCED
SCLERAL PLUGS
GENE DELIVERY
Si RNA
STEM CELL
ECT
MICROPARTICLE
S
NANOPARTICLES
LIPOSOMES
NIOSOMES
DISCOMES
PHARMACOSOME
S

11. CONVENTIONAL TYPES
 1- SOLUTIONS
 2- SUSPENSIONS
 3- EMULSIONS
 4- OINTMENT
 5- GELS

12. ADVANTAGE
 They are easily administered by the nurse
 They are easily administered by the patient himself.
 They have the quick absorption and effect.
 less visual and systemic side effects.
 better patient compliance.

13. DISADVANTAGE
 The very short time the solution stays at the eye
surface.
 Its poor bioavailability.
 The instability of the dissolved drug.
The necessity of using preservative.

14. IDEAL CHARACTERISTICS
Sterility
Isotonicity
Buffer/pH adjustment
Less drainage tendency
Minimum protein binding

15. Dosage
Form
Advantages Disadvantages
solutions convenience Rapid precorneal
elimination, non sustained
action
suspension Patient compliance, best for
drug with slow dissolution
Drug properties decide
performance loss of both
solutions and suspended
particles
emulsion Prolonged release of drug
from vehicle
Blurred vision, patient non
compliance
ointment Flexibility in drug choice,
improved drug stability
Sticking of eyes lids, blurred
vision, poor patient
compliance

16. CONVENTIONAL
Eye Drops:
 Drugs which are active at eye or eye surface are widely
administered in the form of Solutions, Emulsion and
Suspension.
 Various properties of eye drops like hydrogen ion
concentration, osmolality, viscosity and instilled volume can
influence retention of a solution in the eye.
 Less than 5 % 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.

17. SOLUTIONS
ADVANTAGE-
 Ease of bulk scale manufacturing
 High pt. Aceptibility
 Drug product efficacy
 Stability
 Cost effectiveness

18. EMULSION
 A Fine dispersion of minute droplets of one liquid into
another liquid in which it is generally not soluble or
misceble.

19. EMULSION
 Emulsion are of 2 types-
 1.Oil in Water- use in ophthal bcoz of less irritance nd
better tolerance
 2. Water in Oil
 Eg.- Difluprednate 0.05%
 Difluprednate 0.05% + Moxifloxacin 0.5%
 E/d Cyclosporin is Emulsion

20.  Eg.- Fluribrophen axetil + Castor oil have better
bioavailability and less irritation
 Eg,- Chitosan coating and HPMC coating of
indomethacin increase precorneal residence time

21. Advantage of emulsion
 Improve residence time
 Drug corneal permeation increase
 Sustain drug release

22. SUSPENSION
 Disperssion of finely divided insoluble API in an
aqueous solvent consisting of suitable suspending and
dispersing agent
 Its activity is particle size dependent. So if size is
optimum then optimal activity is achieved.
 Suspension must be resuspended by shaking to
provide accurate dosage.

23. SUSPENSION
 Eg.- Tobramycin 0.3% + Dexa 0.1% (but have high
viscosity)
 Tobra 0.3% + Dexa 0.05% (TobraDex ST) have very low
settling rate
 Moxi 0.5% + Prednisolone 1%
 Prednisolone 1%
 Nepafenac 0.1% eye drop is suspension
 Natamycin
 Brinzolamode

24. OINTMENTS AND GELS
 Prolongation of drug contact time with the external
ocular surface can be achieved using ophthalmic
ointment vehicle but, the major drawback of this
dosage form like, blurring of vision & matting of
eyelids can limit its use.

25. GELS
 Eg.- pilocarpine 4% gel
 Eg.- several artificial tear preparations are formulated as
ophthalmic gels
 Eg.- treatment with Timolol 0.5% gel once daily in the
morning acheives intraocular pressure level equal to twice
daily solution

26. OINTMENTS
 Mixture of semisolid and solid hydrocarbons (parrfins)
that have melting point at ocular temp. (34 c).
 When applied to inferior conjuctival sac, ointments
melt quickly and the excess spread out onto the lid
margin, lashes, skin of lids.
 It has a therapeutic effect for 6hr.
 This method may be of practical value in paediatric
and geriartic age group.

27.  Early formulations of ointment contained waxy grades
of petroleum or unwashed lanolin which interfered
with corneal wound healing.
 Newer ointments not contain these but should be used
cautiously in ulcer with impending perforation. And
should not be used in any surgical wound in which
there is a question of wound integrity, such as when
difficulty is experienced maintaining the Ant.
Chamber at surgery.

