Ocular drug delivery system (ODDS)

Ocular Drug Delivery System
[ODDS]
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
avengersagar16@gmail.com
2015-2016
Department of Pharmacy (Pharmaceutics) | Sagar savale6/7/2016 1

Contents
2
 Introduction
 Difference between Ophthalmic and Ocular Drug Delivery System
 Major classes of drugs used are
 Composition of Eye
 Lacrimal nasal drainage
 Barriers in Ocular Absorption
 Barriers Avoiding Drug Delivery
 Anatomy and Physiology of the Eye
 Mechanism of Ocular Absorption
 General Pathway for Ocular Absorption
6/7/2016 sagar kishor savale

6/7/2016 3
 Ocular Absorption
 Factors Affecting Intraocular Bioavailability
 Disadvantage of Conventional Ocular Drug Delivery System
 Ideal Requirements for ocular drug delivery
 Additives
 Absorption of Drugs in the Eye
 Corneal Absorption
 Approaches To Improve Ocular Drug Delivery
 General safety considerations
 Ideal ophthalmic delivery system
Contents
sagar kishor savale

6/7/2016 4
Contents
 Drug Release Kinetics
 Mathematical models
 Classification of Ocular Drug Delivery Systems
 Ideal Ophthalmic Delivery System
 Ophthalmic inserts
 Evaluation Test of Ocular products
 References
sagar kishor savale

5
Introduction
Definition
 “They are specialized dosage forms designed to be instilled onto the external surface of the
eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in
conjunction with an ophthalmic device”.
 “The Novel approach of drug delivery system in which drug can Instilled on the cull de sac
cavity of eye is known has Ocular drug delivery system”.
 cull de sac cavity: the space between eye lids and eye balls.
 The most commonly employed ophthalmic dosage forms are solutions, suspensions, and
ointments.
 But these preparations when instilled into the eye are rapidly drained away from the ocular
cavity due to tear flow and lacrimal nasal drainage.
6/7/2016 sagar kishor savale

6/7/2016 6
 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.
 The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming
solutions, ocular inserts , intravitreal injections and implants.
sagar kishor savale

6/7/2016 7
Sr.
No.
Ophthalmic DDS Ocular DDS
1 Conventional System Novel System
2 Old Concept New Concept
3 Addition of Preservatives Do Not Addition of Preservatives
4 High Dosing Frequency Low Dosing Frequency
5 Minimum release rate of drug Maximum release rate of drug
6 Limited Flexibility Extreme Flexibility
7 Minimum Absorption rate Maximum Absorption rate
8 Minimum Bioavaibility Maximum Bioavailability
Difference between Ophthalmic and Ocular Drug Delivery System
sagar kishor savale

6/7/2016 8
Major classes of drugs used are
 Miotics e.g. pilocarpine HCl
 Mydriatics e.g. atropine
 Cycloplegics e.g. atropine
 Anti-inflammatories e.g. corticosteroids
 Anti-infectives (antibiotics, antivirals and antibacterial)
 Anti-glucoma drugs e.g. pilocarpine HCl
 Surgical adjuncts e.g. irrigating solutions
 Diagnostic drugs e.g. sodium fluorescein
 Anaesthetics e.g. tetra Caine
sagar kishor savale

6/7/2016 9
COMPOSITION OF EYE
 Water - 98%,
 Solid -1.8%,
 Organic element
Protein - 0.67%,
Sugar - 0.65%,
NaCl - 0.66%
 Other mineral element: sodium, potassium and ammonia - 0.79%.
 Artificial Tear: The solution intended to rewet hard lenses in situ are referred
has rewetting solutions or artificial tear.
sagar kishor savale

6/7/2016 10
Lacrimal nasal drainage:
sagar kishor savale

6/7/2016 11
BARRIERS IN OCULAR ABSORPTION
It includes,
• Solution drainage
• Cornea as rate limiting barrier
• Lachrymation
• Anatomy of cornea
• Tear dilution, 1. Outer-Epithelium (lipophilic)
2. Middle-Stroma (hydrophilic), Conjunctival absorption
3. Inner-Endothelium (lipophilic )
Precorneal constraints Corneal constraints
sagar kishor savale

BARRIERS AVOIDING DRUG DELIVERY
Drug in tear fluid
Ocular absorption
Corneal route Conjunctival and scleral route Systemic absorption
50-100% of dose
Major route- conjunctiva of eye,
nose
Minor route- lacrimal drainage
system,
pharynx, GIT, aqueous humor
Aqueous humor
Ocular tissue ELIMINATION
6/7/2016 sagar kishor savale 12

6/7/2016 13
Anatomy and Physiology of the Eye
sagar kishor savale

6/7/2016 14sagar kishor savale

6/7/2016 16
 Human eye
 Diameter 23 mm
 Structure comprises of three layers
1. Outermost coat : The clear, transparent cornea and the white, opaque
sclera
2. Middle layer : The iris anteriorly, the choroid posteriorly, and the
ciliary body at the intermediate part
3. Inner layer : Retina (extension of CNS)
 Cornea (Types)
 Epithelium
 stroma
 endothelium (fat-water-fat structure)
 Function: Penetration of the drug depends on Oil-water partition
coefficient
sagar kishor savale

6/7/2016 17
Corneal Cross Section
sagar kishor savale

6/7/2016 18
 Fluid systems in eye
1. Aqueous humor
 Secreted from blood through epithelium of the ciliary body.
 Secreted in posterior chamber and transported to anterior chamber.
2. Vitreous humor
 Secreted from blood through epithelium of the ciliary body.
 Diffuse through the vitreous body.
 Lacrimal glands
 Secrete tears & wash foreign bodies.
 Moistens the cornea from drying out.
sagar kishor savale

6/7/2016 19
 The sclera : The protective outer layer of the eye, referred to as the “white
of the eye” and it maintains the shape of the eye.
 The cornea : The front portion of the sclera, is transparent and allows light
to enter the eye. The cornea is a powerful refracting surface, providing
much of the eye's focusing power.
 The choroid : is the second layer of the eye and lies between the sclera
and the retina. It contains the blood vessels that provide nourishment to
the outer layers of the retina.
 The iris : is the part of the eye that gives it color. It consists of muscular
tissue that responds to surrounding light, making the pupil, or circular
opening in the center of the iris, larger or smaller depending on the
brightness of the light.
sagar kishor savale

6/7/2016 20
 The lens is a transparent, biconvex structure, encased in a thin transparent
covering. The function of the lens is to refract and focus incoming light
onto the retina.
 The retina is the innermost layer in the eye. It converts images into
electrical impulses that are sent along the optic nerve to the brain where the
images are interpreted.
 The macula is located in the back of the eye, in the center of the retina. This
area produces the sharpest vision.
sagar kishor savale

6/7/2016 21
Mechanism of Ocular Absorption
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 60å,Only
access to small ionic & lipohilic molecules
• Trans cellular transport: transport between corneal epithelium &
stroma.
sagar kishor savale

6/7/2016 22
General Pathway For Ocular Absorption
sagar kishor savale

6/7/2016 23
Corneal Absorption
Depend upon physicochemical
properties of drug
Only access to small ionic &
lipophilic molecules
Outer Epithelium: rate limiting
barrier
Trans cellular transport:
transport between corneal
epithelium & stroma
e.g. pilocarpine
Non-Corneal Absorption
Penetration across Sclera &
Conjunctiva into Intra
Ocular tissues
Non-Productive: because
penetrated drug is absorbed
by general circulation.
Minor pathway
Important for drug with low
corneal permeability
e.g. inulin
OCULAR ABSORPTION
sagar kishor savale

