Contents Introduction Objective Anatomy of the Eye Routes of drug delivery of the eye Mechanism of ocular absorption Factors affecting intra-ocular bioavailability Barriers of ocular drug absorption Methods to overcome drug barriers Evaluation Conclusion Reference Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. Applied topically to the cornea, or instilled in the space between the eyeball and lower eyelid Definition: Ocular DDS are designed to instilled on to topical or intra-ocular or peri-ocular to eye. Most commonly used ocular dosage forms- - Solutions - Suspensions - ointments 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.

1. OCULAR DRUG
DELIVERY SYSTEMS
Presented By: Miss. Sneha A. Pachore
(M.Pharm 1st Year)
Dept. of Pharmaceutics

2. Contents
 Introduction
 Objective
 Anatomy of the Eye
 Routes of drug delivery of the eye
 Mechanism of ocular absorption
 Factors affecting intra-ocular bioavailability
 Barriers of ocular drug absorption
 Methods to overcome drug barriers
 Evaluation
 Conclusion
 Reference
1

3.  Ocular administration of drug is primarily associated with the
need to treat ophthalmic diseases.
 Applied topically to the cornea, or instilled in the space
between the eyeball and lower eyelid
 Definition: Ocular DDS are designed to instilled on to topical or
intra-ocular or peri-ocular to eye.
 Most commonly used ocular dosage forms-
- Solutions
- Suspensions
- ointments
 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. 2

4. OBJECTIVE
 The main objectives of ocular administration of drug is:
1. To treat ophthalmic diseases: e.g. Inflammation, conjunctivitis
2. To correct disorder: Glaucoma
3. For diagnostic purpose: poisoning due to ant-cholinergic drug
e.g. Belladona
 The newest dosage forms for ocular drug delivery are:
Gels Liposomes
Solutions Nano-suspenstions
Polymeric drug carriers Implants
4

5. 5

6. 6

7. ROUTES OF ADMINSTRATION
1. Instillation into conjuctival sac :
2. Sub- conjuctival injection : sclera allows the free transit of
molecules of considerable size. E.g. antibiotic or steroids
3. Sub tenon’s injection :
2types-
1. Antrior injection- found between back of cornea &
front of lens, contains aqueous humor. E.g. corticosteroids are
occasionally used in the treatment of severe uveitis
2. Posterior injection- found between lens & retina ,
vitreous humor contains. Used in t/t of chronic equatorial and mid
zone posterior uveitis, including inflammation of the macular
region.
7

8. 8

9. Drug in tear fluid
Ocular Absorption
(5% of the dose)
Corneal Route:
- 1o route
- small,
lipophilic
drugs
Conjunctivital and
Scleral Route:
- Large Hydrophilic
drugs
Systemic absorption:
(50 – 100 % of dose)
Major Routes:
- Conjunctiva
- Pharynx
- GI tract
- Skin at the cheek &
lids
- Aqueous humor
- Inner ocular tissues
Aqueous Humor
Ocular Tissues Elimination

10. 10

11. 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.
7. Physico-chemical properties of the drug.
8. Limited & poor corneal permeability.
9. Poor residence time of drug in eye.
10. Poor rate of absorption.
11. High dosing frequency.
11

12.  Precorneal 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)
12

13. 13

14. 1. Drug loss from ocular surface: by lacrimation, by systemic
absorption.
2. Lacrimal fluid – eye barrier: lipophilic/hydrophilic drugs
3. Blood – ocular barrier:
 The reason why it is difficult to achieve relevant therapeutic dose
within the eye is primarily due to presence of multiple barriers
 When a dosage form is either administered topically or
systematically it faces multiple obstacles before it reaches to the
site of action.
1. Anatomical barrier: cornea
2. Physiological barrier: reflex blinking
3. Drug & dosage form related barriers
14

15. 1. CORNEA:
 The greatest barrier to drug penetration is Corneal epithelium -
only non ionized drug penetrate.
 It is rich in cellular membrane & is more susceptible to
penetration by drugs which are lipophilic.
 Stroma- only ionized drug can pass.
 Drugs which are hydrophilic in nature can pass through middle
layer i.e. stroma
 So, drug must have capacity to exist in both ionized and non-
ionized form for a better penetration
 Eg- homatropine
15

16. 2. REFLEX BLINKING:
 Normal eye dropper delivers 25-56 μL
 However eye can transiently hold up to 30 μL & rest is lost either
by naso-lacrimal drainage or by reflex blinking (5-7 blinks/min)
significantly decreasing overall drug available for therapeutic
response so it ultimately affect bioavailability of drug.
 So therapeutic response we expect is not obtained.
16