28. VESICULAR SYSTEM
 Vesicular drug delivery system can be defined as highly
ordered assemblies consisting of one or more concentric
bilayers formed as a result of self-assembling of
amphiphilic building blocks in presence of water.
 Vesicular drug delivery systems are particularly important
for targeted delivery of drugs because of their ability to
localize the activity of drug at the site or organ of action
thereby lowering its concentration at the other sites in
body.

29. VESICULAR SYSTEM TYPES
 1.- LIPOSOMES
 2.- NIOSOMES
 3.- DISCOSOMES
 4.- PHARMACOSOMES

30. LIPOSOMES
Liposomes are biocompatible and
biodegradable lipid vesicles made
up of natural lipids and about
25–10 000 nm in diameter.
 They are having an intimate contact with the corneal and
conjunctival surfaces which is desirable for drugs that are
poorly absorbed, the drugs with low partition coefficient,
poor solubility or those with medium to high molecular
weights and thus increases the probability of ocular drug
absorption.

31. NIOSOMES AND DISCOMES
 The major limitations of liposomes are chemical instability,
oxidative degradation of phospholipids, cost and purity of
natural phospholipids.
 To avoid this niosomes are developed as they are chemically
stable as compared to liposomes and can entrap both
hydrophobic and hydrophilic drugs.
 They are non toxic and do not require special handling
techniques.

32. Niosomes are nonionic surfactant vesicles that have
potential applications in the delivery of hydrophobic or
amphiphilic drugs.
Discomes may act as potential drug delivery carriers as
they released drug in a sustained manner at the ocular site.
 Discosomes are giant niosomes (about 20 um size) containing poly-
24- oxy ethylene cholesteryl ether or otherwise known as Solulan 24.
Pharmacosomes: This term is used for pure drug vesicles
formed by the amphiphilic drugs.
 The amphiphilic prodrug is converted to pharmacosomes
on dilution with water.

33. Non ionic surface active agent
phospholipid
Hydrophilic drugs in aqueous
region encapsulated
Lipophilic drugs located in
the hydrophobic lamella
NIOSOME Vs LIPOSOME

34. Niosomes are microscopic lamellar structures, which
are formed on the admixture of non-ionic surfactant of
the alkyl or dialkyl polyglycerol ether class and
cholesterol with subsequent hydration in aqueous
media.
Structurally, niosomes are similar to liposomes, in that
they are also made up of a bilayer. However, the
bilayer in the case of niosomes is made up of non-
ionic surface active agents rather than phospholipids
as seen in the case of liposomes.

35. CONTROL RELEASE SYSTEM
 1- IMPLANTS
 2- IONTOPHORESIS
 3- DENDRIMER
 4- MICROEMULSION
 5- NANOSUSPENSION
 6- MICRONEEDLE
 7- MUCOADHESIVE POLYMER
 8- INSERTS

36. IMPLANTS
 Implants help in circumventing multiple
introcular injection and associated
complications.
 Implants use for drug delivery in posterior
ocular tissue

37. IMPLANTS
 For chronic ocular diseases like cytomegalovirus
(CMV) retinitis, implants are effective drug delivery
system. Earlier non biodegradable polymers were used
but they needed surgical procedures for insertion and
removal.
 Presently biodegradable polymers such as Poly Lactic
Acid (PLA) are safe and effective to deliver drugs in the
vitreous cavity and show no toxic signs

38. Eg. Of Implants-
 NONBIODEGRADABLE-
 VITRASERT- controlled release of ganciclovir for t/t of CMV
retinitis.
 RETISERT- release of Fluocinolone acetonide for t/t of chronic
uveitis of post. Segment.
 BIODEGRADABLE-
 SURODEX- release Dexamethasone for controle of postop
inflamation.
 OZURDEX- for t/t of Macular Edema

39. IONTOPHORESIS
In Iontophoresis direct current drives ions into cells or
tissues. For iontophoresis the ions of importance should
be charged molecules of the drug.
Positively charged of drug are driven into the tissues
at the anode and vice versa.
 Ocular iontophoresis delivery is not only fast,
painless and safe but it can also deliver high
concentration of the drug to a specific site.

40. Types of iontophoresis-
1. transcorneal
2. transscleral

41. DENDRIMER
 Dendrimer are nanosized, highly branched, star shaped
polymerise system
 Its highly branched structure allow incorporation of wide
range of drugs (Hydrophobic and Hydrophilic )
 Dendrimers can successfully used for different routes of
drug administration and have better water-solubility,
bioavailability and biocompatibility.

42. MICROEMULSION
Microemulsion is dispersion of water and oil
stabilized using surfactant and co- surfactant to reduce
interfacial tension and usually characterized by small
droplet size (100 nm), higher thermodynamic stability
and clear appearance.
Selection of aqueous phase, organic phase and
surfactant/co-surfactant systems are critical
parameters which can affect stability of the system

43. NANOSUSPENSION
Nanosuspensions have emerged as a promising
strategy for the efficient delivery of hydrophobic
drugs because they enhanced not only the rate and
extent of ophthalmic drug absorption but also the
intensity of drug action with significant extended
duration of drug effect.
For commercial preparation of nanosuspensions,
techniques like media milling and high-pressure
homogenization have been used.

