OCULAR DRUG DELIVERY SYSTEM

Dr. Muhammad Harris Shoaib

LIMITATION OF CONEVENTIONAL SYSTEM

TOPICAL
Complex ocular physiological and cellular barrier Cornea, a major barrier to absorption Instilled dose lost by protective mechanism such as
Solution drainage Lacrimation Systemic absorption via conjuctiva (Not required for topical)

SYSTEMIC
Poor access to the internal structure within the globe Blood Ocular barrier

OBJECTIVES FOR ADVANCED OCULAR DRUG DELIVERY SYSTEM

To find newer, effective, predictable and safe drug molecules for various ocular conditions and disease they are poorly controlled now To improve the ocular dosage form and delivery system by which existing drugs are administered

ANATOMY AND PHYSIOLOGY OF EYE

Eye is an isolated and highly specialized organ of photoreception Made up of three layers
Outer fibrous protective sclera Middle vascular uvea including choroid, the ciliary body and the iris Inner neural retina

Eye overall divided into two segment

Anterior Segment Posterior Segment

ANTERIOR SEGMENT
The Cornea
The anterior segment of the eye is bound anteriorly by a transparent cornea and a small portion of the sclera. The junction where the cornea and the sclera join is called the limbus The human cornea is approximately 0.5 mm thick in the center, with the periphery being thicker than the central part. It is a transparent avascular structure that receives its nourishment and oxygen supply from aqueous humor and the tear film The tissue is composed of five layers: the epithelium, bowmans membrane, stroma, descemets membrane, and the endothelium

Epithelium Outer protective layer 5-6 layers of superficial squamos and basal columnar epithelial cells Numerous microvilli protrude into the lacrimal film from these cells. The microvilli are covered by mucin and glycocalix. The superficial epithelial cell layers have tight junctional complexes between adjacent cells called zonulae occludentes. These junctional complexes prevent the passage of watersoluble drugs with low lipophilicity across the cornea. The corneal epithelium is a reasonably hydrophobic tissue Drugs to cross the cornea it should have an oilwater partition coefficient greater than 1.

Bowmans Membrane Bowmans membrane is an acellular thin layer made of collagen fibrils. Anteriorly it is separated from the epithelium by a basement membrane. It does not offer high diffusional resistance and as such it is not a rate limiting barrier Stroma This corneal layer is a highly organized structure constituting 90% of the cornea. It consists of parallel collagenous lamellae. Between the lamellae lies the modified fibroblast known as keratocytes. The stromal layer becomes a limiting barrier for permeation of lipophilic drug Minimal resistance to hydrophilic drugs

Descemets Membrane Descemets membrane is a thin homogeneous layer between the stroma and the endothelium. Endothelium The corneal endothelium is a single-layered squamous epithelium on the posterior surface of the cornea. The endothelial cells do not posses tight junctions. This layer does not act as a barrier to drug molecules. Plays an important role in regulation of corneal hydration by transferring bicarbonate and chloride into the aqueous humor.

Conjunctiva
The conjunctiva is a vascularized mucous membrane that covers the inner surface of the eyelids and the anterior part of the sclera. It offers less resistance to the passage of drug molecules than the cornea.

Iris
The iris is the most anterior portion of the uveal tract. The iris consists of the pigmented epithelial cell layer, the iridic sphincter and dilator muscles, and the stroma The anterior surface of the irisis the stroma, which contains melanocytes, blood vessels, smooth muscle, parasympathetic and sympathetic innervations. Individual eye color varies according to the number of melanocytes present in the stroma. Ocular pigmentation may be an important factor relative to ocular bioavailability owing to drugmelanin binding. The iris has high enzymatic activity, resulting in low ocular bioavailability.

Ciliary Body
Composed of the ciliary muscle and the ciliary processes Ciliary muscle plays an important role in accommodation Ciliary processes are the highly vascularized folds protruding into the posterior chamber. These are covered by a two-layered epithelium, the inner nonpigmented and the outer pigmented epithelium. The nonpigmented epithelial cells are attached to each other by junctional complexes, which obstruct the diffusion of large molecules into the aqueous humor.

