ANATIMY OF THE EYE INTRODUCTIONFACTORS AFFECTING OCCULAR

BIOAVAIBILITYROUTES FOR OCCULAR DRUG DELIVERYELIMINATION ROUTES CONVENTIONAL EYE PREPARARIONSRECENT TRENDS IN ODDSEVALUATION OF ODDSRESEARCH WORK IN ODDSREFERANCES

CONTENTS

INTRODUCTION: The ocular drug delivery systems is the specialized dosage

forms designed to be instilled onto the topical, intraocular or periocular to the eye or used in conjunction with an ophthalmic device.

Conventional topical therapeutic dosage form includes : Solutions, Suspensions, Ointments.

Novel ocular drug delivery systems includes: Microemulsions, Nanoparticles, Liposomes, Niosomes, Nanosuspensions, Dendrimers, Implants and Hydrogels.

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 drainage.

To increase ocular bioavailability and retention time on the ocular surface, numerous ophthalmic vehicles such as viscous solutions, suspensions, emulsions, ointments, aqueous gels, and polymeric inserts, have been investigated.

4

Continual inflow and outflow of lacrimal fluid

Corneal permeability Absorption of the drug into cornea and

conjuctiva Interaction of the drugs with the proteins of

the lacrimal fluid. Drainage of the instilled solution Metabolism

Topical bioavailability can be improved by –Maximizing pre-corneal drug absorptionMinimizing pre-corneal drug loss

VISCOSITY IMPROVER: It Increases drug contact time. generally hydrophilic polymers- e. g cellulose, polyalcohols, polyacrylic acids, sodium carboxy methyl cellulose,carbomer is uses.

PENETRATION ENHANCER: Act by increasing corneal uptake by modifying the integrity of the corneal epithelium

PRODRUGS: modification of chemical structure - selective, site specific

BIOADHESIVE POLYMERS: Adheres to the mucin coat covering the

conjuctiva and corneal surface of the eye. Thus prolongs the residence time of drug in the

conjuctival sac.

Topical

Trans - scleral

Intravitreal Systemic

(not Shown)

TOPICALLY APPLIED OCULAR DOSAGE FORM

Diffusion Dissolution Erosion

Drug in tear film

Lacrimal turnover

Metabolism

Irritation

Also induces lacrimation

Drainage

Loss

Absorption Corneal&

Conjunctival

Drug in inner ocular

structures & aqueous humour

ONLY 1-5 % OF ADMINISTERED

DOSE

Mucoadhesives contain the dosage form which remains adhered to cornea until the polymer is degraded or mucus replaces itself.

Types-1. Naturally Occurring Mucoadhesives- Lectins,

Fibronectins 2. Synthetic Mucoadhesives-PVA,Carbopol, carboxy

methyl cellulose, cross-linked polyacrylic acid. Drugs incarporated into this are pilocarpine,

lidocaine, benzocaine and prednisolone acetate.

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The polymer undergoes swelling in water,

Entanglement of the polymer chains with mucin on the epithelial surface.

The un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin.

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Dosage forms Advantages Disadvantages

solution Convenience Loss of drug by drainageNonsustained action

Suspention Patient complianceBest for drugs with slow dissolution

Drug properties decide performance

Emulsion Prolonged release of drug from vehicle

Patient non complianceBlurred visionPossible oil entrapment

Ointment Flexibility in drug choiceImproved drug stability Increased tissue contact timeInhibition of dilution by tearsResistance to nasolacrimal drainage.

Sticking of eyelidsPoor patient complianceBlurred visionNo true sustained effectDrug choice limited by partition coefficient

Gels ComfortableLess blurred vision than ointment

No rate control on diffusionMatted eyelids after use

Irodible insert Sophisticated and effective delivery systemFlexibility in drug type and dissolution rateNeed only be introduced into eye and not removed

Patient discomfort Movement of system around eye can cause abrasion

Non-irodible insert Controlled rate of releaseProlonged deliveryFlexibility for type of drug selected

Patient discomfortIrritation to eyeTissue fibrosis

Topical eye drops:-Solutions

- Suspensions

- Powders for reconstitution

- Sol to gel systems

-Ointments

- Gels - Ocular inserts

1- Solutions:- Ophthalmic solutions are sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation into the eye.

1-The very short time the solution stays at the eye surface.

The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration and the instilled volume.

2- its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal drainage)

3- the instability of the dissolved drug4- the necessity of using preservatives.

 Phase transition system (In-situ gel):  These are liquid dosage forms which shift to the gel

or solid dosage form when instilled into the Cul-de–sac “.It is a Hydrogel.