6/7/2016 24
Factors Affecting Intraocular Bioavailability
Includes,
• Pre corneal
• Corneal
• Interior of the eye
1.Inflow & outflow of lacrimal fluids.
2. Efficient naso-lacrimal drainage.
3. Interaction of drug with proteins of lacrimal fluid or Protein Binding.
4. Dilution with tears.
5. Corneal barriers.
6. Physico-chemical properties of drugs.
7. Active ion transport at cornea.
8. Limited and poor corneal permeability.
9. Metabolism or Degradation of Lysozyme enzyme present in eye.
10. Plasma Value Profile
11. Poor Residence Time
12. Poor rate of absorption of drug
13. High dosing Frequency
Factors responsible for minimum ocular Bioavailability,
sagar kishor savale

6/7/2016 25
Disadvantage of Conventional Ocular Drug Delivery System
 Less Bioavailability
 Protein binding
 Lacrimation
 Peak valley Profile
 Less intimate contact
 Patient Incompliance
sagar kishor savale

6/7/2016 26
Ideal Requirements for ocular drug delivery
 Sterility
 Free from foreign particles
 Isotonicity
 Buffer
sagar kishor savale

6/7/2016 27
Additives
 Buffering Agent
 Preservatives
 Solubilizing Agent
 Thickening Agent
 Antioxidant
 Isotonic agent
 Chelating agent
 Vehicle sagar kishor savale

6/7/2016 28
Absorption of Drugs in the Eye
Factors affecting drug availability:
1. Rapid solution drainage by gravity, induced lachrymation, blinking reflex, and
normal tear turnover.
 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
2. Superficial absorption of drug into the conjunctiva and sclera and rapid removal by
the peripheral blood flow
sagar kishor savale

6/7/2016 29
3. Low corneal permeability (act as lipid barrier)
In general:
 Transport of hydrophilic and macromolecular drugs occurs through scleral
route.
 Lipophilic agents of low molecular weight follow transcorneal transport by
passive diffusion.
4. Metabolism
 Enzymatic biotransformation: Esterases, oxidoreductases, Peptidases,
Glucuronide Sulfate transferases, Lysosomal enzymes
sagar kishor savale

6/7/2016 30
Corneal Absorption
Poor
Bioavialability
Protective
mechanism (short
residence time)
Blinking
Reflex lacrimation,
Nasolacrimal drainage
Anatomy of eye
Barrier properties of
cornea
sagar kishor savale

6/7/2016 31
Corneal absorption
sagar kishor savale

6/7/2016 32
Approaches To Improve Ocular Drug Delivery
 Viscosity enhancers
 Eye ointments
 Gel (hydrogel and organogels)
 Prodrug or Double Prodrug
 Penetration enhancers
 Liposomes
 Niosomes
 Nanosuspension
 Microemulsion
 Nanoparticles/Nanospheres (polymeric and lipidemic)
 In situ-forming gel
 Implants
 Corneal Collaging Sheets
sagar kishor savale

6/7/2016 33
 Enhancement of bioavailability
1. Increase in viscosity of formulation leads to decrease in drainage.
2. Slows elimination rate from the precorneal area and enhance contact
time.
3. Generally hydrophilic polymers, eg. Methyl cellulose, polyvinyl
alcohols, polyacrylic acids, sodium carboxy methyl cellulose,
carbomer is used.
4. A minimum viscosity of 20 cst is needed for optimum corneal
absorption.
sagar kishor savale

6/7/2016 34
 Use of penetration enhancers
1. Act by increasing corneal uptake by modifying the integrity of the
corneal epithelium.
2. Substances which increases the permeability characteristics of the
cornea by modifying the integrity of corneal epithelium are known as
penetration enhancers.
 Modes of actions
1. By increasing the permeability of the cell membrane.
2. Acting mainly on tight junctions.
sagar kishor savale

6/7/2016 35
 PRODRUGS
1. Prodrug enhance corneal drug permeability through modification
of the hydrophilic or lipophilicity of the drug.
2. The method includes modification of chemical structure of the
drug molecule, thus making it selective, site specific and a safe
ocular drug delivery system.
3. Drugs with increased penetrability through Prodrug formulations are
epinephrine, phenylephrine, timolol, pilocarpine.
sagar kishor savale

6/7/2016 36
 USE OF MUCOADHESIVES IN OCULAR DRUG
DELIVERY
 Polymereric mucoadhesive vehicle: Retained in the eye due to noncovalent
bonding with conjunctival mucin.
 Mucin is capable of picking of 40-80 times of weight of water.
 Thus prolongs the residence time of drug in the conjuctival sac.
 Mucoadhesive contain the dosage form which remains adhered to cornea until the
polymer is degraded or mucus replaces itself.
 Types
1. Naturally Occurring Mucoadhesive - Lectins, Fibronectins
2. Synthetic Mucoadhesive - PVA,Carbopol, carboxy methyl cellulose, cross-
linked polyacrylic acid.
sagar kishor savale

6/7/2016 37
Nanoparticle
For water soluble drugs.
Size:10-1000nm
Drug is Dispersed, Encapsulated, or Absorbed
Produced by Emulsion Polymerization
Polymerization is carried out by : Chemical initiation, Gamma
irradiation, Visible light.
Emulsifier stabilizes polymer particle
Polymer used are Biodegradable.
E.g. :- Nanoparticle of Pilocarpine enhances Mitotic
response by 20-23%.
sagar kishor savale

6/7/2016 38
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.
 Since many drugs are also amphiphiles, they can form the vesicles.
Advantages
 Drug metabolism can be decreased.
 Controled release profile can be achieved.
sagar kishor savale

6/7/2016 39
Liposome
Biodegradable, Non-toxic in nature.
Vesicle composed of lipid membrane enclosed in an
aqueous volume.
Formed when matrix of phospholipids is agitated in
aqueous medium to disperse two phase.
Phospholipids used are : Phophotidylcholine, Phophotidic acid,
Sphingomyline, Phosphotidyleserine, Cardiolipine
sagar kishor savale

6/7/2016 40
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.
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.
sagar kishor savale

6/7/2016 41
 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.
Non ionic surface active agent
phospholipid
Hydrophilic drugs in aqueous
region encapsulated
Lipophilic drugs located in
the hydrophobic lamella
NIOSOME Vs LIPOSOME
sagar kishor savale

6/7/2016 42
CONTROL DELIVERY SYSTEMS
1. 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.
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.
3. Dendrimer:
 Dendrimers can successfully used for different routes of drug administration and
have better water-solubility, bioavailability and biocompatibility.
sagar kishor savale

6/7/2016 43
4. 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.
5. Nanosuspensions:
 Nanosuspension 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.
sagar kishor savale

6/7/2016 44
6. 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.
7. Mucoadhesive Polymers:
 They are basically macromolecular hydrocolloids with plentiful hydrophilic
functional groups, such as hydroxyl, carboxyl, amide and sulphate having
capability for establishing electrostatic interactions
 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).
sagar kishor savale

6/7/2016 45
Advances in ocular drug delivery
1. Ophthalmic gel for pilocarpine
 Poloxamer 407 (low viscosity, optical clarity, mucomimetic property)
2. Ophthalmic prodrug
 Dipivalyl epinephrine (Dipivefrin)
 Lipophilic  increase in corneal absorption
 Esterase within cornea and aqueous humor
3. Continuous delivery system based upon the osmotic property
 Thin flat layer, contoured three-dimensional unit
 Conform to the space of the upper cul-de-sac
 Delivery of diethyl carbamazine in ocular onchocerciasis
sagar kishor savale

