This document discusses formulation and evaluation of ocular controlled drug delivery systems. It begins by describing the anatomy of the eye and barriers to drug delivery. Various approaches to optimizing ocular delivery are discussed, including improving contact time, permeability and site specificity. Requirements for controlled delivery systems include overcoming issues with pulsed dosing, providing sustained delivery and increasing bioavailability. Several recent trends in ocular dosage forms are described, such as polymeric solutions, phase transition systems, mucoadhesive forms and collagen shields. Evaluation methods for ocular inserts are also outlined, along with case studies on pilocarpine delivery systems.

1. FORMULATION & EVALUATION
OF OCULAR CONTROLLED DRUG
DELIVERY SYSTEM
Presented by
Saiesh phaldesai

2.  Human eye has a spherical shape
with a diameter of 23mm
 cornea , lens , viterous body not
have blood suply
 Oxygen and nutrients are supplied
by aqueous humour
 Cornea is formed by criss crosing
layer of collagen and bounded by
elastic laminae

3. EYE BALL
 The wall of the human eye (globe) is composed
of concentric layer;
 The outer fibrous layer.
 A middle vascular layer :
Uvea tract - choroid,
cilliary body, and iris.
 A nervous layer-the retina.

4.  The sclera consist of tough fibrous layer
 Both cornea and sclera withstand the intraocular
tension maintained in the eye
 The eye is constantly cleansed and lubricated by the
lacrimal appartus
1. lacrimal gland
2. lacrimal canal
3. lacrimal sac
4. nasolacrimal duct

5. COMPOSITION OF TEAR
The secretion is a clear, watery fluid containing
numerous salts, glucose, other organic
compounds, approximately 0.7% protein and the
enzyme, lysosome.
Water-98.2% Organic Protein0.67%
Solids-1.8% element Sugar-0.65%
Nacl-0.66%
Urea-0.03%

6. FORMULATION OF OCULAR
DELIVERY SYSTEM
The conventional ocular dosage form for
delivery of drugs are :
I. Eye drops
II. Eye ointments
III. Eye suspension

7. Eye drops : -
Advantages : most prescribed dosage form
easy to instill
Disadvantage : rapidly drained away
1.2% bioavailabilty
large fluctuation in intraocular drug level
get diluted in the tear
freq . adm’n needed to maintain sustained level
limited corneal permeability
very dose is reqd
7

8. Eye ointments : -
Advantages :
larger contact time and greater
bioavailability although slower onset and
time of peak absorption
.

9. Eye suspension : -
Advantages : longer duration of
action
Disadvantages : impredictable
release
change in drug level due to const
inflow and outflow of lacrimal fluid
this effects drug dissolution from
insoluble drug particles

10. Approaches made towards optimization of ocular delivery
systems:
 1) Improving ocular contact time
 2) Enhancing corneal permeability
 3) Enhancing site specificity

11. REQ UISITE OF CONTROLLE D
DR UG DELIVERY SYSTEM
1) To overcome the side effects of pulsed dosing (frequent
dosing and high concentration) produced by conventional
systems.
2) To provide sustained and controlled drug delivery.
3) To increase the ocular bioavailability of drug by increasing
corneal contact time. This can be achieved by effective
coating or adherence to corneal surface.
4) To provide targeting within the ocular globe so as to prevent
the loss to other ocular diseases.

12. 5) To provide comfort and compliance.
6) To provide the protective barriers like drainage,
lacrimation and diversion of exogenous
chemicals into systemic circulation by
conjuctiva.
7) To provide the better housing of delivery
system in eye.
8) To provide prolonged drug release.

13. FACTORS INFLUENCING OCULAR
BIOAVAILABILTY
1. Dilution of drug soln
2. Nasolacrimal drainage
3. continuous inflow & outflow of lacrimal fluid
also cause loss of drug
4. The lacrimal fluid constituent like proteins
degrade the drug
5. Productive and non productive absorption of
topically applied drug

14. THE FOLLOWING RECENT TRENDS OF
DOSAGE FORMS ARE IN VOGUE:
 1) Controlled ocular delivery systems:
1. Polymeric solutions
2. Phase transition systems
3. Mucoadvesive/ bioadhesive dosage forms
4. Collagen shields
5. Pseudolatices
6. Ocular penetration enhancers
7. Ocular iontophoresis.