Types of In- situ Gels:

1.Thermoreversible gel:- This type of the hydrogel containing polymer which

forms the gel when got to the physiological temperature. (37°C). e.g., Poloxamer F127

It contains polymer which forms the gel upon the physiological (native pH 4.5 to tear pH 7.4).

e.g. Cellulose Acetate Phthalate Gerlite® :

Cellulose acetate hydrogen phthalate latex, typically shows very low viscosity up to pH 5, and forms clear gel in few seconds when in contact with tear fluid pH 7.2 to 7.4 and hence, release contents over prolong period of time

3.Ion induced gel:- This produce gel of the polymer when it get

sodium ion (2.6 g/L) in contact. e.g.,Low Acetyl Gellan Gum.

  4. Dilution induced gel:- Gel is formed due to the dilution with

aqueous phase(water). e.g., Lutrol. 

Classification of Hydrogels

Hydrogels

Preformed gel

In situ forming gel

Cellulose

Poly(Vinyl alcohol

Hyaluronic acid

Carbomer

Carbomer

Gellan gum

Poloxamer

CAP Latex

Alginates

Formulation:

**It is suitable for moisture sensitive drugs and has longer contact time than drops.

-Ointments are used as vehicles for antibiotics, sulfonamides, antifungals and anti-inflammatories.-Petrolatum vehicle used as an ocular lubricant to treat dry eye syndromes.

*Gels have increased residence time and enhanced bioavailability than eye drops..

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

Advantages: Increasing contact time and improving

bioavailability. Providing a prolong drug release and thus a

better efficacy. Reduction of adverse effects. Reduction of the number of administrations and

thus better patient compliance.

Ocusert: A truly continuous controlled release and Zero order

kinetic fashion was achieved using ocusert. Pilocarpine ocuserts ( by Alza corporation of

California.) The system consists of a Pilocarpine – alginate core

(drug) in gel form sandwiched between two transparent, rate controlling ethylene-vinyl-acetate copolymer membranes. Titanium dioxide encloses the drug reservoir circumferentially.

The micro porous membrane permit the tear fluid to penetrate into the drug reservoir compartment to dissolve drug from the complex.

When this is placed under the upper or lower eyelid, the pilocarpine molecules dissolved in the lacrimal fluid are released through the rate-controlling membranes at predefined rates for week..

Two types of Ocuserts® are available Ocusert® pilo- 20 Ocusert® pilo- 40 more popular among younger patients as compared

to elder population. slow release of the drug can effectively control the

increased intraocular pressure in glaucoma, with a minor incidence of side-effects, such as miosis, myopia, etc.

high cost of the device as this system is non biodegradable, required to be

removed and replaced .

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.

consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.

- 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 conjuctivall sac, gradually dissolves within 1 h, while releasing the drug.

- Advantage: being entirely soluble so that they do not need

- to be removed from their site of application.

Soluble Ocular Inserts:  Poly(vinyl alcohol)insert(PVAI): Thin, elastic & oval shaped plates impregnated with

antibiotics, sulfonamides , pilocarpine, or other drugs used in ophthalmology.

Limitations:- Poor patient compliance and difficulty of self –insertion.

  Soluble ophthalmic drug insert (SODI) Thin, elastic, oval plates made of polymers & copolymers

of polyacrylamide, ethyl acrylate & poly vinyl pyrrolidine impregnated with drug.

When SODI inserted in to the conjunctival sac, it absorbs tears rapidly, swells and dissolves in about 30 to 90 min.

Polypeptide device:- Insert composed of cross-linked polypeptide matrix. The insert gradually erodes in the eye and dissolves out

completely after about three weeks of wear.

TECHNOLOGIES:  PROSERT: ophthalmic placebo insert which is insoluble, sterile, and

biocompatible. one or several active components and allow its releasing in a

programmed or controlled way.

Advantages of PROSERT: An excellent bioavailability by permanent contact of the

active component with the ocular tissues . use of a smaller of active component in comparison with

liquid treatment. No preservatives so no risk of allergy. A better adhesion to the treatment as only one PROSERT can

cover a long period. PROSERT does not either dissolve in water or fragment and

allows a controlled releasing of the active component without blurred vision.

PROSERT can be removed at any time.

  MYDRIASERT: The first application of PROSERT technology is a

mydriatic called MYDRIASERT that received its Marketing Authorisation Application.

It is an insoluble ophthalmic insert, gradually releasing two well known active ingredients: phenylephrine & tropicamide.

It is indicated in pre surgical mydriasis.

