OCULAR DRUG DELIVERY

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Eye Anatomy

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Drug fate in the eye 3 .

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Conventional drug Delivery
1. Eye drops  Spillage from eye  Overflow on eyelids 2. Eye ointments  Interference with vision 3. Ophthalmic gels Less interference with vision  Matted eyelids

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Problems with conventional dosage forms 

Drainage & spillage of the instilled solution Lacrimation & tear turnover Tear evaporation Drug metabolism Nonproductive absorption Limited corneal area & poor corneal permeability Binding to lachrymal protein
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cycloplegics. antibacterials. solvent 7 . The adjuvants used for ophthalmic adjustment of tonicity. stabilizing the active ingredients against decomposition. increasing solubility. imparting viscosity. antiglaucoma drugs. buffering & adjustment of pH. diagnostics etc. surgical adjuncts.Conventional Ocular Delivery System Miotics. mydriatics.

physiology & biochemistry of the eye render this organ impervious to foreign substances.Introduction Objective of ocular NDDS is to maintain the drug in the biophase for an extended period of time. tear dilution. It is challenge to the formulator to circumvent the protective barriers of the eye so that the drug reaches the biophase in sufficient concentration. The anatomy. 8 . tear turnover & conjuctival absorption. The precorneal constraints responsible for poor ocular bioavailability of conventional ophthalmic dosage forms are solution drainage. Physiological barriers to diffusion & productive absorption of topically applied drug exist in the precorneal & corneal spaces. lacrimation.

Most of the drug is rapidly lost through the nasolacrimal drainage immediately following dosing. If the patient does not blink. the eye can hold about 30 µL without spilling on the cheek. 9 . The conjunctiva also possess relatively large surface area making the loss significant. The drainage allows the drug to be absorbed across the nasal mucosa into the systemic circulation. The instilled dose leaves the precorneal area within 2 minutes of instillation. The natural tendency of the cul-de-sac to reduce its volume to 7-10 µL. The ophthalmic dropper delivers 50-75 µL of the eye drops.Introduction««« Drug solution drainage is the most significant factor in reducing the contact time of the drug with the cornea & consequently ocular bioavailability of topical dosage forms.

Tears dilute the drug remained in the cul-de-sac which reduces the transcorneal flux of the drug. Topical application of the drug is further made inefficient by tear turnover. Due to all these factors typically less than 1% of the instilled drug reaches aqueous humor. Further the hydrophobic nature of the corneal epithelium also contribute to the poor bioavailability. Both conjunctival & nasal mucosa are the potential sites for systemic absorption of topically applied drug. The drug entity. 10 . Metabolism in the precorneal area also account for the further loss of the drug. pH. tonicity of the dosage form as well as formulation adjuvant stimulate tear production.Introduction««.

Thus. Enhancing site specificity 3. the challenges to develop novel ocular drug delivery system are. The existing ocular drug delivery systems are thus fairly primitive & inefficient.Introduction««. Enhancing corneal permeability 11 . Improving ocular contact time 2. 1.

The NODS V. Use of polymers II. Penetration Enhancers 12 .Prodrugs IX.Novel Systems I.Liposomes VIII. Ophthalmic Inserts IV. Mucoadhesives III. Nanoparticles VII. Collagen shield drug delivery VI.

PVP. Polymers used ² PVA.I. The increased solution viscosity reduces the solution drainage. Natural polymers namely sodium hyaluronate & chondroitin sulfate are also used as viscosity builders. CMC & HPC Increasing the solution viscosity of pilocarpine solution through the incorporation of MC reduced the solution drainage rate constant 10 times while 2 fold increase in its aqueous humor concentration found. 13 . MC. Role of Polymers in Ocular Delivery Incorporation of polymers into an aqueous vehicles increases the ocular contact time of drug.

14 .Role of Polymers in Ocular Delivery« In considering this approach of increasing solution viscosity to enhance ocular drug absorption the lipophilicity of the drug should be taken into account. No statistically significant increase in aqueous humor concentrations of drug whose PC exceeded 10 was observed on increasing solution viscosity from 1-90cps. Increasing solution viscosity has limited utility.

