1. OCULAR DRUG DELIVERY
PRESENTED BY-
TARUN POKHARIYAL
M.PHARM. (PHARMACEUTICS)
JAIPUR NATIONAL UNIVERSITY
(JAIPUR)
1
2. CONTENTS
o INTRODUCTION
o EYE:ANATOMY & PHYSIOLOGY
o ABSORPTION OF DRUG IN EYE
o PHARMACOKINETIC
o CONTROLLED OCULAR DRUG SYSTEMS
o OCULAR DRUG DELIVERY DEVICES
o OTHER DELIVERY DEVICES
o RETROMETABOLIC DRUG DESIGN
o EVALUATION
o ADVANCED DELIVERY SYSTEM
o FUTURE TRENDS
o CONCLUSION
o REFERENCES
2
3. INTRODUCTION
Drug administration through eyes is just for
effect in eyes
To reduce the systemic absorption of drug is
primary goal
The normal volume of tears = 7 ul
the blinking eye can accommodate a volume of
up to 30 ul without spillage
the drop volume = 50 ul
3
4. ADVANTAGES-
disadvantages
1. Accurate dosing. 1. Perceived by patient as
2. Absence of preservative foreign body.
2. Movement around the
3. Increase in shelf life due to eye.
absence of water. 3. Occasional loss during
sleep or while rubbing
4.Best of drug with slow eyes.
dissolution eg.suspension 4. Interference with
vision.
5.Flexibilty in drug choice 5. Difficulty in placement
7.Rapid action & removal.
8. Self medication is easy 6.Patient non compliance
9.Decrease side effects to 7. Blurred vision
other organs 8. Irritation in eyes
9.Not suitable for running
people
4
6. The sclera: The protective outer layer of the eye
The cornea: The front portion of the sclera.
transparent and allows light to enter the eye.
Diameter-11.7mm and thickness -0.5-0.7mm
The choroid the second layer.
lies between the sclera and the retina.
contains the blood vessels & provide
nourishment to the outer layers of the retina.
The iris gives it color.
consists of muscular tissue that responds
to surrounding light,
6
7. The lens transparent, biconvex
structure, function-refract and focus
incoming light onto the retina.
The retina is innermost layer in the eye.
converts images into electrical impulses that
are sent along the optic nerve to the brain
where the images are interpreted.
The macula located in the back of the eye, in
the center of the retina. This area produces
the sharpest vision.
7
8. The inside of the eyeball is divided by the
lens into two fluid-filled sections.
The larger section at the back of the eye is
filled with a colorless gelatinous mass
called the vitreous humor.
The smaller section in the front contains a
clear, water-like material called aqueous
humor.
The conjunctiva is a mucous membrane
that begins at the edge of the cornea and
lines the inside surface of the eyelids and
sclera,
serves to lubricate the eye.
8
9. OPTHALMIC DISORDERS
COJUCNCTIVITIS- inflammation of conjuctiva
DRY EYE SYNDROME-inadequate wetting of
ocular surface
GLAUCOMA-
IRITIS-pain and inflammation
ROSACEA
BLEPHARITIS-inflammation of lid margin
CHALAZIA-meibomian cysts of eylid
KERATITIS
9
11. • Penetration across Sclera & Conjuctiva into Intra
Ocular tissues
• Non-Productive: because penetrated drug is
Non-Corneal absorbed by general circulation
Absorption
• Outer Epithelium: rate limiting barrier, with pore size
60å,Only access to small ionic & lipohilic
molecules
Corneal • Trans cellular transport: transport between corneal
epithelium & stroma.
Absorption
11
12. OCULAR ABSORPTION
Corneal Non-Corneal
Absorption Absorption
Depend upon physicochemical Penetration across Sclera &
properties of drug Conjunctiva into Intra
Ocular tissues
Only access to small ionic & Non-Productive: because
lipophilic molecules penetrated drug is absorbed
by general circulation.