It is a balanced salt solution was developed for hydration and clarity of the cornea during surgery.

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 resin,

hydroxyethylmethacrylate- Contain 30 – 80% water so are permeable to

oxygen- Have two types: daily wear and extended wear

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

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

Products for soft contact lenses:Cleaners- To remove lipid and protein debris formulation:1- viscolizing surface-active agent: to enable gentle friction with fingertips2- antibacterial-fast acting: benzalkonium chloride

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 Enzyme protein digest- For occasional cleaning followed by washing

before wearing Formulation:- Proteolytic enzyme: papain solution tablet to

produce a solution when dissolved in water-

Wetting solutions- To achieve rapid wetting by the lachrymal fluid

and promot comfort- Facilitate insertion of the lens- Provide lubrication Consist of: viscosity-increasing agent (hydroxy

ethyl cellulose + wetting agent (polyvinyl alcohol) + preservatives (benzalknonium chloride or sodium edetate + buffers and salts to adjust

pH and tonicity.

Two Major Approaches:

To enhance corneal permeability either by mild as transient structural alteration of corneal epithelium or by modification of chemical structure of the drug molecules. 

To enhance corneal permeability either by mild as transient structural alteration of corneal epithelium or by modification of chemical structure of the drug molecules. 

Recent occular drug delivery system

Polymeric solutions Phase transition systems Mucoadhesive/bioadhesive dosage form Collagen shields Pseudolatices Micro emulsions Ion exchange resin suspension Iontophoresis

Polymeric Solution:  The addition of polymers to the eye drop

solutions increases the contact time with cornea.

The polymer used are:◦ Methyl cellulose◦ Poly vinyl alcohol,◦ Hydroxy Propyl cellulose,◦ Poly vinyl pyrrolidine etc.

TECHNOLOGIES:  DuraSite® DRUG DELIVERY TECHNOLOGY: DuraSite®is a polymer that prolongs the

residence time of the formulation in the eye. The DuraSite delivery system, whereas

conventional eye drops typically last a few mins. and are unable to sustain therapeutic drug levels. DuraSite remains in the eye for several hrs.,

during that time the active ingredient is gradually released. This allows lower conc. of drug to be administered over a longer period of time.

This minimizes the inconvenience of frequent dosing reduces the potential related adverse effects.

AQUASITE®: AquaSite was the first product developed

utilizing DuraSit technology. The product contains the DuraSite

formulation and demulcents for the symptomatic treatment of dry eye.

 

 AzaSite: AzaSite ( ISV- 401) is an ocular anti infective

product candidate containing the drug azithromycin. AzaSite is formulated with DuraSite. DuraSite offers the benefit of prolonged release of the active drug azithromycin..

ISV-205: ISV -205 product candidate contains the drug

diclofenac, formulated in the DuraSite sustained release delivery vehicle.Diclofenac is a NSAID, currently used to treat ocular inflammation.

Mucoadhesive / bioadhesive Dosage form:

BODI – Bioadhesive Ocular Drug Inserts If the polymer adhere to the mucin the interaction

reffered to as mucoadhesion. Mucoadhesive adjuvants are generally

macromolecular hydrocolloids with numerous hydrophilic functional groups like carboxyl, hydroxyl, amide, sulphate show electrostatic or hydrophobic interaction and H-bonding with surface.

Ideal properties: Exhibit a nearly zero contact angle to allow

maximum contact time with mucin. Chain flexibility to diffuse and penetrate through

mucin. Higher molecular weight.

MATERIAL:- PORCINE SCLERAL TISSUE : WHICH BEARS A COLLAGEN COMPOSITION SIMILAR TO

THAT OF THE HUMAN CORNEA.

DRUG LOADING :-BY SOAKING IN DRUG SOLUTION.

STRUCTURE :- 0.1 MM THICKNESS 6 – 9 MM DIAMETER.

ADVANTAGES:- 1) BIOLOGICAL INERTNESS 2) STRUCTURAL STABILITY 3) GOOD BIOCOMPATIBILITY 4) LOW COST OF PRODUCTION

DISADVANTAGES:- 1) INSERTION TECHNIQUE IS DIFFICULT 2) EXPULSION OF THE SHIELD MAY OCCUR 3) NOT FULLY TRANSPARENT AND THUS REDUCE VISUAL ACTIVITY

MARKETED PRODUCTS:- 1) MEDI LENS® ( CHIRON, IRVINE, CA) 2) PRO SHIELD® (ALCON, FORT WORTH, TX)

Pseudolatices:Organic solution of polymer is dispersed in an

aqueous phase to form o/w type emulsion. Water is removed partially to an extent that

residual water is sufficient enough to keep polymeric phase discrete and dispersed, such dispersions are referred to a pseudolatices. Which on application leave an intact non invasive continuous polymer film which reserves drug.