Mucoadhesives External surfaces of the globe of the eye is coated with the thin film of glycoprotein called as mucin. Goblet cells on the conjunctiva secrets mucin & it forms the thin layer over conjunctiva & cornea. The mucin layer is capable of taking about 40-80 times its weight of water due to substantial number of sugar groups present in polypeptide backbone. 15 . Natural & synthetic polymers that bind to the mucin non covalently used for drug delivery.II. conjunctiva epithelium & cul-de-sac. The mucin layer forms a part of precorneal tear film which continuously bathes the corneal epithelium.

polycarbophil. They remain in contact with the precorneal tissues until mucin turnover causes elimination of the polymer.. number of polar groups for hydrogen bonding & balance of lipophilic to hydrophilic sections in the polymer chain. Good mucoadhesion in the eye is achieved with polymers possessing the correct charge density. carbopol. CMC.Mucoadhesives«.g. e. Electrostatic attraction also responsible for bioadhesion till some extent. These bioadhesive polymers help in prolonging the release of the drug from a dosage form by localizing it at a specific site where mucus present. PMMA. PAA. sodium alginate. 16 . Hydrogen bonding play an important role in bioadhesion.

Viscosifying Polymers iscosifying 17 .

It also offers the potential advantage of improving patient by reducing the dosing frequency Desired criteria for a controlled release ocular insert are: 1.III. 8. 6. 2. 4. 3. Ophthalmic Inserts Polymer based delivery devices for placement into cul-de-sac. It offers an attractive approach to the problem of prolonging precorneal drug residence time. 7. 5. Comfort Lack of explosion Ease of handling & insertion Non interference with vision & oxygen permeability Reproducibility of release of kinetics Sterility Stability Ease of manufacture 18 .

Ocusert ii. Contact lens iii.Ophthalmic Inserts«« Ophthalmic inserts are of 2 types: 1. Nonerodible Inserts i. Ocufit 2. Erodible Inserts i. SODI iii. Smaller devices are better retained than larger ones & rod shaped are better retained than oval ones. 19 . Minidisc Retention of these inserts are a function of size & shape. The Lacrisert ii.

Sterility. Patient comfort. User acceptance. Lack of expulsion during wear. 20 . Applicability to a variety of drugs. Reasonable price.Essential Requirements« Physician acceptance. Stability. Ease of handling and insertion. Ease of manufacture. Lack of toxicity. Non-interference with vision and oxygen permeability Reproducibility of release kinetics.

21 . each insert can be made to contain a precise dose which is fully retained at the administration site).   Reduction of systemic absorption (which occurs freely with eye drops via the nasolacrimal duct and nasal mucosa).  Possibility of releasing drugs at a slow. constant rate. Accurate dosing (contrary to eye drops that can be improperly instilled by the patient and are partially lost after administration. hence a prolonged drug activity and a higher bioavailability with respect to standard vehicles.Advantages  Increased ocular residence.

permeation enhancers. thus reducing the risk of sensitivity reactions.Advantages« Better patient compliance.  Increased shelf life with respect to aqueous solutions. 22 . Such as pro-drugs. salts acting as buffers. Exclusion of preservatives. mucoadhesives. etc. microparticulates. resulting from a reduced frequency of administration and a lower incidence of visual and systemic side-effects   Possibility of targeting internal ocular tissues through non-cornea1 (conjunctival. scleral) routes. and   Possibility of incorporating various novel chemical/technological approaches.

Disadvantages A capital disadvantage of ophthalmic inserts resides in their ¶solidity·.. in the fact that they are felt by the (often oversensitive) patients as an extraneous body in the eye   This may constitute a formidable physical and psychological barrier to user acceptance and compliance  Initial discomfort.e.    Their interference with vision and A difficult placement (and removal. i. The occasional inadvertent loss during sleep or while rubbing the eyes. for insoluble types) 23  . Their movement around the eye.