6/7/2016 46
4. Gel delivery system
 Biodegradable polyisobutyl-cyano acrylate (PIBCA) colloidal
particulate system of pilocarpine to incorporate it into a Pluronic F127
(PF 127)-based gel delivery system.
5. Mucoadhesive Polymer
 mucoadhesive polymer, the tamarind seed polysaccharide, as a
delivery system for the ocular administration of hydrophilic and
hydrophobic antibiotics.
sagar kishor savale

6/7/2016 47
 Phase Transition System
1. Solution that are liquid in the container and thus can be instilled as eye
drop becomes gel on contact with the tear fluid and provide increased
contact time with the possibility of improved drug absorption and
increased duration of therapeutic effect.
2. Liquid-gel phase transition-dependent delivery system vary according to
the particular polymer employed and their mechanism for triggering the
transition to a gel phase in the eye take advantage of change in
temperature, pH, ion sensitivity, or lysozymes upon contact with tear
fluid.
sagar kishor savale

6/7/2016 48
EXAMLE OF POLYMER
POLYMER MECHANISM
Lutrol FC – 127 and Poloxamer 407 Viscosity increased when their temperature
raised to eye temperature.
Cellulose acetate phthalate latex Coagulates when its native pH 4.5 raised by
tear fluid to pH 7.4
Gelrite Forms clear gel in the presence of cations
sagar kishor savale

6/7/2016 49
OCULAR DELIVERY
SYSTEMS
CONVENTIONAL VESICULAR
CONTROL RELEASE PARTICULATE
o IMPLANTS
o HYDROGELS
o DENDRIMERS
o IONTOPORESIS
o COLLAGEN SHIELD
o POLYMERIC
SOLUTIONS
o CONTACT LENSES
o CYCLODEXRIN
o MICROONEEDLE
o MICROEMULSIONS
o NANO
SUSPENSION
o MICROPARTICLES
o NANOPARTICLES
o LIPOSOMES
o NIOSOMES
o DISCOMES
o PHARMACOSOMES
ADVANCED
o SCLERAL PLUGS
o GENE DELIVERY
o Si RNA
o STEM CELL
o SOLUTION
o SUSPENSION
o EMULSION
o OINTMENT
o INSERT
o GELS
sagar kishor savale

6/7/2016 50
Figure. Some of the routes of administration in the eye
Cont..
sagar kishor savale

6/7/2016 51
Topical
administration
• eye drops
• Ointments
• Gels/
emulsions
Systemic
(Parenteral)
Administration
transport
molecules through
the choroid into
deeper layers of the
retina
Oral
Administration
Periocular and
Intravitreal
Administration -
periocular route-
includes
subconjunctival,
subtenons,
retrobulbar, and
peribulbar
administration
sagar kishor savale

6/7/2016 52
General safety considerations
A. Sterility:
 Ideally, all ophthalmic products would be terminally sterilized in the final
packaging.
 Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to
normal autoclaving temperatures and times (121°C for 20-30 min).
 Such heat-resistant drugs may be packaged in glass or other heat-deformation-
resistant packaging and thus can be sterilized in this manner.
 Most ophthalmic products, however cannot be sterilized by heat due to the active
principle or polymers used to increase viscosity are not stable to heat.
 Most ophthalmic products are aseptically manufactured and filled into previously
sterilized containers in aseptic environments using aseptic filling-and-capping
techniques.
sagar kishor savale

6/7/2016 54
B. Ocular toxicity and irritation
 Albino rabbits are used to test the ocular toxicity and irritation of ophthalmic
formulations.
 The procedure based on the examination of the conjunctiva, the cornea or the iris.
- E.g. USP procedure for plastic containers:
 Containers are cleaned and sterilized as in the final packaged product.
 Extracted by submersion in saline and cottonseed oil.
 Topical ocular instillation of the extracts and blanks in rabbits is completed and
ocular changes examined.
sagar kishor savale

6/7/2016 55
C. Preservation and preservatives
 Preservatives are included in multiple-dose eye solutions for maintaining the product
sterility during use.
 Preservatives not included in unit-dose package.
 The use of preservatives is prohibited in ophthalmic products that are used at the of
eye surgery because, if sufficient concentration of the preservative is contacted with
the corneal endothelium, the cells can become damaged causing clouding of the
cornea and possible loss of vision.
 So these products should be packaged in sterile, unit-of-use containers.
 The most common organism is Pseudomonas aeruginosa that grow in the cornea
and cause loss of vision.
sagar kishor savale

6/7/2016 56
C. Preservation and preservatives
sagar kishor savale

6/7/2016 57
Manufacturing considerations
A. Manufacturing Environment:
The environment should be sterile and particle-free through:
 Laminar-flow should be used throughout the manufacturing area.
 Total particles per cubic foot of space should be minimum.
 Relative humidity controlled to between 40 and 60%.
 Walls, ceilings and floors should be constructed of materials that are hard, non flaking,
smooth and non-affected by surface cleaners or disinfectants.
 Ultraviolet lamps provided in flush-mounted fixtures to maintain surface disinfection.
 Separate entrance for personnel and equipment should be provided through specially
designed air locks that are maintained at negative pressure relative to the aseptic
manufacturing area and at a positive pressure relative to the noncontrolled area
sagar kishor savale

6/7/2016 58
B. Manufacturing Techniques:
 Unpreserved formulations of active drug (s):
The blow/fill/seal method
 It is used for manufacture of unpreserved ophthalmic products , especially for
artificial tear products.
 In this first step is : To extrude polyethylene resin at high temperature and pressure
and to form the container by blowing the polyethylene resin into mold with
compressed air. The product is vented out, and finally the container is sealed on the
top.
sagar kishor savale

6/7/2016 59
The blow /fill/seal method:
sagar kishor savale

6/7/2016 60
C. Equipment
 All tanks, valves, pumps and piping must be of best available Grade of corrosion –
resistant stainless steel.
 All products-contact surface should be polished either mechanically or be
electropolishing to provide a surface as Free as possible from scratches or defects.
 Care should be taken in the design of such equipment to Provide adequate means of
cleaning and sanitization.
sagar kishor savale

6/7/2016 61
Ideal ophthalmic delivery system
 Following characteristics are required to optimize ocular drug
delivery system:
 Good corneal penetration.
 Prolong contact time with corneal tissue.
 Simplicity of instillation for the patient.
 Non irritative and comfortable form.
 Appropriate rheological properties.
sagar kishor savale

6/7/2016 62
Drug Release Kinetics
 The mathematical models are used to evaluate the kinetics and mechanism of drug
release from the tablets.
 The model that best fits the release data is selected based on the correlation
coefficient (r) value in various models.
 The model that gives high ‘r’ value is considered as the best fit of the release data.
sagar kishor savale

6/7/2016 63
Mathematical models
 Zero order release model
 First order release model
 Hixson-crowell release model
 Higuchi release model
 Korsmeyer – peppas release model
sagar kishor savale

6/7/2016 64
ZERO ORDER RELEASE EQUATION
• The equation for zero order release is
Qt = Q0 + K0 t
where
Q0 = initial amount of drug
Qt = cumulative amount of drug release at time “t”
K0 = zero order release constant
t = time in hours
• It describes the systems where the drug release rate is independent of
its concentration of the dissolved substance.
sagar kishor savale

6/7/2016 65
 A graph is plotted between the time taken on x-axis and the cumulative percentage
of drug release on y-axis and it gives a straight line.
sagar kishor savale

6/7/2016 66
FIRST ORDER RELEASE EQUATION
• The first order release equation is
Log Qt = Log Q0+ Kt /2.303
where
Q0 = initial amount of drug
Qt = cumulative amount of drug release at time “t”
K = first order release constant
t = time in hours
• Here, the drug release rate depends on its concentration
sagar kishor savale