II. ION EXCHANGE RESIN TECHNOLOGY•The beta-1-adrenergic cardioselectivity of betaxolol hydrochloride was proven effective in lowering intraocular pressure with fewer sideeffects than either timolol maleate or levobunolol.•However, the introduction of betaxolol ionic suspension (Betoptic S) in 1990 provided an even more significant innovation because it provided the same efficacy as betaxolol solution but with a superior safety and tolerance profile

In addition to systemic side effects, the beta-blockers used in glaucoma topical therapy are known to produce a brief episode of stinging and/or burning upon instillation in some patients. The discomfort associated with topical administration. of betaxolol 0.5%solution is due to the high localized concentration of drug. at the cornea nerve endings. Betaxolol is a lipophilic molecule, which resembles. a long hydrophobic chain with a small hydrophilic end-group. Because of this. in addition to systemic side effects, the beta-blockers used in glaucoma topical hydrophobicity, it penetrates the cornea very well. Since the cornea has a network of sensory nerve endings making it very sensitive to external stimuli, exceeding the threshold value causes the nerve ending to fire, resulting in discomfort. Thus to improve comfort (or reduce discomfort)it isnecessary to reduce and/or control the penetration of betaxolol into the cornea, thereby reducing the drug concentration below the threshold value at the nerve endings.

it was this side-effect profile that presented pharmaceutical scientists with the challenge of developing a delivery system that both minimized the ocular discomfort and reduced the systemic absorption that was associated with beta-blockerswhile maintaining efficacy.

In addition, ideally, the drug delivery system should also the provide longer residence time in the precorneal area, and minimize systemic exposure thus providing same amount (mass) of drug at one-half the concentration.

The controlled release of a topical opthalmic beta bloker at a known release rate was achieved by binding betaxolol to an ion exchang resin.

Figure1.hypothetical comfort thresold

•ION EXCHANGE RESIN TECHNOLOGY FOROPHTHALMIC APPLICATIONSThe first successful ophthalmic product for topical application using ion exchange-resin technology was betaxolol ionic suspension (Betoptic S, 0.25%) for glaucoma.

A. The Formulation•Betaxolol ionic suspension contains 0.28% betaxolol hydrochloride equivalent to 0.25% betaxolol bound to Amberlite resin with 0.01% benzalkonium chloride as an antimicrobial preservative. The betaxolol ionic suspension formulation also contains disodium edetate, mannitol, hydrochloric acid, or sodium hydroxide to adjust the pH, and purified water as shown in Table 1.

Ingredients concentretion

Bitaxolol HCL 0.28%

Mannitol b

Disodium editate 0.01%

Carbomer 934p 0.01%

Amberlite b

Benzalkonium chloride b

Purified water 100.0%

a. Equivalent to 0.25% betaxolol base.b. The cationic exchange polymer is present in the formulationin sufficient quantity to bind 85%or more of the betaxololpresent.

Betaxolol HCl.

Amberlite resin [poly(styrenedivinylbenzene)sulfonic acid].

betaxolol is readily released from the polymer,via exchange with positively charged ions like sodium, potassium, and calcium,which are natural constituents of tears. The net effect of placing one or two drops of betaxolol ionic suspension in the eye is that, as Na is exchanged for betaxolol on the polymer, the beta-blocker is released relatively slowly into the lacrimal film. The kinetics of betaxolol release governs the neuronal responses in the eye (particularly those in the cornea) to the molecule. Since betaxolol is released into the lacrimal film more slowly from betaxolol ionic suspension than from betaxolol solution, patient comfort is enhanced.

Mechanism of action of Betoptic Suspension eyedrop.

Comparison of time-release profiles fromtwo preparations of betaxolol 0.5%.

Comfort of Betoptic Suspension as compared to Betoptic Solution.

Micro spheres/ nanoparticles: Particulates such as nanoparticles, nanocapsules,

submicron emulsions, and nanosuspensions improved the bioavailability of ocularly applied drug.

Chitosan : to produce complexes as well as micro and nanoparticles drug delivery systems intended for topical ocular drug delivery.

polycarboxylic acid carriers such as polyacrylic acid and polyitaconic acid a strong potential for sustained release of a drug in ocular delivery.

evaluated the use of solid lipid nanoparticles (SLN) as carriers for tobramycin. Compared to commercial eye drops, the tobramycin-loaded SLN produced a significantly higher bioavailability

The drug is applied with an electrode carrying the same charge as the drug.

