ocular drug delivery system (odds)
TRANSCRIPT
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Ocular Drug Delivery System [ODDS]
Mr. Sagar Kishor Savale[Department of Pharmaceutics]
Department of Pharmacy (Pharmaceutics) | Sagar savale
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Contents 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
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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
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Contents Drug Release Kinetics
Mathematical models
Classification of Ocular Drug Delivery Systems
Ideal Ophthalmic Delivery System
Ophthalmic inserts
Evaluation Test of Ocular products
References
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IntroductionDefinition “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 in stilled into the eye are rapidly drained away from the ocular
cavity due to tear flow and lacrimal nasal drainage. CONT...
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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.
CONT...
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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
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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
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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.
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Lacrimal nasal drainage:
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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
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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
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Anatomy and Physiology of the Eye
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Human eye Diameter 23 mm Structure comprises of three layers1. Outermost coat : The clear, transparent cornea and the white, opaque
sclera2. Middle layer : The iris anteriorly, the choroid posteriorly, and the
ciliary body at the intermediate part3. 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
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Corneal Cross Section
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Fluid systems in eye1. 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.
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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.
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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.
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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.
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General Pathway For Ocular Absorption
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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
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Factors Affecting Intraocular BioavailabilityIncludes,• 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 Profile11. Poor Residence Time12. Poor rate of absorption of drug13. High dosing Frequency
Factors responsible for minimum ocular Bioavailability,
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Disadvantage of Conventional Ocular Drug Delivery System
Less Bioavailability
Protein binding
Lacrimation
Peak valley Profile
Less intimate contact
Patient Incompliance
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Ideal Requirements for ocular drug delivery
Sterility
Free from foreign particles
Isotonicity
Buffer
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Additives Buffering Agent
Preservatives
Solubilizing Agent
Thickening Agent
Antioxidant
Isotonic agent
Chelating agent
Vehicle
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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
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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
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Corneal Absorption
Poor Bioavialability
Protective mechanism (short
residence time)
BlinkingReflex lacrimation,
Nasolacrimal drainage
Anatomy of eye
Barrier properties of cornea
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Corneal absorption
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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
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Enhancement of bioavailability1. 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.
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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.
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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.
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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.
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NanoparticleFor 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%.
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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.
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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
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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.
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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 encapsulatedLipophilic drugs located in the hydrophobic lamella
NIOSOME Vs LIPOSOME
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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.
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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.
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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).
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Advances in ocular drug delivery1. 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
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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.
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Phase Transition System1. 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.
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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
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OCULAR DELIVERY SYSTEMS
CONVENTIONAL VESICULAR
CONTROL RELEASE PARTICULATE
o IMPLANTSo HYDROGELSo DENDRIMERSo IONTOPORESISo COLLAGEN SHIELDo POLYMERIC
SOLUTIONSo CONTACT LENSESo CYCLODEXRINo MICROONEEDLEo MICROEMULSIONSo NANO
SUSPENSION
o MICROPARTICLESo NANOPARTICLES
o LIPOSOMESo NIOSOMESo DISCOMESo PHARMACOSOMES
ADVANCED
o SCLERAL PLUGSo GENE DELIVERYo Si RNAo STEM CELL
o SOLUTIONo SUSPENSIONo EMULSIONo OINTMENTo INSERTo GELS
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Figure. Some of the routes of administration in the eye
Cont..
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Topical administration
• eye drops• Ointments• Gels/
emulsions
Systemic (Parenteral)
Administrationtransport 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
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General safety considerationsA. 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.
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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.
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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.
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C. Preservation and preservatives
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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
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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.
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The blow /fill/seal method:
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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.
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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.
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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.
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Mathematical models Zero order release model
First order release model
Hixson-crowell release model
Higuchi release model
Korsmeyer – peppas release model
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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.
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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.
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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
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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.
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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
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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.
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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.
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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
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‘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.
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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
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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.
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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.
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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.
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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.
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Advantages And Disadvantages of Eye Drops
Dosage form Advantages Disadvantages
Solutions 1. Convenience2. 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.
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Examples of topical eye drops:
Atropine Sulphate eye drops.
Pilocarpine eye drops.
Silver nitrate eye drops.
Zinc Sulphate eye drops.
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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.
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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
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IsotonicityLacrimal fluid is isotonic with blood having an isotonicity value
Corresponding to that of 0.9% Nacl solution
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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
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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 .
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pH & buffer
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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 .
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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 ).