Outer Epithelium: rate limiting
barrier Minor pathway
Trans cellular transport:
transport between corneal Important for drug with
epithelium & stroma low corneal permeability
e.g. pilocarpine e.g. inulin
12
16. Also
responsible
for serious
side effects
THE NASOLACHRYMAL DRAINAGE SYSTEM
16
17. TRANSCORNEAL PENETRATION
Transcellular pathway
EFFECTED MAINLY BY:-
1.CORNEAL BARRIER
Paracellular pathway
2. PROPERTIES OF DRUG
SECTION THROUGH THE CORNEA.
17
18. Small molecules eg glycerol
m.w.92 are able to penetrate
Contain very hydrophilic
Tissue, mol.size of 500
microm
Can diffuse in stroma
Schematic of corneal structure and its cellular
organization of various transport-limiting barriers 18
19. Physiochemical properties of drug:-
Hydrophilic drugs penetrate through
paracellular pathway
Lipophilic drugs penetrate through
transcellular pathway
Drugs topically applied – passive diffusion
Transport of lysine – NA-K-ATPase pump
involved- carrier mediated transport.
Drug loaded nanoparticles- endocytic
pathway.
19
20. Lipophilicity
Solubility
Molecular size & shape
Charge
Degree of ionization
Chemical equilibrium between ionized and
unionized in eye drop and in lacrimal fluid
effect the penetration of ionizable drug.
Eg -pilocarpine (free base ) and timolol base
penetrate better than its ionized form.
20
21. NON –CORNEAL ABSORPTION
CONJUCTIVA ABSORPTION- for hydrophilic & mol.
Size of 20000-40000 eg. insulin
SCLERA –through perivascular space
through aq. Media of gel
more permeable than cornea
mol.weight 229-1056 eg. Sucrose,inulin
RETINA
BLOOD RETINAL BARRIER
21
30. CONTROLLED DRUG DELIVERY
REQUISITES OF CDDS
a. To overcome the side effects of pulse dosing
b. Provide sustained and controlled drug delivery
c. To increase ocular bioavailability
d. To provide targeting within the ocular globe
e. To circumvent the protective barriers
f. Patient compliance
g. Improved therapeutic effect
30
32. WAYS TO GET THE AIM…..
POLYMERIC SOLUTION
PHASE TRANSITION SYSTEM
MUCOADHESIVE/ BIOADHESIVE SYSTEM
COLLAGEN SHIELDS
PSEUDOLATICES
OCULAR PENETRATION ENHANCER
OCULAR IONTOPHORESIS
OCULAR DD DEVICES
32
33. POLYMERIC SOLUTION:- eg. Methyl
cellulose, PVA,HPC,PVP.
Increase the corneal penetration.
PHASE TRANSITION SYSTEMS:-liquid dosage form
eg. Lutrol FC-127
poloxamer 407,
gallen gum : forms in gel in presence of sod. ions
2.6 gm/L sodium ions ions in tears
cellulose acetate pthalate coagulates when pH
increased 4.5 to 7.4 33
34. USE OF MUCOADHESIVES IN
OCULAR DRUG DELIVERY
Mucoadhesives adhered to cornea
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. 34
35. MUCOADHESIVE / BIOADHESIVE DOSAGE FORM:-
Polymer adhere to the mucin
These may be polymeric solution or microparticle
suspension
Muco… polymers mainly macromolecular
hydrocoloids with hydrophilic groups
eg.carboxyl,hydroxyl,amide
35
36. Mechanism of mucoadhesion
• The polymer undergoes swelling
in water,
• Entanglement of the polymer
chains with mucin on the
epithelial surface.
• The un-ionized carboxylic acid
residues on the polymer form
hydrogen bonds with the mucin.
• The water-swellable yet water-
insoluble systems are preferred
36
38. Factors:-
Dissolution of polymer
Chain flexibility
mol. Weight
pH and ionic strength
COLLAGEN SHIELDS:-
It is main constituent of food grade gelatin
Comprise 25% of total body protein in mammels
Drug delivery by collagen shield……
38
39. 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. 39
40. PSEUDOLATICES :-polymeric colloidal dispersion and
film forming agent
OCULAR PENETRATION ENHANCER :-topical
applied peptide and protiens.