6/7/2016 67
 A graph is plotted between the time taken on x-axis and the log cumulative
percentage of drug remaining to be released on y-axis and it gives a straight line.
sagar kishor savale

6/7/2016 68
HIXSON - CROWELL RELEASE EQUATION
• The Hixson - Crowell release equation is
Where
Q0 = Initial amount of drug
Qt = Cumulative amount of drug release at time “t”
KHC = Hixson crowell release constant
t = Time in hours.
• It describes the drug releases by dissolution and with the changes in
surface area and diameter of the particles or tablets
sagar kishor savale

6/7/2016 69
 A linear plot of the cube root of the initial concentration minus the cube root of
percent remaining versus time in hours for the dissolution data in accordance with
the Hixson-crowell equation.
sagar kishor savale

6/7/2016 70
HIGUCHI RELEASE EQUATION
• The Higuchi release equation is
Q=KHt1/2
where
Q = cumulative amount of drug release at time “t”
KH = Higuchi constant
t = time in hours
• The Higuchi equation suggests that the drug release by diffusion.
• A graph is plotted between the square root of time taken on x-axis and
the cummulative percentage of drug release on y-axis and it gives a
straight line.
sagar kishor savale

6/7/2016 72
KORSMEYER-PEPPAS EQUATION
• Korsmeyer – peppas equation is
F = (Mt /M ) = Kmtn
Where
F = Fraction of drug released at time ‘t’
Mt = Amount of drug released at time ‘t’
M = Total amount of drug in dosage form
Km = Kinetic constant
n = Diffusion or release exponent
t = Time in hours
sagar kishor savale

6/7/2016 73
 ‘n’ is estimated from linear regression of log ( Mt/M ) versus log t
 If n = 0.45 indicates fickian diffusion
 0.45<n<0.89 indicates anomalous diffusion or non-fickian diffusion.
 If n = 0.89 and above indicates case-2 relaxation or super case
transport-2.
 Anomalous diffusion or non-fickian diffusion refers to combination of
both diffusion and erosion controlled rate release.
 Case-2 relaxation or super case transport-2 refers to the erosion of the
polymeric chain.
 A graph is plotted between the log time taken on x-axis and the log
cummulative percentage of drug release on y-axis and it gives a
straight line.
sagar kishor savale

6/7/2016 75
Classification of Ocular Drug Delivery Systems
LIQUIDS
Solutions
Suspensions
Powders for
reconstitution
Sol to gel
systems
SEMISOLIDS
Ointments
Gels
SOLID
Ocular inserts
Contact lenses
Erodible inserts
INTRAOCULAR
DOSAGE FORM
Injections
Irrigating
solutions
Implants
sagar kishor savale

6/7/2016 76
Classification of Ophthalmic Dosage Form:
A) Based on Root of
Administration
• 1.Topical Soln: Multiple Dose
container With
Preservatives.
• 2. Intra-ocular Soln: For
Surgery, Single dose,
Without preservative.
• 3.Ophthalmic Soln
Injections: Intra-ocular
injection, given in eye
tissues, without
preservative.
B) Based on Physical
Form
• 1. Aqueous Soln.
• 2. Suspension.
• 3. Ointments.
• 4. Gels.
• 5. Eye Lotions.
• 6. Solid Inserts.
sagar kishor savale

6/7/2016 77
Ideal Ophthalmic Delivery System
 Good corneal penetration.
 Prolong contact time with corneal tissue.
 Simplicity of instillation for the patient.
 Non irrelative and comfortable form.
 Appropriate rheological properties.
 Inert and stable.
sagar kishor savale

6/7/2016 78
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.
sagar kishor savale

6/7/2016 79
Manufacturing Techniques
 Aqueous ophthalmic solution:
Manufactured by dissolution of the active ingredients and a portion of the excipients
into all portion of water.
The sterilization of this solution done by heat or by sterilizing Filtration through sterile
depth or membrane filter media Into a sterile receptacle.
This sterile solution is then mixed with the additional required Sterile components such
as viscosity –imparting agents, Preservatives and so and the solution is brought to final
Volume with additional sterile water.
sagar kishor savale

6/7/2016 80
Advantages And Disadvantages of Eye Drops
Dosage form Advantages Disadvantages
Solutions 1. Convenience
2. Usually do not interfere with
vision of patient.
1. Rapid Precorneal elimination.
2. Non sustained action.
3. To be Administered at frequent
intervals.
Suspension 1. Patient compliance.
2. Best for drug with slow
dissolution.
3. Longer contact time
1. Drug properties decide performance
loss of both solutions and suspended
particles.
2. Irritation potential due to the particle
size of the drug.
Emulsion 1. Prolonged release of drug
from vehicle
1. Blurred vision.
2. patient non compliance.
sagar kishor savale

6/7/2016 81
Examples of topical eye drops:
 Atropine Sulphate eye drops.
 Pilocarpine eye drops.
 Silver nitrate eye drops.
 Zinc Sulphate eye drops.
sagar kishor savale

6/7/2016 82
Inactive Ingredients in Topical Drops
 The inactive ingredients in ophthalmic solution and Suspension
dosage forms are necessary to perform one or more of the Following
functions:
Adjust concentration and tonicity,
 Buffer and adjust pH
 Stabilize the active ingredients against decomposition
 Increase solubility
 Impart viscosity
 And act as solvent.
sagar kishor savale

6/7/2016 83
 Tonicity and Tonicity-Adjusting Agents
 The pharmacist should adjust the tonicity of an ophthalmic Correctly (i.e.., exert an
osmotic pressure equal to that of tear fluid , generally agreed to be equal to 0.9%
NaCl ).
 A range of 0.5-2.0% NaCl equivalency does not cause a Marked pain response and
a range of about 0.7-1.5% Should be acceptable to most person.
 Commonly tonicity adjusting ingredients include : NaCl, KCL, buffer salts,
dextrose, glycerin, propylene glycol, mannitol
sagar kishor savale

6/7/2016 84
 Isotonicity
Lacrimal fluid is isotonic with blood having an isotonicity value
Corresponding to that of 0.9% Nacl solution
sagar kishor savale

6/7/2016 85
 pH Adjustment and Buffers
pH adjustment is very important as pH affects
1- To render the formulation more stable
2- The comfort, safety and activity of the product. Eye irritation increase in
tear fluid secretion Rapid loss of medication.
3- To enhance aqueous solubility of the drug.
4- To enhance the drug bioavailability
5- To maximize preservative efficacy
sagar kishor savale

6/7/2016 86
 pH Adjustment and Buffers
 Ideally , every product would be buffered to a pH of 7.4 (the normal physiological
pH of tear fluid ).
 When necessary they are buffered adequately to maintain Stability within this range
for at least 2 years.
 If buffers are required there capacity is controlled to be As low as possible (low
buffer capacity) thus enabling the Tear to bring the pH of the eye back to the
physiological range .
sagar kishor savale

6/7/2016 87
 pH & buffer
sagar kishor savale

6/7/2016 88
 Stabilizers & Antioxidants
 Stabilizers are ingredients added to a formula to decrease the rate of decomposition
of the active ingredients.
 Antioxidants are the principle stabilizers added to some ophthalmic solutions ,
primarily those containing epinephrine and other oxidizable drugs.
 Sodium bisulfite or metabisulfite are used in concentration up to 0.3% in
epinephrine hydrochloride and bitartrate solutions.
 The several antioxidant system have been developed, These consists of ascorbic acid
and acetylcysteine and sodium thiosulfate .
sagar kishor savale