17. 3. DRUG & DOSAGE FORM RELATED FACTORS:
 Physio-chemical properties of drug molecule become even more
important in case of Ocular Drug Delivery because of complex
anatomical & physiological constrains.
 Rate of absorption from the site of administered site depends
highly upon physical properties of drug molecule
 E.g. - Solubility
- Lipophilicity
- Molecular weight & size
- Surface area of absorption
- Degree of ionization
17

18. i. Solubility:
o It is dependent on pKa of drug & pH of solution, with these
parameters one can determine ratio of ionized & unionized
molecules.
o Usually ionized molecules can readily permeate biological
membranes.
o Permeability of unionized pilocarpine is almost 2 times greater
than its ionized form.
o In case of ionized species, their charge can also affect
permeability across cornea.
18

19. ii. Lipophilicity:
o Liophilicity & corneal permeability displays sigmoidal
relationship. Because of differential permeability of different
layers of cornea towards lipophilic drugs.
o Hydrophilicity of inner layer of cornea (stroma) requires higher
hydrophilicity for optimal permeation.
19

20. iii. Molecular weight & size:
o Molecular weight & size of molecule has ability to decide
permeability of drug through para-cellular route.
o The diameter of tight junctions present on corneal epithelium
is less than 2nm so molecules less than 500 Daltons are able to
permeate easily.
o Conjunctiva has larger para-cellular pore diameter so permeation
of larger molecules such as small & medium peptides ( 5000-
10000 Daltons)
o E.g. Sucrose (mol. Wt. 342 Daltons) permeates 16 times faster
than Insulin ( mol. Wt. 5000 Daltons)
20

21. iv. Surface area of absorption:
o Ocular system offers limited surface area for absorption of drug
i.e. much smaller than GI tract.
o There is no more space for keeping higher dosage form in ocular
system.
21

22. 1. Solutions
2. Suspensions
3. Emulsions
4. Ointments
5. gels
22

23. 1. Solution:
 Dilutes with tear and wash away through lachrymal
apparatus
 Does not interfere with vision of patient.
 Administer at frequent intervals
2. Suspension :
 Longer contact time
 Irritation potential due to the particle size of drug
3. Ointment:
 Longer contact time and greater storage stability
 Producing film over the eye and blurring vision
23

24. 4. Emulsions:
o Prolonged release of drug from vehicle but blurred vision,
patient non compliance and oil entrapment are the drawbacks.
5. Gels:
o Comfortable, less blurred vision but the drawbacks are matted
eyelids and no rate control on diffusion.
24

25. 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,
osmolarity, 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.
25

26. 26

27.  Ideal Requirements For Ocular DDS
1. Sterility
2. Isotonicity
3. Buffer/pH adjustment
4. Less drainage tendency
5. Minimum protein binding
27

28. 28
A. Bioavailability
enhancement:
1. Viscosity
adjustment
2. Penetration
enhancers
3. prodrug
B. Controlled release
1. Implants
2. Iontophorasis
3. Inserts
4. Mucoadhesive
polymers
5. Micro-particulates
C. Vascular Drug
Delivery system
1. Liposomes
2. Niosomes
3. Pharmacosomes

29. A. BIOAVAILABILITY ENHANCEMENT:
1. Viscosity adjustment:
o Increase in viscosity of formulation leads enhancement of
bioavailability to decrease the drainage.
o Slow elimination rate from pre-corneal area & enhance contact time.
o E.g. Generally hydrophylic polymers, methyl cellulose, polyvinyl
alcohols carbomers, HPMC are used.
o A minimum viscosity of 20cst is needed for optimal corneal
absorption
29

30. 2. Penetration Enhancers:
o It acts by enhancing corneal uptake by modifying the integrity of
corneal epithelium.
o Substance which increases the permeability characteristics of
cornea by modifying the integrity of corneal epithelium is called
as Penetration Enhancers.
o Mode of action:
1. By increasing the permeability of cell membrane
2. By acting on tight junctions.
30

31. 3. Prodrugs:
o Prodrug enhance corneal drug permeability through modification
of hydrophilicity or lipophilicity of the drug
o The method includes modification in chemical structure of drug
molecule thus making it selective, site specific & safe system.
o Drugs with increased permeability through prodrug formulations
are e.g. epinephrine, timolol, pilocarpine
31

32. B. CONTROLLED RELEASE DRUG DELIVERY
SYSTEM
 Release at a constant rate for a long time
 Enhanced corneal absorption
 Drug with not serious side effect or tolerate by the patient
1. Implants
2. Iontophorasis
3. Inserts
4. Mucoadhesive polymers
5. Micro-particulates
32