Percentage moisture loss 6. Compatibility study 24 . Content uniformity 3. Uniformity of Weight 4. In-vivo drug release 8. Thickness of film 2.Evaluation Of Ocular Inserts 1. Accelerated stability studies 9. Percentage moisture absorption 5. In-vitro drug release 7.

NON-ERODIBLE INSERTS 25 .

flexible.A.1. elliptical device consisting of three layers Membrane 1 & 4 ² outer layers of EVA Membrane 2 ² retaining ring of EVA impregnated with titanium dioxide Membrane 3 ² Pilocarpine reservoir gelled with alginate 26 . It is available as Ocusert® Pilo 20 & Ocusert® Pilo 40 Sterile. Flat.S. Ocusert® It is developed by Alza Corporation First marketed in the U. in 1974 It is used in the treatment of chronic glaucoma.

Ocusert®«.. removal of system from the eye 27 . risk of loss of insert from eye. The higher release rate of Ocusert® Pilo 40 is achieved by making its rate controlling membrane thinner & by the use of flux enhancer di 2ethylhexyl)phthalate Precise controlled delivery of pilocarpine Disadvantages ² patient discomfort. All these four membranes put together Retaining ring of EVA(Ethylene Vinyl Acetate) impregnated with Ti02 for visibility purpose It is preprogrammed to release pilocarpine at constant rate 20 or 40 µg/hr around the clock for 7 days.

Most of the drug released in first 30 minutes from presoaked contact lens.2. corneal ulcers. The supply of oxygen to the eye tissues & the build up of harmful metabolite such as CO2 complications also arises during use of presoaked contact lens. characterized by marked thinning of cornea. The use of preservative benzalkonium chloride leads to toxic effects. 28 . Contact Lens Therapeutic soft lenses are often used to aid corneal wound in patients with infection. The residence time of drugs using presoaked lenses is not significantly prolonged.

Contact Lens«. an alternative approach is to incorporate the drug either as solution or suspension of solid particles in the monomer matrix. The polymerization is then carried out to fabricate the contact lens With this approach the release of the drug is significantly prolonged to many hours compared to presoaked lenses as well the problem of concentration of preservative is eliminated. Thus.. since the drug is added without any preservative Disadvantages are problem of discomfort & difficulty in handling and insertion particularly in case of presoaked lenses 29 .

It was designed to fit the shape and size of the human conjunctival fornix It is 1. 30 .9 mm in diameter and 25-30mm in length. rod-shaped device made of silicone elastomer Patented in 1992 by Escalon Ophthalmics Inc.3. Ocufit SR® It is a sustained release.

31 .The insoluble Ocufit® reportedly retention combines two and sustained important features. placebo devices were retained for 2 weeks or more in 70% of the cases The insoluble Ocufit® reportedly combines two important features. long drug release. long retention and sustained drug release. When placed in the upper fornix of volunteers.

ERODIBLE INSERTS 32 .

translucent rod shaped device made of HPC without any preservative is used for treatment of dry eye syndrome The device is introduced by Merck.4. Lacrisert® It is a sterile.5mm It is useful in treatment of patients with keratitis sicca whose symptoms are difficult to treat with artificial tear alone 33 . Sharp & Dohme It weighs 5mg & measures 12.7mm in diameter with a length of 3.

lubricates cornea. Day long relief from dry eye syndrome is reported from a single insert placed in the eye early in the morning. 34 . forms a hydrophilic film which stabilizes the tear film & hydrates.It is inserted into the inferior fornix where it imbibes the water from the conjunctiva & cornea.

it softens in 10-15 seconds & assumes the curved configuration of the globe The film turns into a viscous polymer mass.25 : 0. The SODI® Soluble Ophthalmic Drug Insert (SODI) is a small oval wafer developed by Soviet scientists The unit is made from acrylamide. N-vinylpyrrolidone & ethylacrylate (ratio 0.5.25 : 0.5) It weighs 15-16mg which is placed in the inferior cul-de-sac where wetted by the tear film. thereafter in 30-60 minutes it becomes polymer solution A single SODI application constitutes once a day therapy for the treatment of glaucoma 35 .