6/7/2016 89
 Surfactants
The order of surfactant toxicity is :
anionic > cationic >> nonionic
 Several nonionic surfactants are used in relatively low Concentration to aid in
dispersing steroids in suspensions and to achieve or to improve solution clarity.
 Those principally used are the sorbitan ether esters of oleic acid ( polysorbate or
tween 20 and 80 ).
sagar kishor savale

6/7/2016 90
 Viscosity-Imparting Agents
 Polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, Hydroxy ethyl
cellulose, and carbomers, are commonly used to increase the viscosity of solution
and suspensions (to retard the rate of setting of particles)
 They increase the ocular contact time , there by decreasing the drainage rate,
increase the mucoadhesiveness and Increasing the bioavailability.
Disadvantage :
 produce blurring vision as when dry, form a dry film on the eye lids. make
filteration more difficult.
Commercial viscous vehicles are :
 polyvinyl alcohol (liquifilm)
 hydroxypropyl methylcellulose (isopto )
sagar kishor savale

6/7/2016 91
Vehicles
 Ophthalmic drop (using purifies water USP) as the solvent.
 Purified water meeting USP standards may be obtained by: Distillation,
deionization, or reverse osmosis.
 Oils have been used as vehicles for several topical eye drops products that are
extremely sensitive to moisture.
 When oils are used as vehicles in ophthalmic fluids, they must be of the highest
purity.
sagar kishor savale

6/7/2016 92
Packaging
 Eye drops have been packaged almost entirely in plastic dropper bottles
The main advantage of the Drop-Trainer are:
 convenience of use by the patient
 decreased contamination potential
 lower weight
 lower cost
 The plastic bottle and dispensing tip is made of low-density polyethylene (LDPE)
resin, which provides the necessary flexibility and inertness.
 The cap is made of harder resin than the bottle.
sagar kishor savale

6/7/2016 93
 A special plastic ophthalmic package made of polypropylene is introduced. The
bottle is filled then sterilized by steam under pressure at 121°C.
 Powder for reconstitution also use glass containers , owing to their heat-transfer
characteristics, which are necessary during the freeze-drying processes.
 The glass bottle is made sterile by dry-heat or steam autoclave sterilization.
 Amber glass is used for light-resistance.
Packaging
sagar kishor savale

6/7/2016 94
Ointment
 Prolongation of drug contact time with the external ocular surface can be achieved
using ophthalmic ointment vehicle.
 The ointment base is sterilized by heat and appropriately filtered while molten to
remove foreign particulate matter.
Ointment base is
sterilized by heat and
filtered while molten to
remove foreign
particulate matter.
It is then placed into a
sterile steam jacketed to
maintain the ointment
in a molten state and
excipients are added
The entire ointment
may be passed through
a previously sterilized
colloid mill
sagar kishor savale

6/7/2016 95
 Ophthalmic ointment:
 The ointment base is sterilized by heat and appropriately filtered while
molten to remove foreign particulate matter
 It is then placed into a sterile steam jacket kettle to maintain the ointment
in a molten state under aseptic conditions, and the previously sterilized
active ingredient (s) and excipients are added aseptically.
 The entire ointment may be passed through a previously sterilized colloid
mill for adequate dispersion of the insoluble components . After the product
is compounded in an aseptic manner ,it is filled into a previously sterilized
container.
sagar kishor savale

6/7/2016 96
 Advantages
1. Longer contact time and greater storage stability.
2. Flexibility in drug choice.
3. Improved drug stability.
 Disadvantages
1. Sticking of eyes lids.
2. Blurred vision.
3. Poor patient compliance
4. Interfere with the attachment of new corneal epithelial cells to their normal base.
5. Matting of eyelids
sagar kishor savale

6/7/2016 97
Examples
 Chloramphenicol ointment.
 Tetracycline ointment.
 Hydrocortisone ointment.
sagar kishor savale

6/7/2016 98
Gels
1. Ophthalmic gels are composed of mucoadhesive polymers that provide localized
delivery of an active ingredient to the eye. Such polymers have a property known
as bioadhesion.
2. These polymers are able to extend the contact time of the drug with the
biological tissues and there by improve ocular bioavailability.
Advantages
1. Longer contact time.
2. Greater storage stability.
Disadvantages
1. Blurred vision but less then ointment.
2. Poor patient compliance.
sagar kishor savale

6/7/2016 99
Gel-Forming Solutions
 Solution that are liquid in the container and thus can be instilled as eye drops but
forms gel on contact with the tear fluid and provide increased contact time with the
possibility of improved drug absorption and Duration of therapeutic effect.
 liquid-gel phase transition-dependent delivery system vary according to the
particular polymer(s) employed and their mechanisms for triggering the Transition
to a gel phase in the eye.
 Take the advantage of changes in temperature ,pH, ion sensitivity, lysozymes upon
contact with tear fluid.
sagar kishor savale

6/7/2016 100
Different mucoadhesive polymers were added to poloxamer
 Carbopol 940
 Hydroxypropylmethyl cellulose (HPMC)
 Hydroxyethyl cellulose (HEC)
sagar kishor savale

6/7/2016 101
Semisolid Dosage Forms: Ophthalmic Ointments and Gels
 Packaging
Ophthalmic ointment are packaged in :
1.Small collapsible tin tube usually holding 3.5g of product. the pure tin tube is
compatible with a wide range of drugs in petrolatum-based ointments.
2.Aluminum tubes have been used because of their lower cost and as an alternative
should the supply of tin.
sagar kishor savale

6/7/2016 102
Plastic tubes made from flexible LDPE resins have also been considered as an
alternative material.
 Filled tubes may be tested for leakers.
 The screw cap is made of polyethylene or polypropylene.
 The tube can be a source of metal particles and must be cleaned carefully before
sterilization (by autoclaving or ethylene oxide).
sagar kishor savale

6/7/2016 103
IMPLANTS
 Implants have been widely employed to extend the release of drugs in ocular fluids and tissues
particularly in the posterior segment. Implants can be broadly classified into two categories
based on their degradation properties: (1) biodegradable and (2) Non biodegradable
 With implants, the delivery rate could be modulated by varying polymer composition.
 Implants can be solids, semisolids or particulate-based delivery systems.
sagar kishor savale

6/7/2016 104
Suspensions
 If the drug is not sufficiently soluble, it can be formulated as a
suspension.
 A suspension may also be desired to improve stability, Bioavailability
,and efficacy.
 The major topical ophthalmic suspensions are the steroid anti-
inflammatory agents.
 An ophthalmic suspension should use the drug in a microfine form;
usually 95% or more of the particles have. Diameter of 10µm or less.
sagar kishor savale

6/7/2016 105
• Aqueous suspensions:
 Are prepared in much the same manner, except that Before bringing to the final
volume with additional sterile water .
 The solid that is to be suspended is previously rendered sterile by – heat ,exposure to
ethylene oxide ,ionizing radiation (gamma ), sterile filtration.
 The particle size should be monitored.
sagar kishor savale

6/7/2016 106
Examples,
 Prednisolone acetate suspension.
 Besifloxacin suspension.
 Blephamide suspension.
 Fluorometholone.
sagar kishor savale

6/7/2016 107
 Topical ophthalmic emulsions generally are prepared by dissolving or dispersing the active
ingredient(s) into an oil phase, adding suitable emulsifying and suspending agents and mixing
with water vigorously to form a uniform oil-in-water emulsion.
 Each phase is typically sterilized prior to or during charging into the mixing vessel.
 High-shear homogenation may be employed to reduce oil droplet size to sub-micron size
which may improve the physical stability of the oil micelles so they do not coalesce.
 The resulting dosage form should contain small oil droplets, uniformly suspended.
 To prevent flocculation, creaming and coalescence of the emulsions, manufacturers
commonly add surfactants to increase the kinetic stability of the emulsion so that the
emulsion does not change significantly with time.
Emulsions
sagar kishor savale