15. 2) Ocular drug delivery devices:
1) Matrix-type drug delivery systems.
i) Hydrophilic soft contact lenses
ii) Soluble ocular inserts
iii) Scleral buckling materials
2) Capsular-type drug delivery systems.
i) Ocuserts and related devices
ii) Implantable silicone rubber device
3) Implantable drug delivery pumps.
i) Osmotic minipump and implantable infusion system
4) Others.
i) Ocufit & lacrisert
ii) Minidisk ocular therapeutic system
iii) New ophthalmic delivery system.

16. CONTROLED OCULAR DELIVERY
SYSTEM
A) Polymeric solution: the addition of polymers like
methyl cellulose , poly vinyl alcohol, hydroxy
propyl cellulose and poly vinyl pyrolidine to the
eye drop solutions increases the corneal
penetrations of drugs. This is presumably due to
an increase viscosity, which decrease the rapid
initial drainage rate, increase corneal contact
time and thus sustains to some extent the initial
tear concentration of drug

17. B) Phase transition systems: these are the liquid dosage
forms which shift to the gel or solid phase when
instilled into the cul-de-sac.
There are three types of phase transition systems:
i) Temperature dependent phase transition systems:
polymers that are normally used are lutrol FC-127 and
poloxamer 407,
ii) pH triggered phase transition systems:
cellulose acetate phthalate and carbopol
iii) Ion-activated systems:
gelrite and gellan is a new phase transition system

18. C) Mucoadhesive/ bioadhesive dosage forms
1) A good bioadhesive should exhibit a near zero
contact angle to allow maximal contact with the
mucin coat.
2) To diffuse and penetrate into mucin layer,
flexibility in chain of polymer is required.
3) An increase in molecular weight to a critical
value, increases the bioadhesion.
4) pH and ionic strength of dosage from also
affects the bioadhesion performance

19.  Increases the corneal contact time
 water soluble polymers face the disadvantage of
having a short half life.
 The adhesion often detaches itself from the rate
controlling drug delivery device and caused a
premature release of drug.
 Ex- . polycarbophil exhibits strongest
bioadhesion at an acidic pH, Hydroxy propyl
cellulose(HPC), polyacrilic acid, PEG, dextrans,
hyaluronic acid, polygalactouronic acid,
xyloglucon etc

20. D)Collagen Shields:
 For the drug delivery, the shields are rehydrated in
water solution of drug, where the drug is absorbed by
the protein matrix and is released once the shield
dissolves in eye.
 As the dissolution time for the cross linked collagen
shields are longer than those of the non cross linked
type they might be useful ocular delivery devices
because they can allow to achieve higher drug
concentration in cornea and aqueous humor.
 Drawbacks:
Application of shield requires anaesthetize the cornea.
Often produce some discomfort.

21. E) Pseudolattices: are a new class of polymeric colloidal
dispersions and film forming agents . Before instillation
of organic solution of polymer, by applying vacuum or by
using controlled temperature, to remove water partially
and to an extent that residual water is sufficient to
disperse in an aqueous phase to form a o/w type
emulsion. Such dispersions are referred as a
pseudolattices.
The drug from such systems is released slowly over a
prolonged period of time ensuring better ocular
availability and patient compliance by avoiding frequent
instillation of preparation.

22. F) Ocular Penetration Enhancers: like actin filament
inhibitors, surfactants, bile salts, chelators and organic
compounds have been used to increase the
bioavailability of topically applied drugs
Drawback: Tissue irritation and damage.
G) Ocular Iontophoresis: is a process in which the direct
current drives ions into the cell or tissues

23. MATRIX – TYPE DRUG
DELIVERY SYSTEM
1.Hydrophilic soft lenses:
These are easy to fit, well tolerated, & hydrophilic
soft contact are more popular for correction of hydro
gel like PHP (helifcon-A) co-polymer(80% of 2-hydroxy-
ethylmethacrylate and 20% of N-vinyl-2-pyrolidone).
16mm - diameter, 0.3mm - thickness,
40% to 45% - hydration.

