Ocular Drug Delivery Systems PDF

Ocular drug delivery Delivered by Dr. MUSA ALBATSH 1  Introduction Drug delivery to the eye is one of the most important areas of modern ocular therapy and presents many opportunities and challenges. The front of the eye...

Ocular drug delivery Delivered by Dr. MUSA ALBATSH 1  Introduction Drug delivery to the eye is one of the most important areas of modern ocular therapy and presents many opportunities and challenges. The front of the eye is accessible and conditions affecting it can be treated by simple topical eye drops. The back of the eye is, however, treated as an entirely separate ocular region, and more advanced delivery systems have been designed for its treatment, including: intraocular injections and implants that can provide sustained drug release over two years. A range of new therapies are being developed for MIP contact lenses.... molecularly treating ocular conditions including cells, genes and imprinted contact lenses proteins, not only the traditional small molecules.  Introduction Classification ocular drug delivery systems: Ideal ophthalmic delivery system: Prolong contact time with corneal tissue. Liquid Simplicity of instillation for the patient. Solutions Non irritative and comfortable form Suspensions Appropriate rheological properties Sol to gel systems Good corneal penetration. Powders for reconstitution Semisolid Ointments Requirements of Ocular drug delivery systems: Gels A. Sterility Solid B. Preservation Ocular inserts C. Isotonicity value D. Buffering E. Viscosity And Thickening Agents  Introduction Q) The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments. These preparations when instilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage. The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions ocular inserts intravitreal injections implants. 4 Anatomy and physiology of the eye 5  Ocular drug delivery routes and elimination pathways Routes and barriers to ocular drug delivery can be: I. The cornea is the main route through which ocular topically administered drugs reach the aqueous humour. II. The blood retinal barrier (retinal pigment epithelium and retinal capillary endothelium) restricts entry of drugs from the systemic circulation into posterior segment of the eye. III. Intravitreal delivery route to directly reach the back of the eye. 6  Ocular drug delivery routes and elimination pathways Ocular drug elimination is via: 1. Drug elimination from the aqueous humour into the systemic uveoscleral circulation 2. Aqueous humour outflow through the trabecular meshwork and Schlemm’s canal 3. Drug elimination from the vitreous humor via diffusion into the anterior chamber 4. Drug elimination via posterior route across blood retinal barrier 7  Some common ocular conditions and pharmacological interventions Ocular drug delivery is undertaken for treatment of local disease at different sites in the eye: Dry eye syndrome: Dry eye is a common disease which occurs when either the tear volume is inadequate or of poor quality (poor functional tear). This often results in unstable tears and consequently ocular surface disease. Dry eye is not curable and management is to control the symptoms and protect the ocular surface from being damaged. The initial treatments include use of tear substitutes and mucolytic eye drops. In advanced cases, the use of anti-infammatory eye drops, surgical intervention to reduce punctual drainage and contact lenses have been shown to be beneficial. 8  Some common ocular conditions and pharmacological interventions Cataract: Cataract is the opacity of lens, which often results from denaturation of the lens protein. Cataracts, which are usually age-related, are the most common cause of treatable blindness worldwide. Surgery is the only treatment and is very effective. It involves replacement of the clouded lens with a synthetically produced intraocular lens. 9  Some common ocular conditions and pharmacological interventions Glaucoma: The glaucoma are a group of diseases in which there is a specific type of damage to the optic nerve (optic disc cupping), resulting in a characteristic pattern of visual field loss; first peripheral and then central vision loss. Glaucoma, a life-long condition, is the leading cause of irreversible blindness worldwide and is the second most common cause of blindness, after cataract. The most important and only modifiable risk factor in this group of diseases is raised intraocular pressure (IOP). It has been shown that reduction in intraocular pressure, medically