6/7/2016 108
Strips
 Ophthalmic strips are made of filter paper and are
individually packed to ensure sterility until the
time of use.
 They can be used in the measurement of tear
production in dry eye conditions.
 E.g. fluorescein sodium used as a diagnostic
strips to visualize defects or aberrations in the
corneal epithelium by staining the areas of
cellular loss.
sagar kishor savale

6/7/2016 109
Injections
 While injections are considered a dosage form for nomenclature purposes, they are not treated
as a dosage form in this paper.
 Instead, refer to the appropriate physical form, such as, suspension, etc., for general
information.
sagar kishor savale

6/7/2016 110
Ophthalmic inserts
1. Non-erodible inserts
 Ocuserts
 Contact lens
2. Erodible inserts
 Lacriserts
 SODI
 Minidisc
sagar kishor savale

6/7/2016 111
 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 copolymer layer.
2. Inner Core - Pilocarpine gelled with alginate main polymer.
3. A retaining ring - of EVA impregnated with titanium di oxide
 Ocuserts
sagar kishor savale

6/7/2016 112
 Ophthalmic inserts are defined as sterile solid or semisolid
preparations, with a thin, flexible and multilayered structure, for
insertion in the conjunctival sac.
sagar kishor savale

6/7/2016 114
 ADVANTAGES
 Reduced local side effects and toxicity.
 Around the clock control of drug.
 Improved compliance.
 DISADVANTAGES
 Retention in the eye for the full 7 days.
 Periodical check of unit.
 Replacement of contaminated unit
 Expensive.
sagar kishor savale

6/7/2016 115
Part Material
 Drug Reservoir Pilocarpine
 Carrier material Alginic acid
 Rate controller Ethylene vinyl acetate
copolymer
 Energy Source Conc. Of Pilocarpine
 Delivery Portal Copolymer membrane
 Developed by Alza Corporation,
Oval flexible ocular insert,
Release Rate:20-40mg/hr for
7day
sagar kishor savale

6/7/2016 116
Ocular Inserts
I. Insoluble inserts
• Insoluble insert is a multilayered structure consisting of a drug containing core surrounded
on each side by a layer of copolymer membranes through which the drug diffuses at a
constant rate.
• The rate of drug diffusion is controlled by:
- The polymer composition
- The membrane thickness
- The solubility of the drug
e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system
- 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 for treatment of glucoma.
sagar kishor savale

6/7/2016 117
Insoluble ophthalmic inserts
Diffusion controlled ocular inserts
These consists of a medicated core prepared out of a hydrogel polymer like alginates,
sandwiched between two sheets of transparent lipophilic, rate controlling polymer.
 The drug molecule penetrate through the rate controlling membranes at zero order
rate process.
dQ/dt = Dp Km (Cr-Ct)/δm
dQ/dt = Dp Km Cs/δm (Cr >> Ct sink condition)
eg ; ocusert pilo-20
sagar kishor savale

6/7/2016 118
Sr.no. Pilo-20 Pilo-40
1 Pilocarpine nitrate 20 Pilocarpine nitrate 40
2 5 mg of drug 11 mg of drug
3 20 ug drug is releases per hours for
next seven days
40 ug drug is releases per hours for next
seven days
4 thick thin
5 Barrier functioning No Barrier functioning
6 Drug release rate is less Drug release rate is less
7 Rate of Absorption is less Rate of Absorption is more
8 Limited Flexibility Extreme Flexibility
9 Permeation Enhancers are not
applicable
Permeation Enhancers are applicable
10 Minimum Bioavailability Maximum Bioavailability
Difference between Pilo-20 and Pilo-40 Ocular system
sagar kishor savale

6/7/2016 119
Synthetic and semi- synthetic polymers
Offer additional advantage of simple design & easily processed.
Soluble
synthetic
polymers
Cellulose derivatives- HPC, MC, HEC, HPMC, SOD. CMC
others- poly vinyl alcohol, ethylene vinyl acetate co polymer
Additives Plasticizers- poly ethylene glycol, glycerine, propylene glycol
complexing agent- PVP
Bioadhesives- poly acrylic acids, methyl hyroxy ethyl cellulose
 Soluble cellulose derivative inserts are composed of 30% of water. Presence of
water is unfavorable from stand point of stability of drug.
 Insert can be sterilized by exposure to gamma radiation without the cellulose
component being altered.
sagar kishor savale

6/7/2016 120
 The first soluble ophthalmic drug insert (SODI) developed was of soluble co-
polymer of acrylamide, N- vinyl pyrrolidone & ethyl acetate.
 It was in form of sterile thin films or wafers or oval shape, weighing 15 – 16 mg.
 A new type of ophthalmic insert incorporating a water- soluble bio-adhesive
component in its formulation has been developed to decrease risk of expulsion &
ensure prolonged residence in eye, combined with the controlled release.
 These inserts, named bio-adhesive ophthalmic drug inserts (BODI)
sagar kishor savale

6/7/2016 121
 CONTACT LENS
 Contact lenses can be a way of providing extended release of drugs into the eye.
 Conventional hydrogel soft contact lenses have the ability to absorb some drugs and release
them into the post lens lachrymal fluid, minimizing clearance and sorption through the
conjunctiva.
 Their ability to be a drug reservoir strongly depends on the water content and thickness of the
lens, the molecular weight of the drug, the concentration of the drug loading solution and the
time the lens remains in it.
sagar kishor savale

6/7/2016 122
 The ability of contact lens to load drugs and to control their release is in general
inadequate and the following approaches, based on modifications of the polymer
network, are under evaluation:
(1) Covalent binding of the drug to the lens network via labile bonds;
(2) Inclusion of the drug in colloidal structures that are dispersed in the lens and are responsible
for controlling drug release;
(3) Functionalization of the network with chemical groups that work as ion-exchange resins; and
(4) Creation in the lens structure of imprinted pockets that memorize the spatial features and
bonding preferences of the drug and provide the lens with a high affinity and selectivity for a
given drug.
sagar kishor savale

6/7/2016 123
Types of contact lenses
1- Hard contact lenses
 Made of rigid plastic resin polymethylmethacrylate
 Impermeable to oxygen and moisture
2- Soft contact lenses
 Made of hydrophilic transparent plastic, hydroxyethylmethacrylate
 Contain 30 – 80% water so are permeable to oxygen
 Have two types: daily wear and extended wear
sagar kishor savale

6/7/2016 124
3- Rigid gas permeable (RGP)
- Take the advantages of both soft and hard lenses, they are hydrophobic and oxygen
permeable.
Advantages of hard contact lenses and RGP lenses:
1- strength durability
2- resistant to absorption of medications and environmental contaminants
3- visual acurity
Disadvantages:
1- require adjustment period of the wearer
2- more easily dislodged from the eye
sagar kishor savale

6/7/2016 125
 Advantages of soft contact lenses:
1- worn for longer periods
2- do not dislodge easily
 Disadvantages:
1- have a shorter life span and the wearer must ensure that the lenses
do not dry out
"soft" lens | "hard" lens
sagar kishor savale

6/7/2016 126
Lens Type Chemical Classification Major Characteristics
Hard, Rigid, Hydrophobic PMMA
(Polymethylmethacrylate)
- Negligible gas permeability
- Low water content
- Medium wettability
Soft, flexible, Hydrophilic HEMA
(Hydroxylethylmethylmethacr
ylate)
- High water Content
- Iow gas permeability
- Good wettability
Flexible, Hydrophobic Silicon vinylpyrolidone - Good gas permeability
- Good wettability
Rigid, Hydrophilic CAB (Cellulose acetate
butyrate)
- Good gas permeability
- Good wettability
sagar kishor savale