Aqueous Flow Pathway

Aqueous humor is secreted by the ciliary processes into the posterior chamber at the rate of 2 to 2.5 l/min. Aqueous humor flows continuously from the posterior chamber to the anterior chamber through the pupil and from there it leaves the eye through the trabecular meshwork and Schlemms canal.

Plays an important role in the nourishment and supply of oxygen to the avascular tissues in the eye. It also carries metabolites away from the surrounding tissues. Continuous flow of aqueous humor is important for maintaining the constant volume and intraocular pressure.

Lens
crystalline structure surrounded by the lens capsule. It is located behind the iris and in front of the vitreous. The lens is important for the visual function and together with the ciliary muscle it enables accommodation and protects the retina from harmful ultraviolet radiation.

Lacrimal Apparatus
Tear fluid is secreted by the main lacrimal gland, the acessory glands, and the meibomian glands. The normal tear flow rate is approximately 1 l/min, and it covers the cornea and the conjunctiva. The tear fluid has a nutrition function as well as an antibacterial function. Tear fluid secretion also helps in lubricating the eye and washing away debris. It is drained through the canaliculi, lacrimal sac, nasolacrimal duct, and finally into the nasal cavity.

POSTERIOR SEGMENT
Retina
The retina is a thin, transparent neural tissue extending anteriorly to the pars plana of the ciliary body It is the innermost tissue Consisting of neural layer and the pigmented epithelium The pigmented epithelial cells are connected with tight junctions and forms a barrier the vascular choroid and retina

Vitreous Humor
Vitreous is a clear medium that fills the cavity between the retina and the lens. It is composed of 98 to 99.7% water. The vitreous mainly consists of dissolved collagen, hyaluronic acid, and proteoglycans. It is easily susceptible to bacterial infection, and the treatment of vitreal infections becomes challenging owing to poor bioavailability of the antibiotics. The blood retinal barrier largely prevents the entry of many drugs into the vitreous from the systemic circulation..

The Choroid and the Sclera

The choroid is a highly vascularized tissue between the retina and the sclera. It constitutes the posterior part of the uvea that represents the middle vascular coat of the eye. The primary function of the choroid is to nourish the outer layers of the retina. The sclera is the outermost layer, consisting of collagen bundles and elastic fibers. The sclera functions to both protect the intraocular contents and to maintain the shape of the eye. It is permeable to molecules as large as dextran; hence the transscleral route can be used to deliver drugs to the posterior segment.

ROUTES OF OCULAR DRUG DELIVERY Topical administration

The topical route of administration is used to treat diseases that affect the anterior segment of the eye such as keratitis, conjunctivitis, and glaucoma. They may not provide the desired therapeutic concentration of the drug in the posterior segment of the eye to treat diseases there. Drug delivery vehicles used for topical administration include solutions, colloids, emulsions, suspensions, ointments, solid hydrophilic inserts, therapeutic contact lenses, ratecontrolled release systems, and new delivery systems such as liposomes and particulates.

Advantages of Topical Drug Delivery

Convenient mode of administration Noninvasive Easy enough for self-administration Fewer systemic drug effects

Disadvantages of Topical Drug Delivery

Low ocular bioavailability Ineffectiveness in the treatment of posterior segment diseases

Factor Affecting the Bioavailability of Topically administered Drug

Precorneal Factors Precorneal fluid drainage
After instillation of the liquid dosage form, a significant part (80 to 90%) of it is drained into the nasolacrimal duct. This loss occurs primarily due to thetendency of the eye to maintain the precorneal fluid volume at 7 to 10 l at all times as a protective physiological mechanism Factors influence the drainage rate are instilled volume, viscosity, pH, tonicity, poor buffer capacity of tears and drug type Ocular preparation must have a pH range between 7 7.7

Drug Binding to Proteins

The protein content of tears in humans is about 0.7% of the total body protein. The drug binding to the tear proteins may result in a reduction in free drug concentrations available for pharmacological action at the target site.

