CONTENTS

ANATIMY OF THE EYE INTRODUCTION FACTORS AFFECTING OCCULAR BIOAVAIBILITY ROUTES FOR OCCULAR DRUG DELIVERY ELIMINATION ROUTES CONVENTIONAL EYE PREPARARIONS RECENT TRENDS IN ODDS EVALUATION OF ODDS RESEARCH WORK IN ODDS REFERANCES

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 Suspensions, Ointments. includes : Solutions,

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 instilled 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.

1. The eyeball 2.Optic nerve

3.Tear glands
4. Cornea 5.Sclera 6.Iris 7. Pupil 8. Lens 9. Retina
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 absorption Minimizing 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 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.

BIOADHESIVE

Trans - scleral

Topical

Intravitreal

Systemic (not Shown)

TOPICALLY APPLIED OCULAR DOSAGE FORM

Diffusion

Dissolution Drug in tear film

Erosion

Absorption Corneal& Conjunctival

Irritation Lacrimal turnover Metabolism Drug in inner ocular structures & aqueous humour ONLY 1-5 % OF ADMINISTERED DOSE

Also induces lacrimation

Drainage

Loss

Mucoadhesives contain the dosage form which remains adhered to cornea until the polymer is degraded or mucus replaces itself. Types1. 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.

10

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.

11

Dosage forms solution

Advantages Convenience

Disadvantages Loss of drug by drainage Nonsustained action

Suspention

Patient compliance Drug properties decide Best for drugs with slow performance dissolution
Prolonged release of drug from vehicle Flexibility in drug choice Improved drug stability Increased tissue contact time Inhibition of dilution by tears Resistance to nasolacrimal drainage. Patient non compliance Blurred vision Possible oil entrapment Sticking of eyelids Poor patient compliance Blurred vision No true sustained effect Drug choice limited by partition coefficient

Emulsion

Ointment

Gels

Comfortable No rate control on Less blurred vision than diffusion ointment Matted eyelids after use
Sophisticated and effective delivery system Flexibility in drug type and dissolution rate Need only be introduced into eye and not removed Controlled rate of release Prolonged delivery Flexibility for type of drug selected Patient discomfort Movement of system around eye can cause abrasion

Irodible insert

Non-irodible insert

Patient discomfort Irritation to eye Tissue 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 drug 4- 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. (37C). 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
Cellulose Poly(Vinyl alcohol Preformed gel Hyaluronic acid Carbomer Carbomer Hydrogels Gellan gum In situ forming gel Poloxamer CAP Latex Alginates

Formulation:

-Ointments are used as vehicles for antibiotics, sulfonamides, antifungals and anti-inflammatories. -Petrolatum vehicle used as an ocular lubricant to treat dry eye syndromes. **It is suitable for moisture sensitive drugs and has longer contact time than drops.

*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 ratecontrolling 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. 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.

Types

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 durability 2- resistant to absorption of medications and environmental contaminants 3- visual acurity

Disadvantages: 1- require adjustment period of the wearer 2- more easily dislodged from the eye

Advantages of soft contact lenses:

1- worn for longer periods 2- do not dislodge easily

Disadvantages:

1- have a shorter life span and the wearer must ensure that the lenses do not dry out

"soft" lens | "hard" lens

Products for soft contact lenses:

Cleaners
To remove lipid and protein debris formulation: 1- viscolizing surface-active agent: to enable gentle friction with fingertips 2- antibacterial-fast acting: benzalkonium chloride
-

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

Rinsing and storage solutions

- For occasional cleaning followed by washing before wearing Formulation: - Proteolytic enzyme: papain solution tablet to produce a solution when dissolved in water
-

Enzyme protein digest

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.
-

Wetting solutions

LIMITATIONS OF CONVENTIONAL DRUG DELIVERY Rapid precorneal elimination Solution drainage by gravity Sustained and/or controlled drug release Frequent instillation is necessary Site-specific targeting Conjuctival absorption ADVANTAGES OF AVANCED DRUG DELIVERY

Protect the drug from chemical or enzymatic hydrolysis Increasing contact time and thus improving bioavailability Better patient compliance.

 Two

Recent occular drug delivery system

Major Approaches:
To prolong the contact time of drug with corneal surface.
To enhance corneal permeability either by mild as transient structural alteration of corneal epithelium or by modification of chemical structure of the drug molecules.

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: DuraSiteis 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-blockers while 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 FOR OPHTHALMIC APPLICATIONS The first successful ophthalmic product for topical application using ion exchangeresin 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 Mannitol

Disodium editate Carbomer 934p Amberlite Benzalkonium chloride Purified water

0.28% b
0.01% 0.01% b b 100.0%

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

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 510 mm is placed over the eye and the drug solution is continuously infused into the cup during the iontophoretic treatment.

1ST GENERATION IONTOPHORETIC DRUG DELIVERY USING EYE CUP

IONTOPHORETIC DRUG DELIVERY USING EYE CUP.

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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.

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

DRUG DELIVERY BY OCUPHOR TECHNOLOGY

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 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 multielectrode 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

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Ocular Drug Delivery Devices:

1.
2. 3.

4.
5.

Matrix type Hydrophilic soft contact lenses. Soluble ocular inserts. Scleral bulking materials Capsule type ocusert & related devices Implantable silicone rubber devices. Particulate System Microspheres and Nanospheres Vesicular system Liposomes Niosomes Pharmacosomes Discosomes 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 58 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
Retisert (Bausch & Lomb Inc.), an intravitreal implant containing fluocinolone acetonide (FA)], is approved by FDA for the treatment of noninfectious 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.