6. It is like a miniature contact lens with a diameter of 4-5mm. The major component of OTS is a silicone based prepolymer. The OTS can be hydrophilic or hydrophobic to permit the release of both water soluble & insoluble drugs. 36 . OTS or Minidisc It consists of a contoured disc with a convex front & a concave back surface in the contact with the eye ball..bis(4-methacyloxy)-butylpolydimethylsiloxane (M2DX).

IV. reproducible dosing in an easily administered preservative free form The drug is incorporated into a water soluble PVA film Each NODS consists of a drug loaded film or flag attached to a handle film by means of thin membrane On contact with the tear film in the lower conjunctival sac the membrane quickly dissolves releasing the flag into the tear film 37 . The NODS The new ophthalmic delivery system (NODS) is a method of presenting drugs to the eye within a water soluble drug loaded film It provides for accurate.

IV. The NODS«.
The flag hydrates & disperses allowing diffusion & absorption of the drug The handle is provided with a paper backing for strength Both soluble drugs such as pilocarpine & insoluble drugs such as tropicamide can be formulated into the NODS The delivery of insoluble drug in NODS has shown improved bioavailability compared with a standard solution

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The NODS

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V. Corneal Collagen Shields

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tendons. including the eye 41 .V. Corneal Collagen Shields Collagen: Collagen is a structural protein that can be safely applied to eye tissues Collagen is the structural protein of bones. ligaments and skin and comprises more than 25% of the total body protein in mammals Collagen is a naturally occurring protein that is totally safe for use on and in the body collagen is an essential element for healing wounds anywhere in the body.

V. Corneal Collagen Shields« The creation of collagen shields has provided a means to promote wound healing & to deliver the drugs It seemed that naturally occurring enzymes in the tear film caused the collagen contact lens to dissolve over a period of time Collagen is extracted & moulded into contact lens configuration The shields are sterilized by gamma radiation then dehydrated 42 .

the surface coat (the sclera or the cornea) must be incised to allow access to the interior part of the eye   Healing of incision is of crucial importance to the success of the surgery The wound must be adequately protected from the external environment as well as from the blinking action of the eyelids 43  . As the shield dissolves the drug is released gradually in the tear film. maintaining high concentrations on the corneal surface & increasing drug permeation through the cornea & into the aqueous humor  Potential use for the collagen shields is that of ocular surface protection In nearly all types of eye surgery.V. Corneal Collagen Shields«  Drugs can be incorporated in the collagen matrix during manufacture.

while others (Medilens. Fort Worth.V. Chiron Ophthalmics. Irvine. One of these (Bio-Car. Alcon Surgical. FL) is made of porcine scleral collagen. Corneal Collagen Shields«  In addition to patching therapy. Texas) are prepared from bovine corium tissue 44 . California. ophthalmologists have used special soft contact lenses (called "bandage" contact lenses) to provide protection to the surface of the eye  Therapeutic corneal bandages. Bausch and Lomb. and ProShield. Clearwater.

V. it would appear to be an ideal alternative to bandage contact lenses for protecting the eye  This area of research is in its infancy and is being conducted primarily at the UIC Eye Center  Preliminary results have shown that the collagen shield can indeed provide an adequate protective environment to allow healing of surgical and traumatic wounds to the eye 45 . Corneal Collagen Shields«  These bandage contact lenses are expensive and have been associated with some complications. particularly when they are used over a long period of time  As the collagen shield contains a naturally occurring protein.

and drug delivery and the potential for better and faster wound healing may eventually make these shields a standard part of ophthalmic practice 46 .  protection.V. Corneal Collagen Shields« It should be pointed out that collagen shields are mostly used as a bandage lens. and their use as drug delivery systems is still experimental   The future for collagen shields is highly promising The characteristics of providing ocular lubrication.

encapsulation of drugs in nanoparticles. Nanoparticles The use of nanotechnology-based drug delivery systems (1-100nm) like nanosuspensions. like dexamethasone. gancyclovir   Depending on their particle charge.  In addition to these points. surface properties and relative hydrophobicity.VI. budenoside. can also provide protection for the drug and hence prolong exposure of the drug by controlled release 47 . nanoparticles can be designed to be successfully used in overcoming retinal barriers. solid lipid nanoparticles has led to the solution of various solubility-related problems of poorly soluble drugs.