24.  These lenses are presoaked in prednisolone sodium
phosphate -20min they were able to maintain
aqueous and corneal level 2-3 times higher at 4hr,
than the level obtained after topical administration of
plain predinsalone soln .
 Idoxuridine , polymixin B, pilocarpine
24

25. 2.Soluble ocular insert :
These ate thin, elastic, oval plates and made from
polymer (PVA) and co-polymer of polyamide,
ethylacrylate and vinyl pyrrolidine.
when SODIs inserted into a conjunctival sac. It
absorbs tears rapidly, swells and dissolves-30-90min
and release the drug in a controlled manner.
Eg : hydrocortisone 10 mg SODI

26. 3. Scleral buckling materials :
These are used in retinal detachment surgery as they
causes post operational infection . So to prevent this
complication, scleral buckling material can be made
to absorb an antibiotic.
₪ Gelatin film
₪ Solid silicon rubber

27. CAPSULAR - TYPE DRUG
DELIVERY SYSTEM
1.Ocusert and related device :
The system consists of a pilocarpine and alginic acid are
sandwiched between 2 thin transparent-rate controlling
ethylene-vinyl acetate co-polymer membrane. A retaining
ring of same material impregnated with titanium dioxide
encloses the drug resorvoir.
Eg : pilo -20 , pilo -40

28. 1.Ocusert and related device :
Drug release controlling
polymer
Titanium dioxide ring
Drug reservoir
Polymer membrane

29. 2.Implantable silicone rubber device :
 By using this device hydrophobic drug can deliver
at a constant release rate.
 BCNU (1,3bis{-2-chloro ethyl}-1-nitrosurea) is an
intraocular malignancy agent.
 It consists of 2 sheet of silicone rubber glued
together only at the edges with silicone adhesive,
which release the drug at constant rate about (200-
400µg/h).

30. IMPLANTABLE DRUG DELIVERY
SYSTEM
Osmotic mini pump & Implantable infusion
system :
 The osmotic mini pump is a useful implantable drug
delivery system with a constant drug delivery rate with
a pumping duration of up to 2 weeks.
 The implantable infusion system, the pumping force is
generated by an expanding fluid (a fluorocarbon in
liquid gas equilibrium) at body temperature.

31. OTHER DELIVERY DEVICES
OCUFIT:
Sustained release, rod shaped device made up of silicone
elastomer and these are designed to fit the shape and
size of the human conjunctional.
LACRISERT:
Cylindrical device, which is made of cellulose and used to
treat dry eye patients. These devices have a long
retention (2-weeks or more) and sustained release.

32. MINIDISK OCULAR THERAPEUTIC SYSTEM
It is a monolithic polymer device, shaped like
miniature contact lens, with a convex and concave
faces. The device can easily be oxygen permeabile
because of its particular size and shape.
Advantage:
Requires less time and less manual skill for
insertion, when compared with lacrisert.

33. New ophthalmic delivery system (NODS): is a
method of presenting drugs to the eye with a
water soluble drug loaded film. It provides for
accurate, reproducible dosing in an easily
administered preservative form
Microsphere / nanosphere :
Poly alkyl cyano acrylate (PACA)
Poly E caprolactone (PECA)
eg or drugs – metipranolol , betaxalol
decrease particle size increase bioavailability

34. Liposomes :
Advantages – controlled release
more favorale for hydrophobic drug
protection from ocular enzymes
non toxic
non irritant
intimate contact with the cornea
increased permiabilty
eg – idoxuridine , pen-G ,
ephenephrine ,
cyclosporin

35. Niosomes :
dialkyl polyoxyetylene ether , cholestrol
vesicles
Advantages : stable
for both hydrophillic and hydrophobic
non toxic
bio–degradable
biocompatable
non immunogenic
improved bioavailabilty
CR and targetting

