ocular drug delivery system (odds)

160
Ocular Drug Delivery System [ODDS] Mr. Sagar Kishor Savale [Department of Pharmaceutics] [email protected] 2015-2016 Department of Pharmacy (Pharmaceutics) | Sagar savale 06/13/2022 1

Upload: sagar-savale

Post on 08-Apr-2017

420 views

Category:

Health & Medicine


5 download

TRANSCRIPT

Page 1: Ocular drug delivery system (ODDS)

05/02/2023 1

Ocular Drug Delivery System [ODDS]

Mr. Sagar Kishor Savale[Department of Pharmaceutics]

[email protected]

Department of Pharmacy (Pharmaceutics) | Sagar savale

Page 2: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 2

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

Page 3: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 4: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 5: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 5

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...

Page 6: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

CONT...

Page 7: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 8: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 9: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 10: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 10

Lacrimal nasal drainage:

Page 11: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 12: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 12

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

Page 13: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 13

Anatomy and Physiology of the Eye

Page 14: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 14

Page 15: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 15

Page 16: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 16

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

Page 17: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 17

Corneal Cross Section

Page 18: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 18

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.

Page 19: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 20: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 21: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 22: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 22

General Pathway For Ocular Absorption

Page 23: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 24: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 24

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,

Page 25: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 25

Disadvantage of Conventional Ocular Drug Delivery System

Less Bioavailability

Protein binding

Lacrimation

Peak valley Profile

Less intimate contact

Patient Incompliance

Page 26: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 26

Ideal Requirements for ocular drug delivery

Sterility

Free from foreign particles

Isotonicity

Buffer

Page 27: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 27

Additives Buffering Agent

Preservatives

Solubilizing Agent

Thickening Agent

Antioxidant

Isotonic agent

Chelating agent

Vehicle

Page 28: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 29: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 30: Ocular drug delivery system (ODDS)

sagar kishor savale05/02/2023 30

Corneal Absorption

Poor Bioavialability

Protective mechanism (short

residence time)

BlinkingReflex lacrimation,

Nasolacrimal drainage

Anatomy of eye

Barrier properties of cornea

Page 31: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 31

Corneal absorption

Page 32: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 33: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 33

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.

Page 34: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 35: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 36: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 37: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 37

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%.

Page 38: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 39: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 40: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 41: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 encapsulatedLipophilic drugs located in the hydrophobic lamella

NIOSOME Vs LIPOSOME

Page 42: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 43: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 44: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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).

Page 45: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 45

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

Page 46: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 47: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 47

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.

Page 48: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 49: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 49

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

Page 50: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 50

Figure. Some of the routes of administration in the eye

Cont..

Page 51: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 51

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

Page 52: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 52

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.

Page 53: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 53

Page 54: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 55: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 56: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 56

C. Preservation and preservatives

Page 57: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 58: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 60: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 61: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 62: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 63: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 63

Mathematical models Zero order release model

First order release model

Hixson-crowell release model

Higuchi release model

Korsmeyer – peppas release model

Page 64: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 65: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 66: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 67: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 68: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 69: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 70: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 71: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 71

Page 72: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 73: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 74: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 74

Page 75: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 76: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 77: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 78: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 79: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 80: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 80

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.

Page 81: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 81

Examples of topical eye drops:

Atropine Sulphate eye drops.

Pilocarpine eye drops.

Silver nitrate eye drops.

Zinc Sulphate eye drops.

Page 82: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 83: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 84: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 84

IsotonicityLacrimal fluid is isotonic with blood having an isotonicity value

Corresponding to that of 0.9% Nacl solution

Page 85: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 86: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 .

Page 87: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 87

pH & buffer

Page 88: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 .

Page 89: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 ).

Page 90: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 )

Page 91: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 92: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 93: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 94: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 95: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 95

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.

Page 96: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 96

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

Page 97: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 97

Examples

Chloramphenicol ointment.

Tetracycline ointment.

Hydrocortisone ointment.

Page 98: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 98

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.

Page 99: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 100: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 100

Different mucoadhesive polymers were added to poloxamer

Carbopol 940

Hydroxypropylmethyl cellulose (HPMC)

Hydroxyethyl cellulose (HEC)

Page 101: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 101

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.

Page 102: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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).

Page 103: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 104: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 105: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 105

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.

Page 106: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 106

Examples,

Prednisolone acetate suspension.

Besifloxacin suspension.

Blephamide suspension.

Fluorometholone.

Page 107: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 108: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 109: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 110: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 110

Ophthalmic inserts

1. Non-erodible inserts Ocuserts Contact lens

2. Erodible inserts Lacriserts SODI Minidisc

Page 111: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 112: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 112

Ophthalmic inserts are defined as sterile solid or semisolid preparations, with a thin, flexible and multilayered structure, for insertion in the conjunctival sac.

Page 113: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 113

Page 114: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 115: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 116: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 116

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.

Page 117: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 117

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

Page 118: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 118

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

Page 119: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 119

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.

Page 120: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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)

Page 121: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 122: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 123: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 124: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 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

Page 125: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 125

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

Page 126: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 126

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

Page 127: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 127

• 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:

Page 128: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 128

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

Page 129: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 129

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:

Page 130: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 130

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.

Page 131: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 132: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 133: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 134: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 135: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 136: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 137: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 138: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 139: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 139

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

Page 140: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 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

Page 141: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 142: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 143: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 144: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 145: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 145

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

Page 146: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 147: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 148: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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. 

Page 149: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 150: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 151: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 152: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 153: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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 .

Page 154: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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.

Page 155: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 156: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 157: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 158: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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

Page 159: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 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: 634-6616. 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

Page 160: Ocular drug delivery system (ODDS)

05/02/2023 sagar kishor savale 160