VI. such as the blood retinal barrier in the eye  The drug delivery systems based on nanotechnology may prove to be the best drug delivery tools for some chronic ocular diseases. the most commonly used polymers are various poly(alkylcyanoacrylates). for example in ophthalmic diseases like chronic cytomegalovirus retinitis  In recent studies of nanoparticles. all of which are biodegradable polymers that undergo hydrolysis in tears 48 . in which frequent drug administration is necessary. Nanoparticles«  Nanotechnology-based drug delivery is also very efficient in crossing membrane barriers. poly-e-caprolactone and polylactic-coglycolic acid.

before.VI. during or after the polymerization 49 . Nanoparticles« Nanoparticles made up of mucoadhesive polymers is one of the site targeting approach used Nanoparticles for ophthalmic drug delivery are produced by emulsion polymerization In this process a poorly soluble monomer is dissolved in the continuous phase which can be aqueous or organic Polymerization can be started by chemical initiation or by irradiation with gamma rays or UV visible light The drugs may be added.

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45%w/v of PVA were retained on the corneal surface for a significantly longer period than suspended in buffer 51 . Liposomes Liposomes are concentric vesicles composed of lipid membrane enclosing an aqueous volume They deliver both hydrophilic & hydrophobic drugs Ocular delivery via liposomes is significant for lipophilic drugs to a greater extent than hydrophilic drugs Liposomes suspended in 1%HPMC & 0.VII.

Size. and The affinity liposomes exhibit towards the corneal surface 52  .VII.      Their retention in the conjunctival sac. Liposomes« The effectiveness of liposomes in ocular drug delivery depends on a number of factors. including   Drug encapsulation efficiency. Stability of liposomes in the conjunctival sac and ocular tissues. Distribution of a drug within liposomes. Charge of liposomes.

leading to an increase in the corneal absorption time  The degree of liposome²cell interaction can be improved by increasing the degree of positive surface charge using stearylamine 53 . Liposomes«  It is considered that solid particles intended for ophthalmic use should not exceed 5²10 micron diameter  Positively charged liposomes seem to be preferentially captured at the negatively charged corneal surface as compared with neutral or negatively charged liposomes  These liposomes bind intimately on the corneal surface leading to an increase of residence time.VII. therefore.

Liposomes«  Liposomes a potentially useful system for ocular delivery they are not very popular because of their short shelf life. and problems in sterilization Further developments to render the vesicular systems more effective:  Use of mucoadhesive polymers Use of either the viscosity increasing agent with vesicles and/or the use of penetration enhancers along with the vesicles in the formulation. limited drug capacity. Viscosity imparting agents prolongs the corneal contact time whereas penetration enhancers increase the rate and amount of drug transport   Collagen corneal shields impregnated with liposomes Entrapmentof drug-cyclodextrin complex within vesicles 54  .VII.

Particulate Systems 55 .

Prodrugs  Prodrugs are pharmacologically inactive derivatives of drug molecules that require a chemical or enzymatic transformation in order to release the active drug within the body  Prodrugs have also been called reversible or bioreversible derivatives and latentiated drugs  Prodrugs are simple chemical derivatives which are one or two chemical or enzymatic steps away from the parent drug  It is a useful technique in improving corneal permeability of drugs 56 .VIII.

e. a new class of pilocarpine double prodrug with adequate amount of aqueous solubility. (dibenzyl)bispilocarpates.VIII. Prodrugs  The concept of double prodrug i.  E. prodrug of prodrug is also gaining importance. improved delivery characteristics & stability 57 .g.