Conjunctival Drug Absorption

The conjunctiva is a highly vascularized mucous membrane lining the inside of the eyelids and the anterior sclera. Drugs are better absorbed across conjunctiva than cornea because of its greater surface area and high permeability. However, such nonproductive conjunctival absorption is a major precorneal loss factor and may lead to side effects,

Systemic Drug Absorption

A fraction of the topically applied dose that reaches the nasal mucosa through the nasalacrimal duct drainage may be absorbed systemically, leading to potential systemic side effects.

Corneal Factors The cornea consists of a hydrophilic stromal layer placed between a lipoidal epithelial layer and a single cell layer of endothelial cells Corneal epithelium acts as a major barrier to the transport of hydrophilic drugs, whereas the hydrophilic stromal layer offers resistance to the passage of relatively lipophilic compounds.

Post Corneal Factors Melanin Binding Drug Metabolism

Periocular Administration
Employed for the treatment of anterior segment diseases when topical administration has failed They are either subconjunctival (underneath the conjunctiva) or sub-Tenon (beneath the Tenons capsule) Used for the administration of antibiotics or antivirals for the treatment of anterior segment pathologies.

Intarocular Administration
Intracameral (Injection into aqueous humor) Intraviteral (Injection into viterous humor) Severe posterior segment diseases including endophthalmitis and retinitis. Repeated intravitreal injections may cause trauma to the eye and break down the blood retinal barrier

Transcelral Administration
Deliver drugs to the posterior segment because of the scleras large surface area and high permeability characteristics Treatment of chorioretinal disorders, endopthalmitis, and vitreous hemorrhage.

OCULAR FORMULATIONS
SOLUTIONS
Most common and usually preferred Various excipients are usually used to maintain
Stability Sterility Increase the precorneal residence time Drug penetration

Viscosity Enhancers
Help in prolonging the retention time of the drug in the precorneal area Decrease the lacrimal drainage of the drug

Water-soluble polymers are used as viscosity enhancers. Cellulose derivatives including methylcellulose, carboxy methylcellulose, and hydroxy propyl methylcellulose are generally used. The concentration range of these polymers usually varies from 0.2 to 2.5% Administration of a highly viscous solution results in reflex tearing and blinking to restore the original viscosity

Tonicity Agents
Topically instilled solutions must be isotonic with tears. Instillation of a hypotonic solution results in water flow from the aqueous layer through the cornea to the surface of the eye. Hypertonic drops may cause discomfort or irritation owing to a dehydrating effect on the corneal epithelium. A 0.9% solution of sodium chloride. Tonicity agents such as sodium chloride, buffering salts, dextrose, and mannitol can be employed.

Buffering Agents
The physiological pH of tears is 7.4 and maintained by substances dissolved in the aqueous layer of the tears, including bicarbonate and proteins. Tear fluid has a small buffer capacity Buffering agents are added in the formulation to maintain Physiological pH for preventing the irritation and discomfort to eye due to pH change by the large quantity of acid and alkali in the formulation To increase drug penetration by selecting pH that favours the unionized form of drug To improve drug stability

Preservatives
Preservative used for ocular preparations must have Broad spectrum of activity Compatibility with other ingredients Nontoxic and nonirritant properties Chemical stability Rapid action Commonly used are Quaternary Ammonium Compounds, Benzalkonium chloride, chlorobutanol, Phenyl mercuric nitrate, Methyl Paraben and Propyl Paraben

Surfactants
Used to solubilize and dispersed drug

Commonly employed are non ionic surfactants such as benzalkonium chloride, benzethonium chloride, polysorbate 20, and dioctyl sodium sulphosuccinate

SUSPENSION
They provide slow dissolution and prolonged release of drug. For optimum therapeutic effect, the rate of dissolution of particles and the rate of absorption through the cornea must be faster than the rate of loss of drug from the eye The particle size is generally less than 10 m in diameter Streoids are usually administered in this form

