3. Non-Corneal
Absorption
• Penetration across Sclera & Conjuctiva into Intra Ocular tissues
• Non-Productive: because penetrated drug is absorbed by
general circulation
Corneal
Absorption
• Outer Epithelium: rate limiting barrier, with pore size 60A,
Only access to small ionic & lipohilic molecules
• Trans cellular transport: transport between corneal epithelium
& stroma.
5. Factors Affecting Intraocular Bioavailability:
• 1. Inflow & Outflow of Lachrymal fluids.
• 2. Efficient naso-lachrimal drainage.
• 3. Interaction of drug with proteins
of Lachrimal fluid.
• 4. Dilution with tears.
Role of Polymer in ODDS.
Solution Viscosity : Solution Drainage.
Polymer Mucoadhesive Vehicle: Retained in the eye
due to non-covalent bonding between with conjuctival
mucine.
Mucine is capable of picking of 40-80 times of
weight of water.
7. Route of
Administration
Advantages Limitations
Topical Convenient to deliver drugs Inefficient delivery to the
posterior segment, nasolacrimal
drainage, short contact time of
drug on the ocular surface
Systemic Convenient to deliver large amounts as compared to
eye drops
Poor bioavailability of drug in the
retina and systemic absorption
Intravitreal Drug delivered directly to the vitreous and retina in
the form of injections and implants
Problems such as cataract,
endophthalmitis, retinal
detachment and hemorrhage
Subconjunctival Both anterior and vitreous level of the drug can be
achieved and act as common route of
administration
Difficult to deliver drugs to the
retina due to the presence of
retinal pigment epithelium
Retrobulbar Provide medication to the posterior segments for
the treatment of posterior diseases
Effect provide by this route is very
less as drug may enter the globe
of the eye
Intracameral Deliver drugs directly to the anterior and vitreous
chamber
Difficult to deliver the drugs to the
posterior segment
Subretinal Deliver drugs to the retina Retinal detachment occurs as a
result of sub retinal delivery
Ocular Routes for Delivery of Bioactives
8. Common Ocular Disorders Associated with Various
Tissues of Eye
Conjunctiva
(Conjunctivitis)
Cornea
(Keratitis)
Sclera
(Scleritis)
Miscellaneous
Infective Conjunctivitis,
Allergic Conjunctivitis
Ulcerative Keratitis,
Non Ulcerative Keratitis
Glaucoma,
Diabetic Retinopathi,
AMD
Episcerates
Scleritis(anterior,
posterior)
9. Principles and practices of various drug delivery
systems to eye
DRUG CATEGORIES
H1 Receptor antagonists
Anti glaucoma drugs
Anti fibrotic drugs
Anti inflammatory drugs
Anti viral drugs
Anti fungal agents
Immunomodulators
Antibiotics
10. Requisites of Controlled Ocular Delivery Systems
• Polymeric solutions e.g.: MC, PVA, HPC& PVP
• Phase transition systems
e.g.: Lutrol FC-127& Polaxomer 407 viscosity
increases when its temperature raised to 37oC
CAP pH sensitive
• Mucoadhesive/Bioadhesive dosage forms
e.g.: Polycarbophil(acrylic acid based polymer)
• Collagen shields, Collasomes
e.g.: antibiotic impregnated soft contact lenses
• Polymeric colloidal dispersions (o/w type emulsion)
• Ocular penetration enhancers
• Ocular Iontophoresis
11. OCULAR DRUG DELIVERY
SYSTEMS
ADVANCED
DELIVERY SYSTEMS
Scleral plugs
Gene therapy
Stem cell
CONTROLLED
DELIVERY SYSTEMS
Implants
Hydrogels
Dendrimers
Iontophorosis
Polymeric solution
Penetration enhanc
Contact lenses
Nano suspensions
Micro emulsions
Cyclodextrins
Phase transition
systems
Mucoadhesives
PARTICULATE
SYSTEMS
Nanoparticles
Microparticles
VESICULAR
DELIVERY SYSTEMS
Liposomes
Niosomes
Pharmacosomes
discomes
RETRO METABOLIC
DELIVERY SYSTEMS
Softdrug Approach
Chemical Delivery Systems
SOLUTIONS
GELS
OINTMENTS
SUSPENSIONS
EYE DROPS
CONVENTIONAL
DOSAGE FORMS
14. Advantages and Disadvantages of Various Delivery Systems to Eye
S.No. Delivery/Dosage
Form
Advantages Disadvantages
1 Drops -easy to apply
-good patient acceptance
-Poor ocular bioavailability
-short duration of action
2 Systemic
administration
-more effective to treat diseases of the
posterior segment of the eye than drops
-do not bypass blood ocular
barriers
-side effects: systemic toxicity
3 Intravitreal,
Periocular,
Subconjuctival
injections
-improve drug absorption
-no systemic toxicity
-deliver to target site of the eye
-inj. Display 1st order kinetics
-short half life
-poor acceptance by patients
4 Implants -The biodegradable implants do not need
to be removed
-stabilization of the drug
-side effects increased risk
-uncontrollable release of
drug to eye
5 Microparticles,
Nanoparticles ,
Liposomes
-increase half life
-decrease peak conc.