33. ADVANTAGE:
 Increase ocular residence, hence improving bioavailability.
 Possibility of providing a prolonged drug release and thus a better
efficacy.
 Lower incidence of visual and systemic side effects.
 Increased shelf life
 Exclusion of preservatives, thus reducing the risk of sensitivity
reactions.
 Possibility of targeting internal ocular tissue through non-corneal
routes
33

34.  Reduction of systemic side effects and thus reduced adverse
effects.
 Reduction of the number of administration and thus better patient
compliance.
 Administration of an accurate dose in the eye, which is fully
retained at the administration site, thus a better therapy.
34

35. 1. IMPLANTS
 Implants help in circumventing multiple introcular injection and
associated complications.
 Implants use for drug delivery in posterior ocular tissue.
 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 35

36. Eg. Of Implants-
 NONBIODEGRADABLE -
1. VITRASERT- controlled release of ganciclovir for treatment of
CMV (cytomegalovirus) retinitis.
2. RETISERT- release of Fluocinolone acetonide for treatment of
chronic uveitis of post. Segment.
 BIODEGRADABLE-
1. SURODEX- release Dexamethasone for control of
postoperative inflammation.
2. OZURDEX- for Macular Edema
36

37. 2. 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
37

38.  TYPES
I. Trans-corneal
II. Trans-scleral
 Antibiotics, antifungals, anesthetics and adrenergics
are delivered by this method.
38

39. 3. 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
39

40. 4. NANOSUSPENSIONS
 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.
40

41. 5. 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 system significantly prolong the drug residence time since
clearance is controlled by rate of mucus turn over.
 They are basically macromolecular hydro-colloids with
plentiful hydrophilic functional groups, such as hydroxyl,
carboxyl, amide and sulphate having capability for
establishing electrostatic interactions.
41

42. OCULAR MUCOADHESIVE POLYMERS
Non-ionics
Hydroxy Propyl Cellulose
Polycationics
Chitosan, Dextran
Polyanionics
Polyacrylic acid derivatives (carbopols,
polycarbophils & CMC)
42

43. Factors affecting mucoadhesion power
 Chain flexibility
 Molecular weight
 pH
 Ionic strength
43

44. 6. INSERTS
 It is polymeric ocular controlled drug delivery system
 The drug is incorporated as dispersion or a solution in the
polymeric support
 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.
44

45. 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.
 Better patient compliance, due to reduced frequency of
administration and less incidence of visual and systemic side-
effects. 45

46.  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.
46

47. 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.
47

48.  CLASSIFICATION :
1 .NON ERODIBLE INSERTS
i. Ocusert
ii. Contact lens
2 .ERODIBLE INSERTS
i. Lacriserts
ii. SODI
iii. Mindisc
48

49. I. NON ERODIBLE INSERTS
A. OCUSERT:
 The Ocusert therapeutic system is a flat, flexible, elliptical device
designed to be placed in the inferior cul-de-sac between the sclera
and the eyelid and to release Pilocarpine continuously at a steady
rate for 7 days.
 The device consists of 3 layers…..
1. Outer layer - Ethylene Vinyl Acetate (EVA) co-polymer layer.
2. Inner Core - Pilocarpine gelled with alginate main polymer.
3. A retaining ring - of EVA impregnated with titanium di-oxide
(pigment) (easy for patient to visualize)
 The ocuserts available in two forms.
 Pilo - 20 :- 20 microgram/hour
 Pilo – 40 :-40 micrograms/hour 49

50. B. CONTACT LENSES:
 These are circular shaped structures.
 Dyes may be added during polymerization.
 Drug incorporation depends on whether their structure is
hydrophilic or hydrophobic.
Drug release depends upon :
 Amount of drug
 Soaking time.
 Drug concentration in soaking solution.
50

51. II. ERODIBLE INSERTS:
 The solid inserts absorb the aqueous tear fluid and gradually
erode or disintegrate. The drug is slowly leached from the
hydrophilic matrix.
 They quickly lose their solid integrity and are squeezed out of the
eye with eye movement and blinking.
 Do not have to be removed at the end of their use.
 Three types :
 1. LACRISERTS
 2. SODI
 3. MINIDISC
51

52. A. LACRISERTS:
 Sterile rod shaped device made up of hydroxyl-propyl- cellulose
without any preservative.
 For the treatment of dry eye syndromes
 It weighs 5 mg and measures 1.27 mm in diameter with a length
of 3.5 mm.
 It is inserted into the inferior fornix.
B. SODI:
 Soluble Ocular Drug Inserts
 Small oval wafer
 Sterile thin film of oval shape
 Weighs 15-16 mg
 Used in – glaucoma
52