eye drops or surgically, can halt or decrease the progression of the visual field loss. 10  Some common ocular conditions and pharmacological interventions Age-related macular degeneration (AMD): AMD is a degenerative disorder that affects the macula, the most sensitive part of the retina, and consequently results in the loss of central vision. Endophthalmitis: Endophthalmitis is the inflammation of the internal layers of the eye. Infectious endophthalmitis most frequently occurs following ocular surgery and penetrating trauma, particularly with retained foreign body. 11  Topical ophthalmic preparations Physiological and biochemical mechanisms exist to protect the eye from harmful stimuli, they sometimes present a barrier to drug absorption. For example:  Basal tears are continuously secreted by the lacrimal glands at an average rate of 1.2 µL/ minute. Reflex tears are triggered by irritants and can vary from 3 to 400 µL/minute, to rapidly eliminate the stimulus.  The eyelid movements associated with blinking. Blinking moves tear fluids and foreign matter to the nasal corner of the lid surface.  Tears contain lysozymes and immunoglobulins which impart an anti-infectious activity. The combined mechanisms of lacrimal drainage and blinking means that administered eye drops are rapidly cleared from the conjunctival sac with residence time ranging from 4 to 23 minutes. 12  Topical ophthalmic preparations Moreover, the rate of drainage from the eye has a positive, linear correlation with instilled volume. To reduce the elimination rate of administered eye drops, it is important that the topical preparations do not cause irritation. This can be achieved by designing their properties to be as close as possible to the lacrimal fluids covering the surface of the eye. 13  Formulating ophthalmic preparations Osmolality Osmolality in healthy, non-dry eyes has an average value of Q 302 mmol/ kg during the daytime. Patients with dry eye syndrome have been found to present with tear film hyperosmolality which contributes to the symptoms of the disease. When the eye is exposed to a hypotonic ophthalmic solution, the corneal epithelium becomes more permeable and water flows into the cornea causing oedema. Hypertonic solutions have a dehydrating effect on the corneal epithelium. Hypotonic and hypertonic solutions are irritating to the eye and therefore induce an increased production rate of tears. 14  Formulating ophthalmic preparations Osmolality Normal tear osmotic pressure is equivalent to 0.9% to 1.0% sodium chloride solution. Solutions of osmotic pressure equivalent to ‫ حفظ‬0.6 to 1.3% sodium chloride appear to be well tolerated by the eye. Ophthalmic solutions can be made isotonic using tonicity agents such as sodium chloride, potassium chloride, buffering salts, dextrose, mannitol and glycerol, if they are compatible with the other ingredients in the formulation. 15  Formulating ophthalmic preparations pH of the formulation. The pH of tears is close to neutral (6.9 to 7.5) and is controlled by various substances dissolved in the aqueous layer of tears: carbon dioxide, bicarbonate and proteins such as the basic lysozyme and an acidic tear prealbumin. Acidic or basic solutions instilled into the eye cannot be neutralized by the tears that are present and therefore reflex tears are generated to dilute the administered drop and eliminate it. The recovery to the original pH of the tear film can vary from a few minutes up to 20 minutes. 16  Formulating ophthalmic preparations pH of the formulation. The duration of recovery is influenced by the pH, volume, and buffer capacity of the administered solution, as well as the age of the patient. It is preferable to formulate as close to physiological tear pH as possible to reduce discomfort and the associated increased lacrimation. Pilocarpine is a natural alkaloid used in the treatment of glaucoma. It undergoes pH-dependent hydrolytic degradation and one of the ways to maintain stability of pilocarpine aqueous solution is to maintain the pH at 4–5 through the use of a weak acidic buffer. 17  Formulating ophthalmic preparations pH of the formulation. Since the pH deviates from the physiological pH of the lacrimal fluids, the constituting buffer must be weak to allow the lacrimal fluids to be restored to their normal pH within a short period of time following instillation. Drug ionization is also important in determining drug solubility and permeability across the corneal epithelium. The extent of ionization can be manipulated through control of the pH of ophthalmic preparations. Commonly used buffers in ophthalmic solutions include borate and phosphate buffers. 