36. SOFT DRUG SYSTEMS (SDS)
Active biological substance which are deactivated in a
predictable and controlled way after they achieve there
therapeutic role
1) Soft analogues – closely structural similarality with
metabolite
2) Active soft compounds – inactive compd +
pharmacophore eg – N – choloramine antimicrobials
3) Inactive metabolite – inactive metabolite converts to
parent drug analogue which after action again
converted into inactive eg – sds of atropine

37. 4) Controlled release of endogeneous soft compds –
harmones and neurotransmitter are the natural SDS
Eg for SDS – soft steroids ,beta adrenargic blocker ,
prostaglandin

38. EVALUATION OF OPHTHLMIC INSERT
Physico-chemical properties:
Moisture Absorption (%)
Moisture loss (%)
Thickness (mm)
Weight Variation (mg)
Folding Endurance
Drug Content- In-vitro kinetics
In-vivo release studied

39. INVIVO STUDIES
For the study purpose :
 Rabbits weighing 2-2.5 kg, they fed—standard diet.
 One drug-ophthalmic insert-right eye-test.
 Blank-left eye-control (cul-de-sac).
 At regular time interval remaining ocular insert were removed
and analyze for the drug content by using uv-visible
spectrophotometer.
Drug released Initial drug Drug content
content at any content after removal
time before placing of occusert
the ocusert from eye

40. PILOCARPINE DRUG DELIVERY
SYSTEM
 It is the chief alkaloid extracted from the leaf lets of
pilocarpus jaborandi and pilocarpus microphyllus.
 Highly preferred---ocular hypotensive agent ---
decrease intra ocular pressure.
 Effect--cholinomimetic,

41. BIOPHARMACEUTICS OF OCULAR
PILOCARPINE ADMINISTRATION
1. Dilution of drug soln
2. Nasolacrimal drainage
3. continuous inflow & outflow of lacrimal fluid
also cause loss of drug
4. The lacrimal fluid constituent like proteins
degrade the drug
5. Productive and non productive absorption of
topically applied drug

42. PRECORNEAL DISPOSITION OF DRUGS
lacrimal fluid Lacrimal
Occular gland
delivery
Precorneal
Corneal
cavity
epithelium
Lacrimal
canal stroma
Conjuctival
Lacrimal uptake
Aq.humor
sac
Nasolacrimal
duct Elimination
Systemic
Circulation

43. Disposition of drug take place by
1. Nasolacrimal drainage (80 %)
2. Tear turn over
3. Productive corneal absorption
4. Non productive conjunctival uptake
nasolacrimal drainage removes the drug untill the volume
reaches to normal residual tear volume (7.5 micro lt)
Smaller the instilation volume better is the bioavailabilty

44. TRANSCORNEAL PERMEATION OF
PILOCARPINE
1. The existence of a permeation barrier in the
lipophilic corneal epithelium
2. Uptake and permeation of drug through
cornea are rapid process
3. Transport of pilocarpine from the cornea to
the anterior chamber is controlled by corneal
endothelium
4. Pilocarpine depot somewhere in the cornea

45.  Transcorneal permeation depends upon nature
of penetrant moleculle
 The drug must have optimum patition coeft to
get absorbed
 Pilocarpine reach the max after 5min in
epithelium and cornea the decline follow
biexponential
 In case of aq.humour and stroma the peak pt is
achieved after 20 min and then declines
 Pilocarpine elimination rate const is same in
cornea and aq.humour
 Corneal epithelium is the main barrier to the
transcorneal permeaton

46. PHARMACOKINETICS OF TRANSCORNEAL
PILOCARPINE PERMEATION
Tear flow
qT
Precorneal k Epithelial kaE Corneal k eE
a Stroma
drug pool surface epithelium kas
ke kaAH k es
Knl kem
Aq.humour
Conjuctiva
Nasolacrimal keAH
drainage
metabolism
Elimination