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 VESICLE
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IN VIVO CORNEAL PERMEABILITY FOR LIPOSOMES

++++ ++++

__

__

>
POSITIVELY CHARGED LIPOSOMES HAS BETTER CORNEAL PERMEABILITY

>

>
=

>

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MAJOR DISADVANTAGES: UNSTABILITY BECAUSE DECOMPOSITION OF PHOSPHOLIPIDS IN FORMULATION.

LIMITED DRUG LOADING CAPACITY.

TECHNICAL DIFFICULTIES IN OBTAINING STERILE LIPOSOMAL PREPARATION.

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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 HYDRATION CHOLESTEROL & SINGLE ALKYL CHAIN NON- INONIC Niosomes SURFACTANT

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.
OH

COOH

COOH

ESTERIFICATION

AMPHIPHILIC DRUG

NH2
A DRUG WITH COOH OR ACTIVE H CONTAINING GROUP.
PHARMACOSOMES GENERATED ON DILUTION WITH WATER
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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.

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.

A.

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 drugdelivery 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.

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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 RESPONSE
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SITE SPECIFIC AND STEREOSPECIFIC BLOKERS. Oxime and Methoxime Analogs of -blockers:
1. Alprenolol and 2. 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.

EXAMPLE:-2

EPINEPHRINE

DIPIVEFRIN

10 FOLD INCREASE IN RESPONSE WAS OBSERVED.

Most 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.

ION PAIR COMPLEX FORMATION

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 -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. Painrelieving 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
1 2 3 4 5 6

Drug
Pilocarpine Pilocarpine Pilocarpine Pilocarpine Pilocarpine Dexamethasone

Formulation
Ointment Emulsion Sol to gel Matrices Hydrogel Suspension

Category
Miotic agent Miotic agent Miotic agent Miotic agent Miotic agent

Polymers / Bases
Petrolatum bases ---C.A.P. HPC & PVP

Polyacrylic acid and Polyacrylamide

---C.A.P., Eudragit RS. 100 and RL 100 Collagen Na hyaluronate Na hyaluronate

Anti-inflammatory

7
8 9 10

Dexamethasone
Pilocarpine nitrate Pilocarpine nitrate Tropicamide

Ocularinsert

Anti-inflammatory
Miotic agent Miotic agent Mydriatic agent

Ocularinsert Ocularinsert Ocularinsert

11

Pilocarpine nitrate

Gel

Miotic agent

Polyacrylic acid

12 13 14 15 16

Timolol Timolol Maleate Methyl Prednisolone Flurbiprofen Timolol maleate

Sol to gel Ocular insert Microspheres Gels Solutions

Anti-glaucoma agent Anti-glaucoma agent Anti-inflammatory Anti-inflammatory Anti-glaucoma agent

Gelrite (PVME - MA) Na hyaluronate Pluronic F 127 Polyacrylic acid

17
18 19

Penicillin G
Pilocarpine Timolol maleate Gentamicin, Tobramycin and Ciprofloxacin Gentamicin, Tobramycin and Ciprofloxacin Sulphacetamide sodium and Trimethoprim

Liposomes
Solution In-situ forming gel Iontophoresis Corneal collagen shield Solution

Antibiotic
Miotic agent Anti-glaucoma agent

Phospholipids
Na hyaluronate HPMC and Polyacrylic acid

20

Anti-infective agents

--Collagen

21

Anti-infective agents

22

Anti-infective agents

---

23 24 25 26 27 28 29 30

Pilocarpine Piroxicam Indomethacin Hydrocortisone Indomethacin Pilocarpine Hydrochloride Ciprofloxacin Insulin

Solution Micro emulsion Nanocapsules Micro emulsion Solution Nanocapsules Gels Ocular insert Ocular devices

Miotic agent Anti-inflammatory Anti- inflammatory Anti-inflammatory Anti-inflammatory Miotic agent Anti-infective agent Anti diabetic

----

Poloxamer and Stearylamine

Poloxamer HP--CD

Chitosan and Poly-LLysine

Pluronic F127,MC,HPMC HPMC,MC,PVP Gelatin sponge

31
32 33

Tropicamide
Indomethacin Ketorolac Tromethamine

Liposomes in gel.
Solution Ocular Inserts

Mydriatic agent
Anti-inflammatory Anti-inflammatory

Polycarbophil
PluronicF68& F127 HPMC,PVP,MC

REFERENCES
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Jagdish balsubhramanium,Shrikani jayant, Kumar Pandit, Invitro in vivo evaluation of the Gelrite Gellan gum based ocular delivery system for indomethacin,Acta Pharm 53(2003),251261.
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 150485 e : In-vitro and in-vivo evaluation of gellan gum based ocular inserts of phenylephrine. ; C.A., vol:147 : number 7 : august 13; 2007.
344379 y : Regenerating pharmaceutical composition : C.A. :vol: 146 ; number 17 : april 23 ; 2007. 79232 n : sustained opthalmic delivery of gatifloxacin from in-situ gelling system: C.A. : vol 147: july 23 :2007. 196937 g : piroxicam nanoparticles for ocular delivery. :C.A. : vol 147 : august 27 :2007.

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.

L. M. COLLEGE OF PHARMACY : PAPER 421 : M. PHARM - II

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