The ground electrode, which is of the opposite charge, is placed elsewhere on the body to complete the circuit.

The drug serves as a conductor of the current through the tissue.

Iontophoresis:

Iontophoresis is an active method of drug delivery, which uses a small electrical current to transport ionized drugs into and through body tissues.

a noninvasive and reproducible means of delivering a model anionic drug to eye tissues, specifically to the retina/choroid.

Iontophoresis of dexamethasone phosphate was studied in healthy rabbits

Dexamethasone levels in the rabbit cornea after a single transcorneal iontophoresis for 1 min was up to 30-fold higher compared to those obtained after frequent eye drop instillation. Also, high drug concentrations were obtained in the retina and sclera 4 h after trans scleral iontophoresis.  

The iontophoretic device The basic design of the iontophoretic devices is a

direct current power source and two electrodes. The ionized drug is placed in the electrode compartment bearing the same charge, and the ground electrode is placed at a distal site on the body.

1ST GENERATION IONTOPHORETIC DRUG DELIVERY – USING EYE CUP

The more common approach is to fill an eye cup with the drug solution, while a metal electrode extended from the current supply submerges into the solution. The eye cup with an internal diameter of 5–10 mm is placed over the eye and the drug solution is continuously infused into the cup during the iontophoretic treatment.

24 / 10 / 07

IONTOPHORETIC DRUG

DELIVERY USING EYE CUP.

1ST GENERATION IONTOPHORETIC DRUG DELIVERY – USING EYE CUP

53 / 78

1The eye cup has two parts: one delivers the drug solution and the other holds the metal electrode and aspirates air bubbles that can disrupt the current supply, thus creates a slightly negative pressure that maintains the applicator in place.

  The ground electrode is attached usually to the

ear of the animal, as close as possible to the former electrode, to obtain minimal resistance.

Different eye-cup shapes exist, including an annular shape silicone probe for transscleral iontophoresis (called ‘Eyegate’, Optis, France) with a 13 mm opening to avoid contact with the cornea.

DRUG DELIVERY BY OCUPHOR TECHNOLOGY

22ND GENERATION IONTOPHORETIC DRUG DELIVERY BY OCUPHOR

TECHNOLOGY

FiG: Ocular iontophoretic system using a saturated hydrogel (OcuPhor), inserted into the inferior cul-de-sac of a human eye. Used by Fischer

54 / 78

2nd generation iontophoresis for eye: The drug applicator is a small silicone shell

that contains a patented silver-silver chloride ink conductive element, a hydrogel pad to absorb the drug formulation and a small flexible wire to connect the conductive element to the dose controller.

At the time of administration, the dry hydrogel matrix is hydrated with the drug solution and placed against the sclera in the lower cul-de-sac of the rabbit eye. The return electrode can be positioned anywhere on the body to complete the electrical circuit.

3rd generation iontophoresis for eye: VISULEX SYSTEM Visulex incorporates the following proprietary

innovations in iontophoresis: Dosing Controller with Key Safety Features for

Ocular Iontophoresis Simple, Comfortable, and Easy to Prepare Drug

Applicator Visulex ST: Optimized Selective Drug Transport

and Flux Enhancement Visulex SR: Formulations for Sustained Release

The Visulex system consists of a user-friendly applicator, a dosing controller, and connecting wires. The device is designed specifically for ophthalmic applications and contains software and algorithm controls and a proprietary multi-electrode monitoring system that together optimize safety. The applicator slips comfortably into the lower cul-de-sac, while conforming to the curvature of the eye. A fine, pliable wire connects the applicator to the current controller. The return electrode can be positioned anywhere on the body to complete the electrical circuit.

Furthermore, Visulex SR increases interval times between treatments. Medical assistant administrations or self-administrations may be possible for certain applications.

Ocular iontophoresis can be delivered by two approaches: Trans-corneal and Trans-scleral iontophoresis.

Examples: Amikacin, Gentamicin, dexamethasone and methyl prednisolone

57 / 78

Ocular Drug Delivery Devices:1. Matrix type

◦ Hydrophilic soft contact lenses.◦ Soluble ocular inserts.◦ Scleral bulking materials

2. Capsule type◦ ocusert & related devices◦ Implantable silicone rubber devices.

3. Particulate System◦ Microspheres and Nanospheres

4. Vesicular system◦ Liposomes◦ Niosomes◦ Pharmacosomes◦ Discosomes

5. Other delivery devices◦ Ocufit® and lacrisert®

◦ Minidisc ocular Therapeutic systems.◦ The New ophthalmic delivery systems (NODS®)

 

MATRIX TYPE

Scleral Bulking Material:  Scleral bulkling materials are used in retinal

detachment surgery.. Two common scleral bulking materials(1) Gelatin film &(2) Solid silicone rubber impregnated with antibiotics. Antibiotic impregnated gelatin disc & silicone

rubber were prepared by immersing into an aqueous antibiotic solution and then dried & they found sustained release from this device.