OINTMENTS
Ointments contain one or a combination of hydrocarbons, mineral oil, lanolin, and polymers such as polyvinyl alcohol, carbopol, and methylcellulose as bases. Drugs administered as ointments have better bioavailability than drops primarily owing to reduced dilution of drug with the tears, prolonged corneal contact time, and reduced drainage. Vehicles used in ophthalmic preparations should not cause discomfort to the eye and should be compatible with other ingredients. The main disadvantage of ointments is that they cause blurring of vision and an increased incidence of contact dermatitis.

OCULAR INDICATION OF CONTROLLED-RELEASE SYSTEMS

Indication 1. Short, topical ocular half-life 2. Small, topical ocular, therapeutic index 3. Systemic side effects 4. Need for combination therapy 5. Drug delivery over a prolonged period Drug &Disease Heparin for Ligneous disease Pilocarpine for chronic open-angle Glaucoma Timolol for Glaucoma and cyclosporin A for graft rejection Cromoglycate and corticosteroid for Asthma and Allergies Acute corneal infections, Corneal Graft rejection episodes Prevention of Corneal Graft Rejection or Herpetic diseases,

6. Long-continued low dosage for therapy or prophylaxis

OCULAR INSERTS
Ocular inserts are defined as preparations with a
Solid or semisolid consistency, Whose size and shape are especially designed for ophthalmic application (i.e., rods or shields). Placed in the lower fornix and, less frequently, in the upper fornix or on the cornea. They are usually composed of a polymeric vehicle containing the drug and are mainly used for topical therapy.

Lacriserts in the lower fornix

DESIRED ATTRIBUTES OF OCULAR INSERTS/OCULAR CONTROLLED DRUG DELIVERY Comfort Ease of handling Reproducibility of release kinetics Sterility Stability Ease of mfg.

Advantages
1. Accurate dosing at a slow constant rate 2. Absence of preservative thus reduces allergic reactions 3. Increase in shelf life due to absence of water. 4.Increased ocular residence, hence a prolonged drug activity and a higher bioavailability with respect to standard vehicles 5. Reduction of systemic absorption (which occurs freely with eye drops via the nasolacrimal duct and nasal mucosa)

Limitations
1. Perceived by patient as foreign body. 2. Movement around the eye. 3. Occasional loss during sleep or while rubbing eyes. 4. Interference with vision. 5. Difficulty in placement & removal.

A) NonNon-Erodible
1. Ocusert 2. Silicone Rubber Devices 3. Contact Lenses 4. Minidisc

B) Erodible
1. SODI. 2. Lacrisert 3. Collagen Shields

Types:
C) Nanoparticle D) Liposome

NON BIOERODIBLE OCULAR INSERTS

Polymers such as Ethylene vinyl acetate, silicone rubber, polymethyl methacrylate and hydroxyethyl methacrylate are used Placed on the cul-de-sac between the cornea and sclera After stated period of time, the inserts are simply removed and discarded Less toxic but less convenient so less patient acceptability RESERVOIR DEVICE OCUSERTS
Marketed by Alza Corp in 1975 It consist of a pilocarpine reservoir with alginic acid, a mixture surrounded on either side by a copolymeric membrane of ethylene vinyl acetate.

Around the diameter of ocusert, an ethylene vinyl acetate ring with titanium dioxide is present to provide the visibility The rate of diffusion is controlled by Polymer composition Membrane thickness Solubility of the drug Presence of additives Pilo-20 and Pilo-40 are available releases drug at the rate of 20 g/hr and 40 g/hr Release kinetics is first order Problems are Cost Longer adaptation times for patients Probability of accidental expulsion Difficulty of handling