Drugs Epinephrine Phenylephrine Prostaglandins Timolol Prodrugs Dipivalyl epinephrine Phenylephrine oxazolidine Therapeutic use Treatment of glaucoma alpha-adrenergic agent PGF methyl and PGF Treatment of glaucoma isopropyl esters alkyl. esters ester cycloalkyl. aryl Beta-Antagonists and carbamate blockers) (beta Pilocarpine Pilocarpic acid mono.Treatment of glaucoma and diesters. phosphate Anti-inflammatory agent ester N-substituted (aminomethyl)benzoate ester Antiviral agent Steroids Acyclovir 58 . quaternary salts of pilocarpine acetate ester.

 The absorption of pilocarpine is mainly limited by its low lipophilicity (log Papp = . coupled with a short duration of action.0.  Thus lipophilic prodrugs of pilocarpine providing controlled release and improved ocular delivery have been developed. concentrated pilocarpine eyedrops must be administered 3-4 times daily resulting in undesirable side-effects and poor patient compliance.Pilocarpine Prodrugs Pilocarpine is a direct-acting cholinergic agonist used for the control of the elevated IOP associated with glaucoma. 59 .  Consequently.15) and its short duration of action is due to rapid elimination.   Pilocarpine shows a low ocular bioavailability (l-3% of instilled dose) due to poor absorption into the cornea.

Pilocarpine Prodrugs  A series of pilocarpit acid monoesters and diesters as prodrugs of pilocarpine  Pilocarpic acid monoesters undergo spontaneous lactonization to pilocarpine in aqueous solution  Monoesters were more lipophilic than pilocarpine and increased the ocular bioavailability of pilocarpine 60 .

5 times compared to pilocarpine. the preparation of ready-to-use eye drops with an acceptable shelf-life was not possible  The stability problem of pilocarpic acid monoesters was overcome by using the double prodrug concept  Pilocarpine double prodrugs.Pilocarpine Prodrugs  Several monoesters also prolonged the duration of action 1.5 h to 18 h at 37°C.4) varied from 0. Although monoesters are more stable in acidic solutions. were prepared by esterifying the alcoholic hydroxyl group of pilocarpic acid monoester 61 . The poor aqueous stability of the practical use monoesters limited their  The half-lives of monoesters in aqueous solution (pH 7. pilocarpic acid diesters.

Penetration Enhancers This is an alternative approach to improve the bioavailability of ocular drugs by incorporation of penetration enhancers The preservative agents used in most formulations serve as potential penetration enhancers. 0.IX. diffusivity & partitioning behavior 62 . E. chlorhexidine gluconate Endothelial degeneration is occurred from the prolonged administration of benzalkonium chloride The potential benefits are negated by toxic effects Endothelial degeneration occur from topical administration of BAK Another approach is ion pair formation which results in altered drug species with respect to ionic size.01% benzalkonium chloride.g.

Duration of action of the ODDS 63 .

Penetration Enhancers 64 .Ocular DDS I. Mucoadhesives III.Prodrugs IX. Use of polymers   Ocular iontophoresis Intraocular solutions II. Collagen shield drug delivery VI. Nanoparticles VII. The NODS V. Ophthalmic Inserts IV.Liposomes VIII.

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 It is a non-invasive technique Iontophoresis is based on the physical principle that ions with the same charge repel (electrorepulsion) and ions with opposite charge attract (electroosmosis).  66 .Introduction  It was first investigated by in 1908 by the German Investigator Wirtz  Iontophoresis is the use of a direct electrical current to drive topically applied ionized substances into or through a tissue.