 

EXAMPLE 1: LACRISERT

It is used in dry eye syndrom A rod shaped pellet of Hydroxy Propyl Cellulose

without preservative is commercially available (Lacrisert). This device is designed as a sustained release artificial tear insert for the treatment of dry-eye disorders. It was developed by Merck, Sharp and Dohme in 1981.

EXAMPLE 2: VITRASERT by Bausch & Lomb.

The Vitrasert® implant is a device that delivers ganciclovir intraocularly in patients with AIDS-related Cytomegalovirus (CMV) Retinitis & can significantly delay progression of CMV when compared with conventional intravenous treatment.

The Vitrasert implant contains ganciclovir embedded in a polymer-based system that slowly releases the drug. The implant, surgically placed in the posterior segment of the eye, allows diffusion of the drug locally to the site of infection for usually 5-8 months after which a new Vitrasert implant can be inserted. Implantation normally takes less than one hour, requires only local anesthesia. Immediately following insertion of the implant, most patients experience transient blurred vision in the operated eye, which generally clears within two to four weeks.

Retisert® (Bausch & Lomb Inc.), an intravitreal implant containing fluocinolone acetonide (FA)], is approved by FDA for the treatment of non-infectious posterior uveitis. The implant contains 0.59 mg of FA and was designed to deliver the drug for up to 1,000 days. The Retisert® implant is composed of a central core consisting of FA compressed into a 1.5 mm diameter Polymers.

Retisert

Particulate System: Microspheres and Nanospheres: The drug absorption in the eye is enhanced

significantly in comparison to eye drop solutions.

Smaller particles are better tolerated by the

patients than larger particles therefore nanoparticles may represent very comfortable ophthalmic prolonged action delivery systems.

This approach shows promise only for

delivering lipophilic drugs.

 Liposomes:  The nature and extent of altered ocular uptake of

liposomes associated agents appear to depend on no of factors.

Physicochemical properties of the entrapped agent Chemical composition Physical characteristics of liposomes. liposomes taken up by the cornea in the order of

positively charged MLV>positively charged SUVs> Negatively charged MLV> Negatively charged SUVs>MLV=SUV.

Limitation:- Chemical instability Oxidative degradation of phospholipids. Cost & Variable purity of natural phospholipids.

LIPOSOMES HAVE POTENTIAL TO ACCOMMODATE

HYDROPHILIC AND LIPOPHILIC DRUG IN A SINGLE

VESICLE43 / 78

OligoLamellarvesicles

Multivesicularvesicles

Multi lamellar

large vesicles

Large uni

lamellarvesicles

Small

Unilamellarvesicles

LIPOSOMES

IN – VIVO CORNEAL PERMEABILITY FOR LIPOSOMES

++++

>++++

>

_ _

>_ _

>

=

45 / 78

POSITIVELY CHARGED LIPOSOMES HAS BETTER CORNEAL PERMEABILITY

MAJOR DISADVANTAGES:- UNSTABILITY BECAUSE

DECOMPOSITIONOF PHOSPHOLIPIDS IN FORMULATION.

LIMITED DRUG LOADING CAPACITY.

TECHNICAL DIFFICULTIES IN OBTAINING STERILE LIPOSOMAL PREPARATION.

46 / 78

Niosomes: Developed to overcome the limitations of liposomes. Vesicular system were formed when a mixture of

cholesterol and single alkyl chain &,Non-ionic surfactants was hydrated. The resultant vesicles, termed as niosomes.

Osmotically active & relative stable .

Advantages Chemically stable Entrap both hydrophilic & hydrophobic drug. Flexible in their characterization ( composition, fluidity

& size)MIXTURE

OF CHOLESTEROL

&SINGLE ALKYL CHAIN

NON- INONIC SURFACTANT

HYDRATION

Niosomes

 Vesicle formation takes place by the association of phospholipids with amphiphillic molecule.

Most topically applied drugs gain access to their receptor site within eye by transcellular diffusion across the corneal epithelium being lipoidal in nature.

The barrier may present a high resistance to ionic or relatively hydrophilic drug . These resistance can be overcome by pharmacosomes.