-localized drug delivery
-side effects
-risk associated drug delivery
6 Cell encapsulation -patient compliance
-limitations of toxicity
-side effects
-risk of operation
7 Iontophoresis -non invasive easy method
-may use in combination
-more patient compliance
-No sustained half-life
-risk of side effects
-frequent administration
required
15. OCULAR DRUG DELIVERY DEVICES
MATRIX-TYPE DRUG DELIVERY SYSTEMS
• Hydrophilic soft contact lenses
• Soluble ocular inserts
• Scleral buckling materials
CAPSULAR TYPE DRUG DELIVERY SYSTEMS
• Ocusert
• Implantable silicone rubber device
IMPLANTABLE DRUG DELIVERY PUMPS
• Osmatic mini pump and implantable infusion system
OTHER DELIVERY DEVICES
• Ocufit, BioCor® and Lacrisert
• Minidisk ocular therapeutic systems
16. Contact Lens
Hydrophilic soft contact lenses
• Made up of hydrogels
• Marketed products are
Bionite was developed by Griffin Lab.
Soflens was developed by Bausch& Lomb
here the drug is fluorescein
• Other drugs: antiviral idoxuridine(IDU)
polymyxin B, pilocarpine
• Ability of presoaked hydrophilic lens
• Contact lenses made from PHP(Hefilcon-A)
copolymer(80% 2-hydroxy ethyl methacrylate &
20% N-vinyl-2-pyrrolidone)
diameter 16mm, thickness 0.3mm&
their hydration was 40-45%
Modern system classifies contact lens into three major types such as (i) soft
(ii) semi soft
(iii) hard contact lens
17. Contact lens hydrogel containing molecular
sites with drug affinity
Liposomes on the surface of a contact lens
hydrogel(left), liposomes with in a contact
lens hydrogels(right)
Drug polymer film coated by a contact lens
hydrogel
18. Ocular Inserts
Ophthalmic inserts
Soluble Bioerodable Insoluble
natural polymer collagen shields reservoir
systems
E.g.:SODI E.g.:Lacrisert,
PVAI minidisc
•Diffusion
based(ocusert)
•Osmatic based
•Soft (presoaked)
contact lenses
Sterile preparations with a thin, multilayered , drug
impregnated solid or semi solid consistency devices
placed into cul-de-sac (or) conjunctival sac
19. Soluble Ocular Inserts
1) Poly Vinyl Alcohol Inserts(PVAI)
• Thin, elastic & oval plates
• Impregnated with antibiotics, sulfonamides, pilocarpine, atropine
etc.
Limitations : poor patient compliance & difficulty of self insertion
2) Soluble Ophthalmic Drug Inserts(SODI)
• Thin, elastic & oval plates
• Composition: polymers and copolymers of polyacryl amide, Vinyl
pyrolidone, ethyl acrylate.
• Weight 15-16mg
• In 10-15 sec softens
• In 10-15 min turns in viscous liquids
• After 30-90 min becomes polymeric solution
Advantage:
• Single SODI application: replaces 4-12 eye drops
• Ones a day treatment of Glaucoma & Trachoma
20. Advantages of ocular inserts
• Increased ocular residence
• Releasing drugs at a
slow,constant rate
• Acurate dosing
• Reduction of systemic absorption
• Better patient compliance
Disadvantages of
ocular inserts
•A capital disadvantage of
ocular inserts resides In
their solidity
•The occasional inadvertent
loss during sleep or while
•Their interference with vision
•Difficult placement of the
ocular inserts
Desired Criteria For Control Release Ocular Inserts.
The following have to be evaluated for
ocular inserts:
1.Uniformity of thickness.
2.Uniformity of weight.
3.Drug content
4.Percentage moisture absorption.
5.Percentage moisture loss.
6.Surface pH.
7.Eye irritancy test.
8.Stability studies.
9.In vitro drug release study.
10.In vivo drug release study.
11.Microbiological studies.