18  Buffering To prepare solutions of lower pH range acetic acid/ sodium acetate and citric acid/ sodium citrate buffers are used. It is important that strong buffers are not used and to use a low concentrations of weak buffers. The pH of an ophthalmic preparation may be adjusted and buffered for one or more of the following purposes : (a) for greater comfort to the eye. (b) to render the formulation more stable. (c) to enhance the aqueous solubility of the drug. (d) to enhance the drug’s bioavailability (i.e., by favoring unionized molecular species). (e) to maximize preservative efficacy. 19  Buffering The pH of normal tears is about 7.4, but it varies; for example, it is more acidic in contact lens wearers. Tears have some buffer capacity. The introduction of a medicated solution into the eye stimulates the flow of tears, which attempts to neutralize any excess hydrogen or hydroxyl ions introduced with the solution. Q) Most drugs used ophthalmically are weakly acidic and have only weak buffer capacity. Normally, the buffering action of the tears neutralizes the ophthalmic solution and thereby prevents marked discomfort. 20  Buffering The eye apparently can tolerate a greater deviation from physiologic pH toward alkalinity (and less discomfort) than toward the acidic range. For maximum comfort, an ophthalmic solution should have the same pH as the tears. However, this is not pharmaceutically possible, because at pH 7.4 many drugs are insoluble in water. A few drugs— notably pilocarpine hydrochloride and epinephrine bitartrate—are quite acid and overtax the buffer capacity of the tears. Most drugs, including many used in ophthalmic solutions, are most active therapeutically at pH levels that favor the Undissociated molecule. 21  Buffering However, the pH that permits greatest activity may also be the pH at which the drug is least stable. For this reason, a compromise pH is generally selected for a solution and maintained by buffers to permit the greatest activity while maintaining stability. An isotonic phosphate vehicle prepared at the desired pH and adjusted for tonicity may be employed in the extemporaneous compounding of solutions. The desired solution is prepared with two stock solutions, one containing 8 g of monobasic sodium phosphate (NaH2PO4) per liter, and the other containing 9.47 g of dibasic sodium phosphate (Na2HPO4) per liter, the weights being on an anhydrous basis. 22  Buffering The vehicles listed in Table 17.3 are satisfactory for many ophthalmic drugs, excepting pilocarpine, eucatropine, scopolamine, and homatropine salts, which show instability in the vehicle. The vehicle is used effectively as the diluent for ophthalmic drugs already in isotonic solution. When drug substances are added directly to the isotonic phosphate vehicle, the solution becomes slightly hypertonic. Generally, this provides no discomfort to the patient. However, if such a solution is not desired, the appropriate adjustment can be made through calculated dilution of the vehicle with purified water. 23  Surface tension The surface tension of tear fluid at physiological temperature in a healthy eye is Q 43.6 to 46.6 mN/m. Administration of solutions that have a surface tension much lower than that of the lacrimal fluid destabilizes the tear film and disperses the lipid layer into droplets that are solubilized by the drug or surfactants in the formulation. The oily film reduces the rate of evaporation of the underlying aqueous layer and therefore once it is lost, dry spots are formed which are painful and irritant. Surfactants are typically included in ophthalmic preparations to solubilize or disperse drugs. Irritation power of surfactants decreases in the following order: cationic > anionic > zwitterionic > non-ionic. Nonionic surfactants are therefore the most commonly used, examples include; polysorbate 20, polyoxyl 40 stearate, polyoxypropylene-polyoxyethylenediol. 24  Viscosity Viscosity enhancing polymers are used in ophthalmic solutions to prolong drug retention in the precorneal tear film and thus enhance drug absorption. Mechanisms proposed are not just reduced drainage rate; the thickness of the precorneal tear film is also increased due to the ability of viscosity- enhancing polymers to drag water and stabilize the aqueous layer as they spread over the corneal surface on blinking. This increased volume acts as a reservoir for the drug so that it is re- spread in the tear film over the cornea with each blink. 