OCUSERTS

MATRIX DEVICE SILICONE RUBBER DEVICE

Consist of two sheets of silicone rubber glued together only at the edges with silicone adhesive A tube of silicone extends from the device to allow reinjection of the drug into the device when depleted Silicone is also used for matrix fabrication of nonerodible ocular inserts Drug incorporation is carried out by applying heat, therefore not suitable for thermolabile drug Better polymer for thermolabile drug is dimethyl siloxane Delivers water insoluble drug 1,3, bis-(2-chloro-ethyl

Silicone Device (a) Before BCNU injection and (b) After BCNU Injection

CONTACT LENSES
Contact lenses both hard and soft are extensively used for correction of vision Only soft contact lenses are used for delivering drug Hard contact lenses are very much uncomfortable to wear Hydrophilic monomers and comonomers are used in these soft contact lenses These soft contact lenses were presoaked or fabricated to absorb aqueous solution of drugs such as pilocarpine, idoxuridine, polymyxin B, chloramphenicol and tetracycline Commonly used polymers are hydroxyethyl methacrylate with PVP, Ethoxy methacrylate and butyl methacrylate have been used to impart flexibility to the soft lens Drug release upto 180 hrs

MINIDISCS
Spherical discoid structure with a convex front curve and concave back curve 4-5 mm in diameter Placed behind the upper and the lower eye lid unlike soft contact lens which placed on the cornea Polymer used is hydroxyethyl methacrylate with ethylene glycol Drug release upto 168 hrs Sulifsoxazole minidiscs are available in market.

BIOERODIBLE OR SOLUBLE OCULAR INSERTS

Device are monolithic type and are meant to gradually erode, disintegrate or get solubilized to release the drug in the Culde-sac

More convenient to wear Disadvantages are Losing solid integrity and getting expelled from eye Difficult to prevent variation in release kinetics due interpatient variability in tear fluid dynamics SOLUBLE OPTHALAMIC DRUG INSERTS (SODI) Small water soluble developed for Cosmonauts who could not use their eye drop in liquid condition Example of soluble inserts are available for various drugs such as Atropine, pilocarpine, neomycin, kanamycin, tetracycline, idoxuridine

Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate. Weight 15-16 mg. In 10-15 sec Softens; In 10-15 min. turns in Viscous Liquids; After 30-60min becomes Polymeric Solution. Single SODI application a day :replaces 4-12 eye drops Instillation or 3-6 application of Ointments COLLAGEN SHIELDS Marketed by Bausch and Lomb as BioCor-12, BioCor-24 and BioCor-72 for delivering the drug upto 12, 24 and 72 hrs Collagen shields are presoaked with drug solution thereby providing rapid release of drug Used for delivering many drugs such as gentamicin, tobramycin, vancmycin etc Causes ocular inflammation

Collagen Shields

LACRISERTS Sterile, Rod Shaped device. Composition: HPC without preservative. Weight:5mg, Dimension 1.25mm and Length:3.5mm Placed in lower conjunctiva with applicator Use:-Dry eye treatment, Keratitis Sica. Problem of blurring of vision and difficulty of inserting the device

LIPOSOMES
Positively charged due to negatively charged surface on the corneal epithelium. Results in increase precorneal residence Degree of dissociation between corneal epithelium and liposomes followed the order MLV+ > SUV+ > MLV- > SUV+ > MLV > SUV Usually polymer coated MLV was used for increase corneal retention Common polymers are Carbopol 934 and Carbopol 1342 as mucoadhesive

LIPOSOMES

OCULAR IONTOPHORESIS
Iontophoresis is a method of drug delivery that utilizes electric current to deliver ionized molecules to the intraocular tissues. To drive the molecules into the tissue either a cathode or an anode is used, depending on the charge of the molecule. Drugs can be delivered to the cornea or the sclera. Transcorneal iontophoretic delivery of antibiotics such as gentamicin and aprofloxacin for treatment of bacterial keratitis Transscleral iontophoresis can be used to directly deliver drugs to the vitreous for treating posterior segment diseases. It may produce discomfort and small areas of necrosis at sites of application.