 

PURE DRUG VESICLES. ( IF DRUG IS AMPHIPHILIC ) VESICLES WITH 100% DRUG LOADING.

COOH

OH

NH2 A DRUG WITH COOH

OR ACTIVE H CONTAINING GROUP.

ESTERIFICATION

AMPHIPHILIC DRUG

COOH

PHARMACOSOMES GENERATED

ON DILUTION

WITH WATER

49 / 78

  Soluble surface active agents when added in

critical amount to vesicular dispersion leads to solubilization or break down of vesicles and translates them in to mixed micellar systems. As a result, large, flattened disc like structure is formed.LARGER THAN NEOSOMES SO BETTER FIT IN

TO CUL- DE - SAC AND THEREFORE NO LOSS DUE TO DRAINAGE.

A. Ocfit• Ocfit® ocular insert is a flexible, rod-shaped formulation

made of medical-grade silicone rubber that can be loaded with a variety of drugs.

B. Mini disc ocular Therapeutic System:  It is a monolithic polymeric device, shaped like miniature

contact lens, with a convex front and a concave back surface in contact with eyeball.

Different versions of the device have been evaluated such as non erodible hydrophilic non erodible hydrophobic & erodible. Gelfoam®

 c. The New Ophthalmic Delivery system® :  Three compartment strip: Water soluble “Medicated film” A thin water soluble “Membrane film” A thicker water soluble “Handle flag” 

D. The Ophthalmic Rod:The ophthalmic rod (OR) is a new ophthalmic drug-delivery system. The rod is made of nontoxic plastic. The active substance is deposited as a thin film on the end of the rod. To deliver the drug, the tip of the rod is introduced into the conjunctival sac and rubbed against the conjunctiva of the lower lid.

The OR is a single-dose sterile applicator. By using the OR the problems of preservation and sterility of eye drops are eliminated, and the risk of cross-infection is avoided.

24 / 10 / 07 58 / 78

ACTIVE DRUG WITH PERMEABITY

PROBLEM

INCTIVE DRUG

WITH NO PROBLEM

OF PERMEABILITY

WHEN ADMINISTERED IN EYE IT UNDERGOES

ENZYMATIC METABOLISM AND CONVERTED IN TO

ACTIVE FORM AND

PROVOKE A RESPONSE59 / 78

SITE SPECIFIC AND STEREOSPECIFIC ß – BLOKERS. Oxime and Methoxime Analogs of β-blockers:

1. Alprenolol and2. Betaxolol

ADVANTAGES:-

1. STABLE AT ROOM TEMPERATURE.

2. LONG LASTING IOP REDUCTION IN EYES.

3. Z / E ISOMER EQUILIBRIUM IS 300 – 500 TIMES FASTER THAN NOMAL DERIVATIVES.

EPINEPHRINE DIPIVEFRIN

☺10 FOLD INCREASE IN RESPONSE WAS OBSERVED.

EXAMPLE:-2

ION – PAIR COMPLEX FORMATIONMost of the beta blockers like Timolol and Carteolol are highly hydrophilic in nature, therefore they suffer permeability problems. Addition of sorbitol into the preparation produce ion-pair complex with hydrophilic drug and this ion pair complex has property similar to the lipophilic drug so it can penetrate easily through the corneal epithelium and problem of permeability can be solved. 

EXAMPLES:TIMOLOL ,CARTEOLOL

SOFT DRUG APPROACH

Produce the desired pharmacological activity at the site of application but at other sites do not show any action even though the same receptor is present. EXAMPLE:- ADAPROLOL – A ß-BLOCKER

- A NEW TOPICAL ANTIGLAUCOMA AGENT

ADVANTAGES:-

1. GOOD CORNEAL PERMEABILITY

2. BETTER STABILITY

3. LESS SIDE EFFECTS ( BRONCO-CONSTRICTION ) BECAUSE SITE SPECIFIC ACTIVITY.

SOLUTION  sterility pH Osmolarity Clarity Tonicity  SUSPENSIONS: Particle size Adsorption on the inner wall of container  PHASE – TRANSITION SYSTEMS: Gelling efficiency

Transparency of formed gel Release pattern  SEMISOLIDS: Ease of application Particle size if drug is suspended.

OCULAR INSERTS: Uniformity of Thickness Insert thickness should be measured at three

different points using Micrometer screw gauge and mean film thickness should be noted.