25  Viscosity Q) Water soluble polymers that have been used to increase solution viscosity include poly vinyl alcohol (PVA), poly vinylpyrrolidone (PVP), various cellulose derivatives, particularly; methylcellulose, hydroxypropyl methylcellulose and carboxymethyl cellulose (CMC) (at concentrations of 0.2–2.5%) and poly ethylene glycols (PEG) (at concentrations of 0.2–1%). 26 PVA  Topical, semisolid ophthalmic preparations The major route by which drugs enter the eye is by simple diffusion via the cornea (from high conc to lower conc). The cornea is a lipophilic epithelial layer and lipophilic drugs are more capable of penetration than hydrophilic compounds. In general, ocular drug penetration is limited due to the short residence time that the ophthalmic preparations have on the surface of the eye because of their rapid removal by tearing, the small surface area of the cornea available for drug absorption and the cornea’s natural resistance to drug penetration. Compared with ophthalmic solutions, ophthalmic ointments and gels provide extended residence time on the surface of the eye. Therefore, increasing the duration of their effects and bioavailability for absorption into ocular tissue. 27 Vip Q) Mention three barriers that can hinder or obstacle the ocular drugs:essay 1) Tears 2)Surface area of cornea 3)Anatomy of cornea 28  Topical liquid ophthalmic preparations Solutions: Ophthalmic solutions are the most common topical ophthalmic preparation. They are typically the easiest to manufacture (have the lowest cost of production) and are relatively easy for a patient or healthcare provider to administer. Ophthalmic solutions are also desirable where a rapid onset of action is required as they do not need to undergo dissolution. This would be the case for local anaesthetics (e.g. lignocaine, proxymetacaine hydrochloride); ocular diagnostics (fluorescein sodium) and ocular preoperative drugs. Moreover, solutions are homogeneous and therefore display a better dose uniformity. A limitation of solutions is that they are rapidly drained out of the eye. Moreover, the rate of drainage is proportional to the size of the drop administered. The volume of eye drops administered from commercial eye dropper bottles has been reported to be in the range of 25 to 56 µL. 29  Topical liquid ophthalmic preparations Suspensions (increase the contact time inside the eye) ocular suspensions has been used to administer drugs which are sparingly soluble in water, e.g. steroids, or to prolong drug release. Particles tend to be retained in the ocular cul-de-sac (the space between the eyeball and eyelid) and slowly go into solution thus increasing the contact time. Q) Particle size and shape need to be carefully selected as some particles can cause irritation of the sensory nerves in the epithelium. The particles of a suspension need to be readily dispersible on shaking by the patient to ensure uniform dose administration. Homogeneity and dose from first to last use. 30  Topical liquid ophthalmic preparations Submicron emulsions Ocular submicron emulsions have also shown potential for prolonging drug release and achieving significantly higher drug concentrations in the cornea and aqueous humour compared to suspensions. Ciclosporin is an immunomodulator with anti-inflammatory effects. It is available at a concentration of 0.05% as a sub-micron emulsion for topical application to the eye. Ciclosporin is hydrophobic (log P=3.0) and has a very poor aqueous solubility of 6.6 µg/ml and cannot therefore be formulated in conventional aqueous ophthalmic vehicles. It has been successfully solubilized in an oil-in-water (o/w) submicron emulsion. The oil phase in Restasis is castor oil and the emulsion is stabilized with the non- ionic surfactant polysorbate 80 and glycerin, which behaves here as a co- surfactant. 31  Topical, semisolid ophthalmic preparations Ointments Ophthalmic ointments have been used as an option to reduce drug drainage by tear flow and therefore increasing corneal residence time. Sustained drug release effects of 2–4 hours are usually observed. Ointments also have the advantage of allowing the incorporation of drugs with poor aqueous solubility. Hydrophobic ointments sometimes improve the stability of hydrolysable compounds, particularly peptides. Soft paraffin and liquid paraffin are commonly used as bases for ophthalmic ointments. Anhydrous, water-soluble bases such as carbomer with poly(ethylene glycol) are also used. 32  Topical, semisolid ophthalmic preparations Ointments Antibiotics, antifungals and steroids are the classes of drugs most available as ointments. Drug bioavailability usually peaks later with ointment vehicles than with solutions or suspensions. Total bioavailability in the aqueous humour can also be significantly greater than with solutions or suspensions Ointments are however more difficult to administer compared to solutions and may give rise to a more variable dose. Also blurring of vision arises which tends to reduce patient compliance making ointments more useful or night-time administration. 