 Iontophoresis usually employs low voltage (10 V or less) to supply a continuous direct current of 0.  Conversely. the ions of importance are charged molecules of the drug or other bioactive substances.5 mA/cm2 or less. negative ions (anions) are attracted to the positive electrode and repelled by the negative electrode.  Iontophoretic transport results from the passage of a current from electrodes into an electrolyte solution and thus into the skin or body  Thus. positive ions (cations) are attracted to the negative electrode (or cathode) and repelled by the positive electrode (or anode). 67 .  When iontophoresis is used therapeutically.

which is of opposite charge.  The drug serves as a conductor of the current through the tissues. The ionized substances are driven into the tissues by electrorepulsion at either the anode (if they carry a positive charge) or the cathode (if they carry a negative charge). The drug is applied with an electrode carrying the same charge of the drug. 68 . & the ground electrode. is placed elsewhere on the body to complete circuit.   The ionized substances are driven into the tissues by electrorepulsion at either the anode (if they carry a positive charge) or the cathode (if they carry a negative charge).

antifungal. antiviral. steroids antimetabolites & genes 69 .  Iontophoresis was extensively investigated for delivering ophthalmic drugs. including antibacterial. These basic operational guidelines have enabled iontophoresis to be used to enhance drug delivery in a wide variety of conditions.

 Transscleral iontophoresis presents more advantages when compared to transcorneal delivery.Routes«. 70 .  The drugs can be delivered either by transscleral or transcorneal iontophoresis. owing to scleral larger surface area. enhanced delivery of the drugs to the posterior segment and least possibilities of systemic absorption.

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the current rate. and R is the resistance in ohms 73 .1st LAW  Laws of physics and chemistry will help to delineate the important parameters in iontophoretic transport.  Those parameters are the amount of drug transported. and the amount of time that current is applied.  The first law is Ohm·s law: V = IR where V is the electromotive force in volts. I is the current in milliamperes (mA).

 With iontophoresis. any change in resistance results in a change in the current.  The result is that the current (mA) increases and must be reduced to maintain a constant current over time. At constant voltage. resistance decreases during the procedure. 74 .

 Precise conditions for specific iontophoretic applications can be expressed as a minimum.2nd LAW  A second law important for iontophoresis is Coulomb·s law: Q = IT where Q is the quantity of electricity. can be expressed as mAminutes. I is the current in mA. or a range of mA-minutes 75 . Q. which is the total current dosage.  Thus. maximum. and T is the time in minutes.

T is the time in minutes. a third important physical principle is Faraday·s law: where D is the drug delivered in gram-equivalents. and F is Faraday·s constant 76 . I is the current in mA. IZI is the valence of the drug.3rd LAW  Finally.

more of the drug enters the tissue. 77 .  The importance of this proportional relationship is that if more current is applied (either by increasing the current rate or increasing the time of application of a constant low current). Faraday·s constant is the electrical charge carried by 1 gram equivalent of a substance.

Factors influencing iontophoretic penetration 78 .

current density)  Biological or physiological variations (site. pH. electrodes.Factors influencing iontophoretic penetration  Physiochemical properties of the compound (molecular size. humidity. charge. presence of other compounds)  The electrical and technical factors (different types of current. treatment length. regional blood flow) . concentration)  The solution factor (type of the buffer.

possible risk of infection and inflammation and hemorrhages. while minimizing the systemic drug exposure  It causes minimum discomfort to patients and is not entirely harmless for ocular tissues  The ease of administration and the potential possibility to apply for example transscleral CCI (Coulomb-controlled iontophoresis) on a repetitive basis make this treatment modality of special interest in chronic and long-term intraocular diseases  This non-invasive drug delivery system minimizes the risk of trauma due to drug delivery ways such as intravitreal or peribulbar injections. 80 .Advantages  High intraocular and especially posterior pole drug tissue concentration in a controlled and safe fashion.

 Some drugs cause long lasting pigmentation after iontophoretic application.  Iontophoresis is restricted to drugs that can be formulated in ionized form. 81 .Disadvantages Cannot deliver drug by iontophoresis if drug causes irritation   There is a limit to the amount of medication that can be delivered usually 5 to 10mg/hr.

 A milliampere meter to measure the current. and   Two electrodes Platinum is the material of choice for the electrodes. since it releases almost no ions. The basic design is a unit with   A power source (either a battery or an on-line unit with a voltage regulator).Iontophoresis Device  Iontophoretic devices vary in complexity. undergoes degradation at a slow rate. and is nontoxic. 82 . A rheostat to control the amount of current flowing through the system.