6/7/2016 127
• Products for soft contact lenses:
Cleaners
- To remove lipid and protein debris
- formulation:
1- vocalizing surface-active agent: to enable
gentle friction with fingertips
2- antibacterial-fast acting: benzalkonium
chloride
Products for soft contact lenses:
sagar kishor savale

6/7/2016 128
• Rinsing and storage solutions
- Remove the cleaning solution, facilitate lens hydration, inactivation of
microbial contamination and prevent the lens from drying out
- Formulation:
- 0.9% Nacl (isotonic)
- Antibacterial- 3% hydrogen peroxide for 30 min followed by
inactivation with sodium pyruvate
sagar kishor savale

6/7/2016 129
Enzyme protein digest
- For occasional cleaning followed by washing before wearing
Formulation:
- Proteolytic enzyme: papain solution tablet to produce a solution when
dissolved in water
sagar kishor savale

6/7/2016 130
Products for hard contact lenses:
• Rinsing and storage solutions
- For cleaning, microbial inactivation and hydration
Formulation:
- surface-active agent
- Antimicrobial:
(0.01% benzalkonium chloride + 0.1% sodium edetate )
Wetting solutions
- To achieve rapid wetting by the lachrymal fluid and promot comfort
- Facilitate insertion of the lens
- Provide lubrication
Consist of: viscosity-increasing agent (hydroxy ethyl cellulose + wetting agent
(polyvinyl alcohol) + preservatives (benzalknonium chloride or sodium edetate +
buffers and salts to adjust
pH and tonicity.
sagar kishor savale

6/7/2016 131
ERODIBLE INSERTS
 The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate.
The drug is slowly leached from the hydrophilic matrix.
 It is Biologically Stable, Biodegradable, Biocompatible, Bio erodible.
 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
sagar kishor savale

6/7/2016 132
 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.
 SODI
 Soluble ocular drug inserts.
 Small oval wafer.
 Sterile thin film of oval shape.
 Weighs 15-16 mg.
 Use – glaucoma.
 Advantage – Single application. Lacriserts
sagar kishor savale

6/7/2016 133
 Minidisc
 Countered disc with a convex front and a concave back surface.
 Diameter – 4 to 5 mm.
 Composition
 Silicone based prepolymer-alpha-w-dis (4-methacryloxy)-butyl poly di methyl
siloxane. (M2DX)
 M-Methyl a cryloxy butyl functionalities.
 D – Di methyl siloxane functionalities.
 Pilocarpine, chloramphenicol.
Minidisc
sagar kishor savale

6/7/2016 134
Soluble Ocular inserts
 Lacriserts is a sterile ophthalmic insert use in the treatment of dry Eye syndrome and
is usually recommended for patients unable to obtain symptomatic relief with
artificial tear solutions.
 The insert is composed of 5 mg of Hydroxypropyl cellulose in a rod-shaped form
about 1.27 mm diameter by about 3.5 mm long.
sagar kishor savale

6/7/2016 135
 Soluble inserts consists of all monolytic polymeric devices that at the end of
their release, the device dissolve or erode.
Types
 Based on natural polymers e.g. collagen.
 Based on synthetic or semi synthetic polymers e.g. Cellulose derivatives –
Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl
acetate copolymer.
 The system soften in 10-15 sec after introduction into the upper conjunctival sac,
gradually dissolves within 1h , while releasing the drug.
 Advantage: Being entirely soluble so that they do not need to be removed from
their site of application.
sagar kishor savale

6/7/2016 136
BIO ERODIBLE INSERTS
 Main component of this type of inserts is the bio-erodible polymers.
 They undergoes hydrolysis of chemical bonds & hence dissolution.
 Bio-erodible matrix controlling the release rate of the drug ensures zero order
release rate.
 Eg., poly (ortho esters), poly (ortho carbonates)
 Great advantage of these bio-erodible polymers is the possibility of modulating their
erosion rate by modifying their final structure during synthesis.
sagar kishor savale

6/7/2016 137
Implantable silicone devices
 Developed for the local delivery of an anti-neoplastic drug to the intra-ocular site.
 Composed of 2 sheets of silicone rubber glued to the edge with adhesive to form
a balloon like sac through which a silicone tubing (0.3 mm dia) is inserted.
 Such devices have significant potential for local controlled delivery of anti-
bacterial, anti-cancer, & anti-viral drugs to anterior chamber of eye.
sagar kishor savale

6/7/2016 138
Other delivery devices
 Ocufit® is a sustained release rod shape device made up of silicone elastomer.
 Lacrisert® is another cylindrical device, which is made of HPC and used for
treating dry- eye patients.
 Mini disk ocular therapeutic systems (OTS)- It is a miniature contact lens shaped,
made of silicone based pre polymer. It requires less time & less manual dexterity for
insertion, when compared with Lacriserts®.
 New ophthalmic delivery system (NODS)- It is a method for delivering precise
amounts of drugs to eye within a water soluble, drug- loaded film.
 When evaluated in humans, the NODS produced an 8 fold increase in BA for
pilocarpine with respect to std. eye drop formulations.
sagar kishor savale

6/7/2016 139
Preparation of ocular insert
Casting method
Polymer solution of diff composition were
prepared in boiling distilled water
Kept aside for 20-24 hrs to get clear solution
& then 10% w/w plasticizer was added &
stirred for 3 hrs
Weighed amounts of drug was added &
stirred for 4hrs to get uniform dispersion
Dispersion was degassed & casted on glass
substrate & dried at 500c for 18-20 hrs
Dried films are carefully removed & inserts of
required dimensions were punched out, wrapped
individually in Al. foilsagar kishor savale

6/7/2016 140
Parameters Lacriserts SODI Minidisc
Sterility Sterile Sterile Sterile
Shape Rod Oval Circular disc
Preservatives Without preservative Without preservative Without preservative
Site of insertion Cul-de-sac Cul-de-sac Cul-de-sac
Weight 5mg 15-16mg Vary
Dimension D = 1.27 mm
L = 3.5 mm
Vary D = 4-5 mm
L = Vary
Diseases Dry eye syndrome Glaucoma Eye infection
Dose replacement 4 times/ hr dose of eye
drops
Eye drops 4-12 times
Eye ointment 3-6 times
Solfisoxazole 170 hrs
Gentamicin 320 hrs
Extra features At morning imbibes
water from conjunctiva.
10-15 sec. – soft
10-15 min. – polymeric
mass
30-60 min. – polymer
solution
Crosslinking of polymer
take places
sagar kishor savale

6/7/2016 141
How To Use Ocular Insert
 To apply the system, wash hands first.
 Tilt your head back, gaze upward and pull down the lower eyelid to make a pouch.
 Place the system into the pouch.
 Blink a few times and roll your eye to move the insert into place.
 Practice inserting and removing the system in the doctor s office where you can be shown the
proper technique.
 Damaged or deformed systems should not be used or kept in the eye.
 Replace with a new system.
sagar kishor savale

6/7/2016 142
Packaging Ocular Insert
 Ophthalmic insert 5 mg supplied in packages of 60 sterile unit dosage forms.
 Each wrapped in an aluminum blister.
 With two reusable applicators.
 A plastic storage container to store the applicators for use.
sagar kishor savale

6/7/2016 143
Evaluation of Ocuserts
Sr. No. Evaluation Parameters No of Units
1 Percentage of Moisture Absorption 3
2 Percentage of Moisture Loss 3
3 Thickness of Film 6
4 Weight Variation 10
5 Drug Content 3
6 In vitro drug release study 3
7 In vivo drug release study Not Fixed
8 Stability test Not Fixed
9 Sterility test Not Fixed
10 Tensile strength 3
11 Water Absorption test 3
sagar kishor savale