44. MICRONEEDLE
Microneedle had shown prominent in vitro
penetration into sclera and rapid dissolution of coating
solution after insertion while in vivo drug level was
found to be significantly higher than the level
observed following topical drug administration like
pilocarpine

45. Microneedle is minimum invasive mode to deliver in
posterior ocular tissue.
Penetrate only 100 um of sclera so deposite drug into sclera
or into suprachoroid space.

46. MUCOADHESIVE POLYMER
 In this dosage form adhere to the precorneal mucus and
residue in the eye until the polymer dissolve or mucin
replace itself.
 These are in early phase of research.
 They are basically macromolecular hydrocolloids with plentiful
hydrophilic functional groups, such as hydroxyl, carboxyl,
amide and sulphate having capability for establishing
electrostatic interactions.

47. Some mucoadhesives are- carboxymethycellulose.
Carbopol, polymethymethacrylate, acrylic acid,
polycarbophil, sodium alginate.
A mucoadhesive drug formulation for the treatment of
glaucoma was developed using a highly potent beta
blocker drug, levobetaxolol (LB) hydrochloride and
partially neutralized poly acrylic acid (PAA).

48. INSERTS
 The ocular insert represents a significant advancement in
the therapy of eye disease. Ocular inserts are defined as
sterile, thin, multilayered, drug-impregnated, solid or
semisolid consistency devices placed into the cul-de-sac
or conjuctival sac, whose size and shape are especially
designed for ophthalmic application.

49. Ocular Inserts as an Ocular Sustained Release Drug
Delivery System
 The main objective of the ophthalmic inserts is to increase
the contact time between the preparation and the
conjunctival tissue, to ensure a sustained release suited for
topical or systemic treatment.
 The advantages of ocular inserts over the traditional
ophthalmic preparation can be summarized as follows-

50. ADVANTAGE
 Increased ocular residence, hence, prolonged drug activity
and higher bioavailability with respect to standard
vehicles.
 Release of drugs at a slow, constant rate
 Accurate dosing (insert contains a precise dose, which is
fully retained at the administration site).
 Reduction of systemic absorption.

51.  Better patient compliance, due to reduced frequency of
administration and less incidence of visual and systemic
side-effects.
 Possibility of targeting internal ocular tissues through non-
corneal (conjunctival scleral) routes.
 Increased shelf life with respect to aqueous solutions.
 Exclusion of preservatives, thus reducing the risk of
sensitivity reactions.
 Incorporation of various novel chemical / technological
approaches, such as pro-drugs, mucoadhesives,
permeation enhancers, micro particulates, salts acting as a
buffer.

52. Disadvantage
 A major disadvantage of ocular inserts resides in their
‘solidity’, that is, they are felt by the (often oversensitive)
patients as an extraneous body in the eye. This may constitute a
difficult physical and psychological barrier to patient
compliance.
 Their movement around the eye, in rare instances, the simple
removal is made more difficult by unwanted migration of the
insert to the upper fornix.
 The occasional unintentional loss during sleep or while rubbing
the eyes.
 Their interference with vision.
 Difficulty in placement of the ocular inserts (and removal, for
insoluble types).

54. A) Insoluble inserts-
e.g. Ocusert®:
 20-40µg/hr for 7day
 Annular ring : Impregnated with Ti02 : For Visibility
54
1. Diffusional Inserts :
•Central reservoir of drug
enclosed in Semi permeable or
microporous membrane for
diffusion of drug.
•Diffusion is controlled by
Lacrimal Fluid penetrating
through it.
•Release follows : Zero Order
Kinetics.

55. 3) Contact Lens :
 Presoaked Hydrophilic lens.
 Drug Release : within 1st 30 Min.
 Alternate approach : incorporate drug either as soln or suspension
.e.g. Pilocarpine.
 Release rate is up to : 180 hr.
55
2) Osmotic inserts
• A central part surrounded by a peripheral part
• Central part-single reservoir or two distinct compartments.
• Peripheral part- an insoluble semi permeable polymer.
•The tear fluid diffuse and induces dissolution.
•Solubilized deposits generate a hydrostatic pressure.
•Drug is then released through these apertures

56.  Use in treatment of Bullous keratopathy, Dry eye
syndrome, corneal condition requiring protection such as
traumatic corneal abrasion or erosions.