53. C. 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.
53

54. C. VESICULAR SYSTEM
 Vesicular drug delivery system can be defined as highly
ordered assemblies consisting of one or more concentric bi-
layers 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.
54

55. 1. 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.
 The major limitations of liposomes are chemical instability,
oxidative degradation of phospholipids, cost and purity of natural
phospholipids.
55

56. 2. NIOSOMES
 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.
 Niosomes are non-ionic surfactant vesicles that have potential
applications in the delivery of hydrophobic or amphiphilic drugs.
56

57. 3. 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.
 Colloidal dispersions of drugs co-valently bound to liquids
57

58. NIOSOME Vs LIPOSOME
58
Non ionic surface active
agent
Phospholipid
Hydrophilic drugs in
aqueous region
encapsulated
Lipophilic drugs located in
the hydrophobic lamella

59. D. PARTICULATES (NANOPARTICLES AND
MICROPARTICLES)
 Nanoparticles- <1 micrometer
 Microparticles- >1 micrometer
 The maximum size limit for microparticles for ophthalmic
administration is about 5-10 mm above which a scratching feeling
in the eye can result upon ocular instillation.
 That is why microspheres and nanoparticles are promising drug
carriers for ophthalmic application.
 Nanoparticles are prepared using bio-adhesive polymers to
provide sustained effect to the entrapped drugs. 59

60. EVALUATION OF OCDDS:
1. THICKNESS OF THE FILM:
 Measured by dial caliper at different points and the mean value is
calculated.
2. DRUG CONTENT UNIFORMITY:
 The cast film cut at different places and tested for drug as per
monograph.
3. UNIFORMITY OF WEIGHT:
 Here, three patches are weighed.
60

61. 4. PERCENTAGE MOISTURE ABSORPTION:
 Here ocular films are weighed and placed in a dessicator
containing 100 ml of saturated solution of aluminium chloride and
79.5% humidity was maintained.
 After three days the ocular films are reweighed and the percentage
moisture absorbed is calculated using the formula =
61
% moisture absorbed = Final weight –
initial weight/ initial weight x 100

62. IN – VITRO EVALUATION METHODS:
1. BOTTLE METHOD:
 In this, dosage forms are placed in the bottle containing
dissolution medium maintained at specified temperature and pH.
 The bottle is then shaken.
 A sample of medium is taken out at appropriate intervals and
analyzed for the drug content.
2. DIFFUSION METHOD:
 Drug solution is placed in the donor compartment and buffer
medium is placed in between donor and receptor compartment.
 Drug diffused in receptor compartment is measured at various
time intervals.
62

63. 3. MODIFIED ROTATING BASKET METHOD:
 Dosage form is placed in a basket assembly connected to a stirrer.
 The assembly is lowered into a jacketed beaker containing buffer
medium and temperature 370C
 Samples are taken at appropriate time intervals and analyzed for
drug content.
4. MODIFIED ROTATING PADDLE APPARATUS:
 Here, dosage form is placed into a diffusion cell which is placed
in the flask of rotating paddle apparatus.
 The buffer medium is placed in the flask and paddle is rotated at
50 rpm at temperature 370C
 Sample are removed at appropriate time intervals & analyzed for
drug content.
63

64. IN- VIVO STUDY:
 Here, the dosage form is applied to one eye of animals and the
other eye serves as control.
 Then the dosage form is removed carefully at regular time
interval and are analyzed for drug content
 The drug remaining is subtracted from the initial drug content,
which will give the amount of the drug absorbed in the eye of
animal at particular time.
 After one week of washed period, the experiment was repeated
for two time as before.
64

65. ACCELERATED STABILITY STUDIES
 These are carried out to predict the breakdown that may occur
over prolonged periods of storage at normal shelf condition.
 Here, the dosage form is kept at elevated temperature or humidity
or intensity of light, or oxygen.
 Then after regular intervals of time sample is taken and analyzed
for drug content.
 From these results, graphical data treatment is plotted and shelf
life and expiry date are determined.
65

66. 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

67. REFERNCES
 Controlled drug delivery – Concepts and Advances, by S.P. Vyas
and Roop K. Khar, page no: 383 – 410.
 Advances in Controlled and Novel drug delivery, edited by N.K.
Jain, page no: 219 – 223.
 Controlled & Novel Drug Delivery System, edited by N.K. Jain,
page No: 83 – 99
 Novel drug delivery systems, by Y.W. Chein, published by Marcel
Dekker, vol.-50, Ocular drug delivery page no: 269 – 301.
 Encyclopedia of Controlled drug delivery, by Mathiowitz E., vol.-
2 page no: 583 – 584
 http://en.wikipedia.org/wiki/carbon_nanotube
67