33  Topical, semisolid ophthalmic preparations Ointments Ophthalmic ointments are cleared from the eye as slowly as 0.5% per minute, compared with solutions which can lose up to 16% of their volume per minute. The ointment base selected for an ophthalmic ointment must be:  Non-irritating to the eye.  Permit the diffusion of the medicinal substance into the eye.  Have a softening point close to body temperature both for patient comfort and for drug release. Mixture of white petrolatum and liquid petrolatum (mineral oil) are utilised as the base in medicated and non-medicated ophthalmic ointments. A gel- base of polyethylene glycol and mineral oil is also used. Medicinal agents are added to an ointment base either as a solution or as a finely micronized powder. The ointment made uniform by fine milling. 34  Topical, semisolid ophthalmic preparations Ointments Ophthalmic ointments must meet the USP sterility test and the test of metal particles. Rendering an ophthalmic ointments sterile requires special techniques and processing. The terminal sterilisation of a finished ointment by standard methods may have some limitations. Steam sterilisation or ethylene oxide methods are ineffective because neither is capable of penetrating the ointment base. Although dry heat can penetrate the ointment base, the high heat required may affect the stability of the drug substance and can separate the ointment base from other components. Because of these difficulties, terminal sterilisation is not undertaken, rather strict methods of aseptic processing are employed as each drug and non- drug component is sterilised and then aseptically weighed and incorporated in a final product, also preservative can be added. Among the antimicrobial preservatives used are combination of and propylparaben 0.01%, chlorobutanol and methylparaben and 0.05% benzalkonium chloride. 35  Topical, semisolid ophthalmic preparations Gels Gels, which are semisolid systems comprising water-soluble bases, are also available and are more favorable than ointments for water soluble drugs. These utilize polymers such as polyvinyl alcohol (PVA), poloxamer, hydroxypropyl methylcellulose (HPMC), Carbopol or Carbomer, dispersed in a liquid. Pilocarpine is a cholinomimetic agent which reduces intraocular pressure and is licensed for glaucoma. It is available as a gel (Pilogel®, Alcon) containing more than 90% water and employing Carbopol 940 (a synthetic high molecular weight polymer of acrylic acid). An equivalent duration of response has been shown with a single instillation. 36  Topical, semisolid ophthalmic preparations Mucoadhesive systems for drug delivery into the eye Other ways to increase the contact time of topical ophthalmic solutions with the ocular surface have been through the use of mucoadhesive polymers. These attach to the mucin coat that covers the conjunctiva and cornea. Mucin has a protein or polypeptide core with carbohydrate chains branching off. The mucin coat serves to protect, hydrate and lubricate the surface of the eye. Mucoadhesive polymers are commonly macromolecular hydrocolloids with numerous hydrophilic functional groups possessing the correct charge density. 37  Topical, semisolid ophthalmic preparations Mucoadhesive systems for drug delivery into the eye They should also exhibit good wetting of the ocular surface to facilitate maximum interaction with the mucin coat. Electrostatic, covalent and hydrogen interactions are the most common between mucoadhesive polymers and mucin. Mucoadhesive polymers can be natural, synthetic or semi- synthetic in nature. The synthetic polymers include polyacrylic acid, polycarbophil as well as cellulose derivatives. The (semi)natural mucoadhesive polymers include chitosan and various gums such as guar, xanthan, carrageenan, pectin and alginate. 