Eg. Actin filament inhibitor
surfactants
bile salt
chelators
organic compounds
OCULAR IONTOPHORESIS:-
40
41. NANOPARTICULATE DRUG DELIVERY
Size:10-1000nm
Types- 1.nanospheres , 2.nanocapsules
Drug is Dispersed, Encapsulated, or Adsorbed
Particulate systems in nanoparticulate drug deliery-
1,Topical system e.g. chloramphenicol
(suspended), 2.local injectable system e.g. 5FU
Polymer used are Biodegradable.
e.g. polyalkylacrylates
41
42. Advantages of nanoparticles
Sustained drug release and prolonged therapeutic
activity
Site-specific targeting
Higher cellular permeability
Protect the drug from chemical or enzymatic
hydrolysis
Efficient in crossing membrane barriers -blood
retinal barrier
Act as an inert carrier for ophthalmic drugs
42
44. OCULAR DRUG DELIVERY DEVICES
IMPLANTABLE
CAPSULAR TYPE DRUG
DRUG DELIVERY DELIVERY
SYSTEM PUMPS
Ocuserts Osmotic
minipumps
Implantable
infusion systems
44
45. HYDROPHILIC SOFT CONTACT LANSES
Bionite was developed in griffin lab.
Soflens was developed by Bausch &Lomb.
contact lanses made from hefilcon-A
Copolymer(80% 2-hydroxy ethyl methacry
-late and 20% N-vinyl-2-pyrollidone)
16 mm in diameter
0.3 mm thick
45
46. OCULAR INSERTS
Classification of
ocular inserts
Insoluble inserts
Bioerodible inserts
• Diffusion e.g.
based(Ocusert®) Lacrisert®, Minidisc.
• Osmotic based
• Soft(presoaked)
contact lenses Soluble inserts e.g.
SODI, BioCor®-12,24,72.
46
47. Desired criteria for ocular inserts
* Ease of handling and insertion
* Lack of expulsion during wear
* Reproducibility of release kinetics (Zero-order
drug delivery)
* Applicability to variety of drugs
* Non-interference with vision and oxygen
permeability.
* Sterility.
* Ease of manufacture
47
49. A) Insoluble inserts-
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.
e.g. Ocusert®:
20-40µg/hr for 7day
Annular ring : Impregnated with Ti02 : For Visibility
49
50. SOLUBLE OCULAR INSERTS:-
Eg. Poly vinyl alcohol inserts
Soluble opthalmic drug insert
Polypeptide devices
SODI –thin elastic oval plate Made from polymer and
Copolymer of polyacrylamide , ethylacrylate and
vinylpyrollidone
MOA:-……
Advantages of SODI
•Single SODI application : replaces 4-12 eye drops Instillation, or
3-6 application of Ointments.
•Once a day treatment of Glaucoma. 50
51. 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.
51
52. LIPOSOMES
• Vesicle composed of phospholipid bilayer enclosing
aqueous compartment in alternate fashion.
• Biodegradable, Non-toxic in nature.
• Types :1.MLV
2.ULV-SUV(upto 100 nm)
LUV(more than 100 nm)
• Polar drugs are incorporated in aqeous compartment while
lipophilic drugs are intercalated into the liposome
membrane
• Phospholipids used- Phophotidylcholine, Phophotidic
acid, Sphingomyline, Phosphotidyleserine,Cardiolipine 52
53. ADVANTAGES DISADVANTAGES OF
• Drugs delivered intact to various LIPOSOMES
body tissues. .
• Liposomes can be used for both
hydrophilic and hydrophobic drug. • They need many modification
• Possibility of targeting and for drug delivery to special
decrease drug toxicity. organs.
• The size, charge and other • Cost .
characteristics can be altered
according to drug and desired
tissue.
53
56. SCLAREL BUCKLING MATERIALS:-
Eg. Gelatin film & solid silicon rubber impregnated
with antibiotic
OCUSERT AND RELATED DEVICES:-
A true controlled and continuous release and zero
order kinetic fashion achieved by ocusert
First marketed by ALZA corporation pilocarpine
ocusert improved the noncompliance problem
56
57. Two types of ocuserts
Ocusert pilo- 20 – 20 µg/h for 7 days
Ocusert pilo- 40- 40 µg/h for 7 days
IMPLANTABLE SILICON RUBBER DEVICES:-
For hydrophobic drugs
BCNU(1,3-bis(2-chloroethyl)-1-nitrosourea)
consist two sheets of silicon rubber (0.13mm thick)
57
58. OSMOTIC MINIPUMP
Generic osmotic minipump(ALZET) is a useful
implantable system.