Uniformity of Weight Drug Content Uniformity Percentage Moisture Absorption Individual inserts were weighed and placed in a

desiccator maintained at high relative humidity using an excess amount of salt in solution. After three days the inserts were taken out and reweighed. Then the percentage moisture absorption was calculated as:

 

Percentage Moisture Loss To check the integrity of the film at dry

conditions. Inserts are weighed individually and kept in a desiccator containing anhydrous calcium chloride. After three days, inserts are taken out and reweighed. Percentage moisture loss is calculated using the formula,

 

In vitro Drug Release Study  Draize Eye Irritancy Test The Draize eye irritancy test is currently the most valuable

and reliable method for evaluating hazard or safety of a substance introduced into or around the eye.

During the test, 100 milligrams of a concentrated solution are dripped into the eyes of six to nine conscious albino rabbits, who may be immobilized in stocks from which only their heads protrude. Their eyes often are held open with clips at the lid.The damage to the rabbits' eyes is recorded at specific intervals over an average period of 72 hours, with the test sometimes lasting 7-18 days. Reactions to the irritants can include swelling of the eyelid, inflammation of the iris, ulceration, hemorrhaging (bleeding), and blindness. Pain-relieving drugs usually are not administered because experimenters claim their use would interfere with test results. If anesthesia is given, the relief is only temporary.

S.No Drug Formulation Category Polymers / Bases

1 Pilocarpine Ointment Miotic agent Petrolatum bases 

2 Pilocarpine Emulsion   Miotic agent  ----

3 Pilocarpine Sol to gel Miotic agent C.A.P.

4 Pilocarpine Matrices  Miotic agent HPC & PVP

5 Pilocarpine Hydrogel  Miotic agent  Polyacrylic acid and

Polyacrylamide

6 DexamethasoneSuspension

Anti-inflammatory   ----

7 Dexamethasone Ocularinsert    Anti-inflammatoryC.A.P.,

Eudragit RS. 100 and RL 100 

8 Pilocarpine nitrate Ocularinsert 

Miotic agent  Collagen

9 Pilocarpine nitrate Ocularinsert  Miotic agent  Na hyaluronate 

10 Tropicamide  Ocularinsert  Mydriatic agent Na hyaluronate

11 Pilocarpine nitrate  Gel  Miotic agent  Polyacrylic acid

12 Timolol Sol to gel Anti-glaucoma agent  GelriteÒ 

13 Timolol Maleate  Ocular insert  Anti-glaucoma agent (PVME - MA) 

14 Methyl Prednisolone  Microspheres  Anti-inflammatoryNa hyaluronate 

15 Flurbiprofen  Gels  Anti-inflammatory  Pluronic F 127 

16 Timolol maleate  Solutions Anti-glaucoma agent   Polyacrylic acid

17 Penicillin G  Liposomes Antibiotic Phospholipids

18 Pilocarpine Solution Miotic agent Na hyaluronate

19 Timolol maleate  In-situ

forming gelAnti-glaucoma agent 

HPMC and Polyacrylic acid 

20Gentamicin,

Tobramycin and Ciprofloxacin 

Iontophoresis Anti-infective agents                                    ---

21Gentamicin,

Tobramycin and Ciprofloxacin 

Corneal collagen shield 

Anti-infective agents  Collagen 

22Sulphacetamide

sodium and Trimethoprim 

Solution Anti-infective agents  ---

23 Pilocarpine Solution Miotic agent   ---- 

24 Piroxicam Micro emulsion  Anti-inflammatoryPoloxamer and Stearylamine

25 Indomethacin  Nanocapsules

Micro emulsionAnti- inflammatory  Poloxamer

26 Hydrocortisone Solution  Anti-inflammatory  HP-ß-CD

27 Indomethacin Nanocapsules Anti-inflammatory  Chitosan and Poly-L-

Lysine

28Pilocarpine

Hydrochloride  Gels Miotic agent 

Pluronic F127,MC,HPMC

29 Ciprofloxacin   Ocular insert  Anti-infective agent  HPMC,MC,PVP 

30 Insulin Ocular devices  Anti diabetic  Gelatin sponge

31 Tropicamide Liposomes in gel.  Mydriatic agent  Polycarbophil 

32 Indomethacin Solution   Anti-inflammatory  PluronicF68& F127 

33 

Ketorolac Tromethamine 

Ocular Inserts  Anti-inflammatory  HPMC,PVP,MC

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EXPLAIN THE VARIOUS DEVICES FOR PROVIDING SUSTAINED RELEASE OF DRUG TO THE EYE.

EXPLAIN THE PHASE – TRANSITION SYSTEM FOR ODDS.

EXPLAIN THE ROLE OF PENETRATION ENHANCERS IN ODDS.

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