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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 )
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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.
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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.
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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
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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
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Manufacturing Techniques
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.
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Advantages1. Longer contact time and greater storage stability.2. Flexibility in drug choice.3. Improved drug stability.
Disadvantages1. Sticking of eyes lids.2. Blurred vision.3. Poor patient compliance4. Interfere with the attachment of new corneal epithelial cells to their normal base.5. Matting of eyelids
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Examples
Chloramphenicol ointment.
Tetracycline ointment.
Hydrocortisone ointment.
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Gels1. 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.
Advantages3. Longer contact time.4. Greater storage stability.
Disadvantages5. Blurred vision but less then ointment.6. Poor patient compliance.
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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.
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Different mucoadhesive polymers were added to poloxamer
Carbopol 940
Hydroxypropylmethyl cellulose (HPMC)
Hydroxyethyl cellulose (HEC)
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Semisolid Dosage Forms: Ophthalmic Ointments and Gels
PackagingOphthalmic 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.
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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).
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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.
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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.
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Manufacturing Techniques
• 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.
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Examples,
Prednisolone acetate suspension.
Besifloxacin suspension.
Blephamide suspension.
Fluorometholone.
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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
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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.
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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.
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Ophthalmic inserts
1. Non-erodible inserts Ocuserts Contact lens
2. Erodible inserts Lacriserts SODI Minidisc
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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
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Ophthalmic inserts are defined as sterile solid or semisolid preparations, with a thin, flexible and multilayered structure, for insertion in the conjunctival sac.
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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.
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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
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Ocular InsertsI. 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.
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Insoluble ophthalmic insertsDiffusion controlled ocular insertsThese 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
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Sr.no. Pilo-20 Pilo-401 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
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Synthetic and semi- synthetic polymers
Offer additional advantage of simple design & easily processed.
Soluble synthetic polymers
Cellulose derivatives- HPC, MC, HEC, HPMC, SOD. CMCothers- poly vinyl alcohol, ethylene vinyl acetate co polymer
Additives Plasticizers- poly ethylene glycol, glycerine, propylene glycolcomplexing agent- PVPBioadhesives- 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.
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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)
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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.
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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.
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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
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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 durability2- resistant to absorption of medications and environmental contaminants3- visual acurity Disadvantages:1- require adjustment period of the wearer2- more easily dislodged from the eye
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Advantages of soft contact lenses:1- worn for longer periods2- 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
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Lens Type Chemical Classification Major CharacteristicsHard, Rigid, Hydrophobic PMMA
(Polymethylmethacrylate)- Negligible gas permeability- Low water content- Medium wettability
Soft, flexible, Hydrophilic HEMA (Hydroxylethylmethylmethacrylate)
- 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
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• Products for soft contact lenses:Cleaners- To remove lipid and protein debris- formulation:1- vocalizing surface-active agent: to enable gentle friction with fingertips2- antibacterial-fast acting: benzalkonium
chloride
Products for soft contact lenses:
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Products for soft contact lenses:
• 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
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Enzyme protein digest- For occasional cleaning followed by washing before wearingFormulation:- Proteolytic enzyme: papain solution tablet to produce a solution when
dissolved in water
Products for soft contact lenses:
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Products for hard contact lenses:• Rinsing and storage solutions- For cleaning, microbial inactivation and hydrationFormulation:- 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 lubricationConsist 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.
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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Preparation of ocular insertCasting 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. foil
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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 mmL = 3.5 mm
Vary D = 4-5 mmL = Vary
Diseases Dry eye syndrome Glaucoma Eye infection
Dose replacement 4 times/ hr dose of eye drops
Eye drops 4-12 timesEye ointment 3-6 times
Solfisoxazole 170 hrsGentamicin 320 hrs
Extra features At morning imbibes water from conjunctiva.
10-15 sec. – soft10-15 min. – polymeric mass30-60 min. – polymer solution
Crosslinking of polymer take places
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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.
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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.
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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
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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.
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Evaluation Test of Ocular productsSr. no.
Evaluation test Eye Drops Eye Suspension Eye Ointment
1 Organolaptic Charactersa) Colourb) 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
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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
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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.
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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.
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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.
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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.
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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
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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
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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 .
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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.
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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
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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
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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
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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
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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: 634-6616. Modern dispensing pharmacy : N K Jain pg: 13.3-14.97. 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. 201611. www.google/images/eye/anatomy& physiology Assessment time: 2am, Date: 5
April. 2016
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