Iontophoresis

NANOPARTICLE TECHNOLOGY
For water soluble drugs. Size:10-1000nm Drug is Dispersed, Encapsulated, or Absorbed Produced by Emulsion Polymerization Polymerization is carried out by : Chemical initiation, Gamma irradiation, Visible light. Emulsifier stabilizes polymer particle Polymer used are Biodegradable. E.g. :- Nanoparticle of Pilocarpine enhances Mitotic response by 20-23%.

POLYMERS IN OCULAR DRUG DELIVERY

Polymers are macromolecules formed from many repeating small units called monomers, which are connected by covalents bond. Each macromolecules is a unit and not an aggregate
CLASSIFICATION SYNTHETIC POLYMERS
Synthetic polymers usually have less than 10 repeating subunits whereas the natural polymers, particularly proteins and enzymes, may have more than 20 repeating sub units Synthetic polymers can be classified into different categories based on their preparation, structure, repeating units, stereoregularity, and the adjacent chain interactions

Based on Preparation Condensation polymers (or step reaction polymers) are essentially polymers in which the monomer units are joined by eliminating a water molecule in each step. Examples are polyester, polyurethane and polyurea Addition Polymer are obtained by joining monomer units by double bond. Examples are polyethylene, polyvinyl chloride, polystyrene and polymethacrylate Based upon structure Linear Polymers

Examples are linear polystyrene

Branched Polymers Star shaped and comb-shaped polystyrene

A A A A A A

Based Upon Repeating Units Homopolymers With identical repeating subunits such as A-A-A . For example Polymethyl methacrylates Copolymers -with different repeating subunits such as Diblock copolymers i.e. A-A-A-B-B-B and Random polymers A-B-BA-B-A-A. Examples of this copolymers are acrylates and methacrylates Based Upon Stereoregularity Atactic-There is no regularity of R groups Isotactic Polymers There is a regularity of R group Syndiotactic Polymers The trans and gauche forms alternate

R CH2 CH R CH2 CH R CH2 CH CH2 CH R

Atactic Polymers

R CH2 CH R CH2 CH CH2 CH R CH2

R CH

Syndiotactic Polymers

CH2

CH R

CH2

CH R

CH2

CH

CH2

CH R

Isotactic Polymers

Based upon Adjacent Interactions Polymers are subclassified into elastomers, plastics, fibers or cellulosics. In elastomers the chain are attracted to each other by London Forces (e.g. Polyethylene) In Plastics the chains are attracted by London as well as the Keesom forces (e.g. PVA) Fibers or cellulosics are polymers in which the chain are attracted by London forces, Keesom forces and hydrogen bonding

NATURAL POYMERS PROTEINS AND PEPTIDES

The building blocks of proteins are aminoacids which are bound by a peptide bond. A peptide bond is an amide linkage between the amino group of one molecule and the carboxyl group of another Proteins are made up of a single polypeptide or a group of polypeptides Enzymes are proteins with catalytic activities. Hormones, the secretion of endocrine glands are also proteins

Proteins are classified as Simple Proteins-Albumin, Globulin, Histones, Collagen Conjugated Proteins Nonprotein i.e. nucleoproteins (Protein + Nucleic Acid) Phospho proteins (Protein + Phosphoric acid) Glycoproteins (Protein + Carbohydrate) Chromoproteins (Protein + Color compounds) Lipoproteins (Proteins + Fatty acids) Membrane proteins (Protein with membranes)

NUCLEIC ACIDS AND SUGARS

Nucleic acids are made up of building blocks called nucleotides Each nucleic acids consist of base, sugar and phosphate Major nucleotides are uridylic acid, cytidilic acids, deoxythymidylic acids, adenylic acids and guanylic acids

The sugars polymers, made up of glucose units as building blocks, for e.g. Starch and Celluloses Starch consist of alpha glucose units. Mainly of three types Amylose Straight chain Plant starch Amylopectin Branched chain plant starch Glycogen-A branched chain animal starch Cellulose is made up of Beta glucose units, a principle constituents in plant cells