21. Scleral Buckling Material
• Two types 1) Gelatin Film
2) Solid Silicone Rubber
• Antibiotic preparations are
chloramphenicol & lincomycin
• Immersing the devices into aqueous antibiotic
solution and then dried. They found sustained
release of the antibiotic from these devices
Use: To prevent postoperative infections after
retinal detachment surgery
22. Ocusert:
• Capsular-type drug delivery systems
• Developed by ALZA corporation
• Oval, flexible ocular insert
• Anular ring impregnated with Ti02 for flexibility
• Dimensions:major axis:13.4mm; minor axis:5.7mm,
thickness:0.3mm
• Two types of ocusert are available, ocusert pilo-20& pilo-40
Part Material
Drug reservoir Pilocarpine
Carrier material Alginic acid
Rate controller Ethylene vinyl acetate (EVA) copolymer
membrane
Energy source Conc. Of pilocarpine
Flux enhancer Di(2-ethyl hexyl) phthalate
23. Advantages of pilocarpine ocuserts over drops :
The ocusert exposes the patient to a lower amount of the drug leading to
reduced side effects
The ocusert provide a continuous control of the intra-ocular pressure
The ocusert is administered only once per week & this will imporve patient
compliance
The ocusert contain no preservative so they will be suitable for patients sensitive
to preservatives in opthalmic solutions
Disadvantages of pilocarpine ocuserts:
They are more expensive than drops
It may be inconvenient for the patient to retain the ocusert in the eye for the full 7 days
The ocusert must be checked periodically by the patient to see that the unit is still in
place
24. Implantable Silicone
Rubber Devices
• Drug delivery device for hydrophobic drugs
e.g.:-BCNU(1,3-bis(2-chloro ethyl)-1-nitroso
urea)---- an intraocular malignancy agent
• The device consists of two sheets of silicone
rubber glued together only at the edges with
silicone adhesive
• A tube of the same material extends from
device
• The device released BCNU at a constant rate
about 200-400mcg/hr
25. Implantable Drug Delivery Pumps
• Osmatic mini pump(ALZET)
Constant drug delivery rate with a
pumping duration of up to 2 weeks
• Implantable infusion
system(Infusaid)
Permitted long term infusion via
refilling
• A drug pellet coated with polyvinyl
alcohol and ethylene vinyl acetate
• A polysulfone capillary fiber
26. Lacrisert
• Sterile , rod shaped device
• Composition: HPC without preservative
• The devices have long retention(2 weeks
or more) and sustained release features
• Weight: 5 mg
• Dimension: diameter 12.7mm, length
3.5mm
Use:- dry eye treatment, keratitis
27. Minidisk
• It shaped like contact lens, with convex
front & concave back surface in contact
with eye ball
• 4-5mm in diameter
• Composition: silicon based polymer
• Hydrophilic or hydrophobic
• Drug release from 170hr
28. Retrometabolic delivery system
• Combination of SAR and SMR Retrometabolic drug design (RMDD)
• Metabolic activation of inactive delivery forms: chemical delivery systems
CDS Drug
inactive active
Alkyl oxime datives oximes(enzymes located in iris-celiary body)
• Metabolic deactivation of specifically designed active species: soft drugs
SD Mi
Active inactive metabolites
hydrocortisone spirothiazolidine
• RMDD represent novel, systemic approach to achieve these goals include
two distinct methods aimed to increase the therapeutic index
SOFT DRUG design
CHEMICAL DELIVERY SYSTEM design
29. The chemical delivery systems(CDSs)- chemical compounds – produced by synthetic chemical
reaction(s) forming covalent bonds between the drug(D) and specifically designed ‘carrier ’
and other moieties. At least one chemical bond needs to be broken for active compound (D)
to be released. The release of active compound from CDSs takes pace by enzymatic or
hydrolytic cleavage.
The basic principle of retrometabolic drug design approaches is that the drug metabolism
considerations should actually be involved at a very early stage of the design process- not as
an after thought in order to explain some of the behaviours of the drug
SAR+SMR=RETROMETABOLIC DRUG DELIVERY SYSTEM
Drug targeting by CDS’s
1.enzymatic physical chemical
based targeting
2.site specific-enzyme activated
targeting
3.receptor based chemical
targeting
Drug targeting by soft drugs
1.soft drug analogs
2.activated soft compounds
3.active metabolite type soft drugs
4.controlled release of endogenous
soft compounds
5.Inactive metabolic approach
30. Nanoparticles
• The drug absorption in the eye is enhanced significantly in
comparison to eye drop solutions
• Poly alkyl cyano acrylate(PACA) nanoparticles and
nanocapsules improve corneal penetration of hydrophilic
and lipophilic drugs
Limitation: disruption of corneal epithelium cell membrane
• Poly- ԑ-caprolactone(PECL) nanocapsules increase ocular
penetration of lipophilic drugs such as metipranolol,
betaxolol.