Pumping duration 2 weeks
IMPLANTABLE INFUSION SYSTEM
Infusaid - device permit long term infusion via
refilling in animals
Pumping force generated by an expending fluid
(Flurocarbon at liq. Gas equilibrium) at body
temp.
58
59. Registered Active Implant size Marketing
name substances status
vitrasert® Ganciclovir Millimeter Clinical use
retisert® Flucinolone Tablet 3mmx 2mmx Clinical use
acetonide 5mm
Medidur Flucinolone Cylindrical tube 3.5 Phase 3
acetonide mm in length and
0.37 mm in diameter
Posurdex Dexamethasone Microsized implant Phase 3
Ozurdex® Dexamethasone intravitreal implant) Clinical use
0.7 mg
59
60. OTHER DELIVERY SYSTEMS
Ocufit –currently developed. Made by silicone
elastomer.
Diameter-1.9 mm & length is 25-30 mm
Lacrisert- made up of cellulose
used to treat dry eye patients.
Minidisc ocular therapeutic system
New opthalmic delivery system
60
61. RETROMETABOLIC DRUG DESIGN
METABOLISM CDSn
CDS1
M1
METABOLISM
D
M2
CDS
Mn
RETROMETABOLIC DESIGN
I1
I2
METABOLISM
Mi
SD
RETROMETABOLIC DRUG DESIGN
61
62. EVALUATION
1. Gelling capacity
2. Rheological properties
3. In vitro drug release
4. Texture analysis
5. Isotonicity evaluation
6. Drug polymer interaction study
7. Thermal analysis
8. Antibacterial activity
9. Occular irritancy test
10. Accelereted stability study
62
63. 11. Thickness of ocular film
12.Drug content uniformity
13.Uniformity of weight
14.% moisture content
15. % moisture loss
16. Sterility testing
17.Growth promotion test
63
64. ADVANCED DELIVERY SYSTEM
1. Cell encapsulation
2. Gene therepy
3. Stem cell therepy
4. Protein ad peptide therepy
5. Sclaral plug therepy
6. Si RNA therepy
7. Oligonucleotide therepy
8. Aptamer
9. Ribozyme therepy
64
65. FUTURE TRENDS
The sustained and controlled release technologies
are being proposed and the possible benefits of
using liposomes, nanoparticles and inserts will
be at store in future.
Targeted drug delivery with modifications of
conventional, advanced and novel ocular drug
deliveries has potential as future drug delivery
for eye.
It is possible to the give effective ocular drug
delivery to any part of the eye.
65
68. CONCLUSION
Very few advanced ocular drug delivery
systems have been commercialized.
The performance of these new
products, however, is still far from being
perfect.
More clinical studies are necessary to provide
further information and insights into these
advanced ocular drug delivery systems.
68
69. REFERENCES
1. “ Targeted and controlled drug delivery system” by Vyas S.P. and Khar K. R.,
published by CBS Publishers and distributors, first edition 2002
2. http://www.jgtps.com journal of global trend in pharmaceutical sciences
Patel vishal & Y.K. Agrawal “current status and advanced approaches in
ocular drug delivery system
3. Kumari A, Sharma PK and Garg VK: Ocular inserts — Advancement in
therapy of eye diseases. Journal Advance Pharmaceutical Technology Research
2010; 3: 87-96.
4. Rathore K.S. review on “in – situ gelling ophthalmic drug delivery system”
International journal of pharmacy and pharmaceutical sciences
5. V. Shankar , A.K. Chandrasekharan , S. durga. “ design and evaluation of
diclofenac sodium ophthalmic inserts. Acta pharamaceutica sciencia 48: 5-10
(2006) .
69
70. The eyes are the mirror of the
soul…
Take care of your eyes
with gentleness.
70