Iontophoresis Device (Eye Gate®) The Eyegate® advantages Non-invasive delivery to anterior and posterior chambers of the eye  Programmable dose control Potential for increased patient safety   Delivery time just 1-4 minutes 83 .

84 .

  The eyecup. is placed over the cornea and filled with the drug solution. 85 . with an internal diameter of 1 cm.Ocular iontophoresis in the Rabbit  A variety of iontophoretic apparatuses exist for use in ocular iontophoresis. Figure shows a diagram of ocular iontophoresis of a positively charged drug in a rabbit.  They mainly consist of either an eyecup or an applicator probe.

connected to the other terminal of the power supply.  The ground electrode. 86 . A metal electrode that is connected to a direct current power supply is submerged in the solution in the eyecup without making contact with the surface of the eye. is attached to the ear of the rabbit via wet (0.9% NaCl) gauze to ensure a good connection.

 Iontophoresis requires a complete electrical circuit with direct current passing from the anode to the cathode and from the cathode back to the anode. the metal (platinum) electrode extends into the eyecup that is filled with the drug solution. which is an excellent conductor of electricity.  The eyecup is placed against the eye and is held in place throughout the entire iontophoresis procedure. With the hand-held applicator probe. to complete the circuit.  The two electrodes are placed as anatomically close to each other as possible on the body. 87 .

88 .

89 .

0 mA and the time be no longer than 10 min.  The current is controlled by a rheostat on the direct current transformer. The drug is placed in a cylindrical eye cup with a central diameter of 9²12 mm. the current should not exceed 2. 90 .  In the case illustrated here.  In general. the drug molecules (cations) have a positive charge. the inner circumference of the eye cup fits within the corneoscleral limbus.

 The positively charged anode drives the positively charged drug molecules from the solution into the eye at a greater rate than would be observed with simple diffusion.  The other electrode (cathode) is connected to the ear or front leg of the rabbit to complete the circuit. the platinum electrode connected to the anode (the positively charged pole) is placed in contact with the solution. Therefore. 91 .

92 .Requirements  The drug solution or preparation to be iontophoresed should be devoid or have a minimum of extraneous ions.  Drugs with one or more pKa values either below pH 6 or above pH 8 are generally excellent candidates for iontophoresis into the eye because these drugs will be in the ionized form at the physiological pH of the eye.  The salt form of a drug is also preferred for iontophoresis since the dissociated salt is highly soluble.

Applications  Glaucoma Ocular Anesthesia Ocular Inflammation Ocular Infection Antiviral Agent for Treatment of Cytomegalovirus Retinitis Herpes Simplex Virus Infection      93 .

94 .

Inc. Inc. Inc Dagan Corporation MedTherm Corporation Parkell Model Phoresor II Auto. Fischer Co. Model MD-1a Dagan 6400 Advanced model Electro-Medicator Model A1 Desensitron II model number ID643DGC Eye Gate Pharma Eye Gate II 95 ..The commercial devices Company IOMED. Inc Life-Tech.PM900 Iontophor-II . General Medical Company Wescor.6111 PM/DX The Drionic unit Macroduct model 3700 Fischer Galvanic Unit.

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Discuss the various polymers used in ocular delivery systems(4) What are ocular inserts? Discuss in detail non-erodible ocular inserts.(7) 97         .Questions«« Give different advantages of ocular drug delivery systems over conventional ophthalmic formulations.(4) What are ophthalmic inserts? Discuss in detail erodible inserts.(4) Write a note on Lacrisert.(2) Discuss various polymers used in ocular drug delivery systems.(3) Explain in detail with examples the role of polymers in ocular drug delivery systems. (2)   Give a detail in Lacrisert and the SODI.(3) Write a note on Lacrisert.(3) Write a need for ocular mucoadhesive preparations.

take care of eyes!!! 98 .´Sight is the sense which is more valuable than all the restµ So.

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