6/7/2016 144
Advantages And Disadvantages of Ocular Inserts
Type Advantages Disadvantages
Erodible inserts  Effective.
 Flexibility in drug type &
dissolution rate.
 Need only be introduced
into eye & not removed.
 Patient discomfort.
 Requiers patient insertion.
 Occasional Product.
Non-erodible
inserts
 Controlled rate of release.
 Prolonged delivery.
 Flexibility for type of drug
selected.
 Sustained release.
 Patient discomfort.
 Irritation to eye.
 Tissue fibrosis.
sagar kishor savale

6/7/2016 145
Evaluation Test of Ocular products
Sr.
no.
Evaluation test Eye Drops Eye Suspension Eye Ointment
1 Organolaptic
Characters
a) Colour
b) Odour
Yes Yes Yes
2 pH Yes Yes Yes
3 Isotonicity Yes Yes No
4 Viscosity Yes Yes Yes (Visco-elastic)
5 Volume fill Yes Yes No (Minimum fill)
6 Clearity test Yes No No (Penetration Test
i.e. Consistency or
Hardness test by
using penetrometer)
7 Leaker Test Yes (Mulitidose
container never
subjected)
No (Particle size
measured)
No
sagar kishor savale

6/7/2016 146
8 Drug Content Yes Yes Yes
9 In vitro drug release Yes Yes Yes
10 In vivo drug release Yes Yes Yes
11 Ex vivo drug release Yes Yes Yes
12 Sterility test Yes Yes Yes
13 Stability test Yes Yes Yes (R.T. 70ºF & Elevated
Temp. 105º F to 120ºF)
14 Metal Test No No Yes
15 Irritant Test No No Yes
Sr.
no.
Evaluation test Eye Drops Eye
Suspension
Eye Ointment
sagar kishor savale

6/7/2016 147
 Thickness Of The Film:
 Measured by dial caliper at different points and the mean value is calculated.
 Drug Content Uniformity:
 The cast film cut at different places and tested for drug as per monograph.
 Uniformity Of Weight:
 Here, three patches are weighed.
 IN – VITRO EVALUATION METHODS:
 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.
 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.
sagar kishor savale

6/7/2016 148
 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 37 degrees Centigrade.
 Samples are taken at appropriate time intervals and analyzed for drug content.
• 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.
 The entire unit is maintained at 37 degree C.
 Aliquots of sample are removed at appropriate time intervals and analyzed for drug
content.
sagar kishor savale

6/7/2016 149
 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.
sagar kishor savale

6/7/2016 150
 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.
sagar kishor savale

6/7/2016 151
 Metal Particles Test
 It is performed using 10 ointment tubes.
 The content from each tube is completely removed onto a clean 60 - mm - diameter
Petri dish which possesses a flat bottom.
 The lid is closed and the product is heated at 85 ° C for 2 h.
 Once the product is melted and distributed uniformly, it is cooled to room
temperature.
 The lid is removed after solidification.
 The bottom surface is then viewed through an optical microscope at 30×
magnification.
 This test is required only for ophthalmic ointments
sagar kishor savale

6/7/2016 152
 The viewing surface is illuminated using an external light source positioned at 45 °
on the top.
 The entire bottom surface of the ointment is examined,
 And the number of particles 50 μm or above are counted using a calibrated eyepiece
micrometer.
 The USP recommends that the number of such particles in 10 tubes should not
exceed 50, with not more than 8 particles in any individual tube.
 limits are not met, the test is repeated with an additional 20 tubes.
 In this case, the total number of particles in 30 tubes should not exceed 150, and not
more than 3 tubes are allowed to contain more than 8 particles .
 Metal Particles Test
sagar kishor savale

6/7/2016 153
 Leakage test
 This test is mandatory for ophthalmic ointments, which evaluates the intactness of
the ointment tube and its seal.
 Ten sealed containers are selected, and their exterior surfaces are cleaned.
 They are horizontally placed over absorbent blotting paper .
 Maintained at 60 ± 3 ° C for 8 h.
 The test passes if leakage is not observed from any tube.
 If leakage is observed, the test is repeated with an additional 20 tubes.
 The test passes if not more than 1 tube shows leakage out of 30 tubes .
sagar kishor savale

6/7/2016 154
 Sterility Tests
 Ophthalmic semisolids should be free from anaerobic and aerobic bacteria and
fungi.
 Sterility tests are therefore performed by the:
1. Membrane filtration technique .
2. Direct - inoculation techniques.
sagar kishor savale

6/7/2016 155
 In the Membrane filtration method:
 A solution of test product (1%) is prepared in isopropyl
myristate and allowed to penetrate through cellulose nitrate
filter with pore size less than 0.45 μ m.
 If necessary, gradual suction or pressure is applied to aid
filtration.
 Sterility Tests
sagar kishor savale

6/7/2016 156
 The membrane is then washed three times with 100 - mL quantities of sterile
diluting and rinsing fluid and transferred aseptically into fluid thioglycolate (FTG)
and soybean – casein digest medium (SBCD) .
 The membrane is finally incubated for 14 days.
 Growth on FTG medium indicates the presence of anaerobic and aerobic bacteria
 Soybean casein digest medium indicates fungi and aerobic bacteria
 Absence of any growth in both these media establishes the sterility of the product.
 Sterility Tests
sagar kishor savale

6/7/2016 157
 In the Direct - inoculation technique :
 1 part of the product is diluted with 10 parts of sterile
diluting and rinsing fluid with the help of an emulsifying
agent
 Incubated in Fluid thioglycolate (FTG) and soybean –
casein digest medium (SBCD) media for 14 days .
 Sterility Tests
sagar kishor savale

6/7/2016 158
 In both techniques, the number of test articles is based on the batch size
of the product.
 If the batch size is less than 200 the containers, either 5% of the
containers or 2 containers (whichever is greater) are used.
 If the batch size is more than 200, 10 containers are used for sterility
testing .
 Sterility Tests
sagar kishor savale

6/7/2016 159
References
1. Remington: The Science And Practice Of Pharmacy. Volume 1 20TH edition pg
no 821-835.
2. Pharmacology: H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore. Fifth edition pg no
136-143.
3. The Theory and Practice of Industrial Pharmacy. Leon Lachman, Herbert A.
Liberman, Joseph l. Kanig. Third edition pg no 653-656.
4. Y.W.Chein , Novel drug delivery systems, second edition, pg 269-300.
5. Dispensing for pharmaceutical by Cooper and gunn’s pg: 634-661
6. Modern dispensing pharmacy : N K Jain pg: 13.3-14.9
7. Text of pharmaceutical formulation : B.M Mithal pg: 268-278.
8. N.K.Jain, Advances in Controlled & Novel Drug Delivery, CBS Publication, &
distributor, New Delhi, pg No.219-223.
9. S.P.Vyas Roop K.Khar ; Controlled Drug Delivery, concepts and advances, Pg
No: 383-410.
10. www.vision-care-guide.com Assessment time: 5pm, Date: 25 Jan. 2016
11. www.google/images/eye/anatomy& physiology Assessment time: 2am, Date: 5
April. 2016
sagar kishor savale

Ocular drug delivery system (ODDS)

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (13)

Similar to Ocular drug delivery system (ODDS)

Similar to Ocular drug delivery system (ODDS) (20)

More from Sagar Savale

More from Sagar Savale (20)

Recently uploaded

Recently uploaded (20)

Ocular drug delivery system (ODDS)