• PECL taken up by the corneal epithelium cells without
damaging the cell membrane
• Colloidal nature of the carrier is the main factor responsible
for favorable corneal transport of drugs
PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERY
31. Liposomes
• non-toxic, non irritant Biodegradable in nature
• Ability to incorporate almost any type of the drug regardless of the
solubility
• Intimate contact with cornea and conjunctival surfaces
• Protect the drug from metabolic enzymes
• Phospholipids used are: phosphotidylcholine, phosphotidic acid,
sphingomyline, phosphotydyleserine, cardiolipine
• 4 fold increase in passage of penicillin G across rabbit cornea & 10 fold
enhancement of indoxole passage across rat cornea were observed when
the formulations compared with solutions
VESICULAR SYSTEM FOR OCULAR DRUG DELIVERY
32. Niosomes are non-ionic surfactant based multilamellar(>0.05µm),small
unilamellar(0.025-0.05µm) or large unilamellar vesicles(>0.1µm) in which an
aqueous solution of solute(s) is entirely enclosed by a membrane resulted from
organization of surfactant macromolecules as bilayers
STRUCTURAL COMPONENTS USED
• Surfactants (dialkyl polyoxy ethylene ether non ionic surfactant)
• Cholesterol
CHOLESTROL:
1. Cannot form bilayers, but bring changes in fluidity and permeability to bilayers.
2. Can be used in high molar concentrations.
3. Stabilize and prevent leak from vesicles.
ADVANTAGES:
•The vesicle suspension being water based offers greater patient compliance over oil
based systems
•Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as
well as ampiphilic drug moieties, they can be used for a variety of drugs.
•The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on
the requirement.
•The vesicles can act as a depot to release the drug slowly and offer a controlled release.
•They are osmotically active and stable.
•They increase the stability of the entrapped drug
•Improves therapeutic performance of the drug by protecting it from the biological
environment and restricting effects to target cells, thereby reducing the clearance of the
drug.
DISADVANTAGES
• Physical instability, Aggregation, Leaking of entrapped drug, Fusion,
Niosomes
33. PHARMACOSOMES
• The vesicle formation takes place not only just by association of
phospholipids but also by amphiphilic molecular association
• Since many drugs are also amphiphiles, they can form the vesicles
Advantages:
• Drug metabolism can be decreased
• Controlled release profile can be achieved
DISCOMES
• Soluble surface active agents when added in critical amount to
vesicular dispersion leads to solubilization or breakdown of vesicles
& translates them into mixed micellar systems
e.g.: Egg yolk phosphotidyl choline liposomes by the addition of
non ionic surfactants of poly oxy ethylene cetyl ether till the lamellar
and mixed lamellar coexist
Advantages:
• Minimal opacity imposes no hindrance to vision
• Increased patient compliance
• Zero order release can be easily attained
34. Advantages of Vesicular Systems
1. No difficulty of insertion as in the case of ocular
inserts
2. No tissue irritation and damage as caused by
penetration enhancers
3. Provide patient compliance as there is no difficulty of
insertion as observed in the case of inserts
4. The vesicular carriers are biocompatible and have
minimum side effects
5. Degradation products formed after the release of
drugs are biocompatible
6. They prevent the metabolism of drugs from the
enzymes present at tear/corneal epithelium interface
7. Provide a prolong and sustained release of drug
35. Conclusion
• Quality, Efficacy and Safety should be the
optimal parameters for drug delivery to
eye in this context, more clinical studies
are necessary to provide further
information and insight in to new ocular
drug delivery system.
36. References
• Ophthalmic Drug Delivery System: Challenges and Approaches
PB Patel, DH Shastri, PK Shelat, AK Shukla
•Ocular Transporters in Ophthalmic Diseases and Drug Delivery;
Edited by Joyce Tombran-Tink, Colin J. Barnstable.
• Targeted & Controlled Drug Delivery Novel Carrier Systems by
S.P.Vyas, R.K.Khar
•Anatomy and Physiology: Tora Tora
• Ophthalmic Drug Delivery Systems--recent Advances:
Dr.K.S.Rathore
Web searched:
•http://www.google/images/eye/anatomy&physiology
http://pharmaxchange.info
Editor's Notes
These are the different drug delivery systems which are used for the ocular therapy