47. qt = normal production rate of tear (.66 micro lt)
knl =1st order rateof elimination through
nasolacrimal drainage
Kc = rate const for conjuctival uptake
Ka = rate const for epithelial uptake
kaE = rate const for absorption into epithelium
keE = rate const for elimination from epithelium
kaS = rate const for absorption into stroma
epithelium
keS = rate const for elimination from stroma
kaAH=rate const for absorption into aq. humour
k AH= rate const for elimination from aq. humour

48. Considering eye as two major
compartment
Precorneneal area
 Aq. Humour
Rate of pilocarpine disappears from the precorneal
compartment as
dCT = -qT CT – KpSc/ hc (CT – CAH)
dt VDe –Knlt + V0
Rate of appearance of pilocarpine in the aq humour
dCAH KpSc (C – C ) - K CAH
= T AH eAH
dt VAH hc VAH

49. CT = drug conc in tear fluid
CAH = conc of drug in aq.humor
KP =specific transcorneal permeation rate (3.675
*10 -4 )
Knl =(0.25 +0.0113 VD ) min-1
SC = surface area of cornea (2 cm2 )
H = thickness of cornea (0.035cm)
V0 = normal residant tear volume (7.5 )
VD = drop size of drug soln instilled
VPC = volume of drug pool in precorneal area
after instillation of eye drops
VAH = volume of aq.humor

50. Elimination of pilocarpine follows biphasic pattern
alpha phase has an
apparent absorption rate 0.50 /min
apparent elimination rate 0.06 / min
Beta phase
apparent elimination rate – 0.016/ min
Stroma endothelium consist one absorption and one
elimination phase which has similar pk as of aq.humour
i.e kaAH = keS
Hence endothelial layer doesnot act as a barrier for the
moment of drug from cornea to aq.humor

51. Epithelium of cornea is the rate controlling barrier
in the transcorneal permeation of pilocarpine
Once the drug reaches the precorneal area it
undergo disposition by various ways
Due to the protein binding also the bioavailability
decreases

52. CONTROLLED OCULAR
PILOCARPINE DELIVERY BY
OCUSERT SYSTEM
The ocusert system is an oval flexible ocular insert
that consists of a core reservoir made from
complexation of pilocarpine with alginic acid
sandwiched between two sheets of a transparent,
lipophilic rate-controlling membrane of ethylene-
vinyl acetate copolymer. When inserted it released
through the rate-controlling membrane according
to a zero-order kinetics process.
52

53. EXPLAIN MATHEMATICALLY BY
EQUATION:
(dQ/ dt)r = Dp km (CR-CT)/hm
Where,
dQ/dt = release rate of pilocarpine from a
unit surface area of the ocusert system.
Dp = diffusivity of plocarpine from in
the ethylene-vinyl acetate co-polymer
membrane with thickness hm
Km = partition coefficient of pilocarpine
towards the membrane.
(CR-CT) = difference in pilocarpine concentration
between the pilocarpine reservoir in the
medicated core (CR) and the tear fluid (CT).

54.  Ifan infinite sink condition is maintained in the ocular
cavity that is CR>>CT then equation is simplified.
(dQ/ dt)r = Dp km Cs/hm.
 The release rate of pilocarpine from the ocusert
system should remain constant until the drug
concentration in the reservoir CR drops off below the
pilocarpine saturation level Cs.

55.  Membrane permiability can be increased by adding
dipthalate during fabrcation
 The release rate is not efeected by the ca inhibitor
ephenephrine , NSAIDS etc .
 8-10 times more efficient than 2% eye drops
 Increased patient complience
 Decreased dosing frequency
 Sustain release
 Less side effects (decreased myopia )

56. REFERENCES
 Vyas S P, Roop K Khar. Controlled Drug
Delivery Concepts and Advances. 1 st Edition
Vallabh Prakashan Delhi.2002.
 Chien Y. W, Novel Drug Delivery System.
Marcell Decker Inc., Ed.1992.
 Jain N. K, Advances In Controlled & Novel
Drug Delivery, CBS Publication, Ed.2003.
 www.soople.com
 www.google.com
56

57. Thank You