57. B) Soluble Inserts
1.SODI: Soluble Ocular Drug Insert.
57
• Small water soluble made of soluble synthetic polymers.
• Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.
• Weight 15-16 mg.
In 10-15 sec Softens;
In 10-15 min. turns in Viscous Liquids;
After 30-60min. Becomes Polymeric Solution.
•Single SODI application : replaces 4-12 eye drops Instillation, or
3-6 application of Ointments.
•Once a day treatment of Glaucoma.
Advantages of SODI :

58. 2.The corneal collagen shield
 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.
 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.
58

59.  Shaped like contact lens
 Thin membrane of porcine or bovine scleral collagen that
conform to cornea when placed on the eye so multiple
base curves are not necessary.
 Typically the drug is loaded into collagen shield by
soaking the shield into intended drug solution prior to
application.
 Hydrated shield form clear, thin film of 0.1mm thickness,
with a diameter of 14.5 and base curve of 9mm.

60.  Packaged in dehydrated state and require rehydration
before application.
 Dissolution rate have 12hr, 24hr, 72hr depending on
collagen cross linking.
 Shield dissolve as a result of proteolytic degradation by
the tear film.
 Before insertion shields must be rehydrated for atleast 3
minutes in saline, lubricating solution, antibiotic or
steroid.
 Prior topical anesthetic may required.

61.  for water insoluble drug such as cyclosporin drug need to
be incorporated into the shield at the time of
manufacturing.
 Collagen shield offers advantage of being entirely soluble
so that it so that it does not need to be removed from its
site of application.

62. C) Biodegradable inserts
1.Lacrisert:
• Sterile, Rod Shaped device.
• Composition: HPC.
• Weight:5mg,
• Dimension:Diameter:12.5mm, Length:3.5mm
• Use:-Dry eye treatment.
2.Minidisc:
 It is made up of counter disc with Convex front & Concave back surface in
contact with eye ball.
 4-5mm in diameter.
 Composition : Silicon based polymer.
 Drug release upto170 hr.
62

63. PARTICULATES (NANOPARTICLES
AND MICROPARTICLES)
Nanoparticle- <1 micrometre
Microparticle- >1 micrometre
The maximum size limit for microparticles for
ophthalmic administration is about 5-10 micrometer
above which a scratching feeling in the eye can result
upon ocular instillation.
 That is why micro and nanoparticles are promising
drug carriers for ophthalmic application.

64.  Nanopaticles are produced by emulsion
polymerisation.
 Polyalkylcyanoacrylate are most commonly used
ophthalmic nanoparicles.
 Many antiglaucoma drugs loaded onto nanoparicles
for testing efficacy.

65. CONCLUSION
All approaches improve ocular drug bioavailability by
increasing ocular drug residence time, diminish side
effects due to systemic absorption and diminishing the
necessary therapeutic amount of drug for therapeutic
response in anterior chamber.
They improve patient compliance by reducing the
frequency of dosing.
They reduce the dose and thereby reduce the adverse
effects of the drug.

66. ROUTES OF ADMINSTRATION
 Instillation into conjuctival sac
 Subconjuctival injection
 Sub tenon’s injection
 Retrobulbar injection
 Peribulbar injection
 Intraocular injection
 Systemic adminstration

67. SUBCONJUCTIVAL INJECTIONS
Use for wider range of substances , as the sclera allows the
free and indiscriminate transit of molecules of
considerable size.
It is usefull when higher intraocular concentration of
antibiotic or steroids are required as in acute anterior
segment infections and inflamtion.

68. SUB-TENON’S INJECTION
2types-
1. Anterior
2. Posterior
Antrior injection offers no advantage over sub conjuctival
injection.
Infact it is associated with perforating the globe
However anterior subtenon’s injection of corticostroids are
occasionaly used in the treatment of severe uveitis.

69. Posterior subtenon’s injection-
Used in t/t of chronic equatorial and mid zone
posterior uveitis, including inflammation of the
macular region.

70. RETROBULBAR INJECTION
 This procedure was originally devloped to anesthetize the
globe for cataract extraction and other intra ocular surgery.
 However retrobulbar corticosteroids are used occasionally
 Retrobulbar alcohol or phenol is rarely adminstrated for
intractable ocular pain in blind eye.

71. PERIBULBAR INJECTIONS
 Its also use the scleral route for acess into eye.
 A short curved needle with its bevel towards the globe is
passed through a conjuctival incision, and medication
injected close to the inflamed tissue.
 Use for t/t of intermediate and posterior inflamations.

72. INTRAOCULAR INJECTION
 1- Intracameral- injected into anterior chamber
 2- Intravitreal- into vitreous
 Half life of many drugs in Aqueous is only a few hours,
but in Vitreous it maybe 1-4 days.

73. SYSTEMIC ADMINSTRATION
 Disease which involve posterior part of retina, optic
nerve or orbit that can not be reached by local
application require systemic adminstration.