38  Improving drug solubility and absorption in topical ophthalmic preparations Drug ionization and salt form The pKa of the drug (acid dissociation constant) and pH determine its degree of ionization in solution. While the pKa can only be altered through structural changes in the molecule, the pH of the drug vehicle can be controlled. A higher proportion of unionized species displays a greater degree of transcorneal permeability, as has been shown with pilocarpine. Pilocarpine is a weak base but to achieve good solubility and stability the eye drops are formulated with an acidic vehicle (pH 3.5–5.5). The physical form of the drug can also be an important determinant of its ocular bioavailability. The salt form can affect solubility and lipophilicity of the drug. Dexamethasone acetate ester displays the optimum balance of solubility and corneal permeability compared to the very water-soluble phosphate salt or lipophilic free base. 39  Improving drug solubility and absorption in topical ophthalmic preparations Cyclodextrins Cyclodextrins (CDs) have shown great potential in improving the solubility of poorly water-soluble drugs. CDs are cyclical oligosaccharides with a lipophilic center and hydrophilic outer surface. They can complex lipophilic drugs in their interior, thus forming water- soluble complexes. This maintains the structure, lipophilicity and hence the permeability of the compounds. The drug is associated with CD by hydrogen bonding, hydrophobic interactions or van der Waals forces. The hydrophilic CDs acts as carriers, delivering water insoluble molecules to the corneal membrane where they can partition from the CD complex. 40  Improving drug solubility and absorption in topical ophthalmic preparations Prodrugs Improved corneal penetration can be gained by prodrugs. A prodrug is a drug with added functionalities that converts into the active parent drug through enzymatic or chemical reactions. Approaches of enhancing corneal penetration using prodrugs include; Optimization of lipophilicity, Enhancement of aqueous solubility, Improved affinity or uptake transporters Evasion of efflux pumps. Drugs with carboxylic acid groups, such as the prostaglandin analogues indicated for glaucoma, have low corneal permeation. This is due to the ionization of the carboxylic acid group at the near neutral pH of tears which reduces permeability through the lipophilic epithelium. One strategy to mitigate this has been esterification of the carboxylic acid group. Since the cornea has high esterase activity, these derivatives can easily revert to their parent form. 41  Sterility of ophthalmic preparations It is a regulatory requirement that preparations intended for ophthalmic use, including those for cleansing the eyes, must be sterile at the time of filling and closing in a sealed container. Ocular infections are extremely dangerous and can rapidly lead to the loss of vision. Eye- cups, droppers and all other dispensers should also be sterile and regulated packaged with the drug product. For ophthalmic preparations, terminal sterilization for products in their final containers should be adopted wherever possible. If the product cannot withstand terminal sterilization then filtration under aseptic conditions should be considered, usually performed using a filter pore size of 0.22 µm or less. 42  Sterility of ophthalmic preparations The raw materials used for aseptic manufacture should be sterile, wherever possible, or should meet a low specified bioburden control limit. Ophthalmic preparations must further more be labelled with duration of use once opened. Preservatives are included in multi-dose containers to destroy and inhibit the growth of microorganisms that may have been accidentally introduced on opening of the container. They are not to be used in products for intraocular administration as they can lead to irritation. Benzalkonium chloride is the most used preservative. Single dose units have been developed to circumvent the use of preservatives while maintaining stability. 43  Sterility of ophthalmic preparations Several multi-dose bottles have been developed that maintain sterility without the use of a preservative; one of these is the ABAK patented filter system which uses a 0.2 µm nylon membrane to prevent bacteria from entering the bottle. It is known as Airless Antibacterial Dispensing System (AADS™, Pfizer) and works by preventing air, and therefore bacteria, from entering the container on dispensing. Furthermore, a silver coil is included in the bottle tip. Silver has antibacterial properties and therefore any bacteria contacting the tip do not contaminate the contents. This system guarantees three months of sterility. 44  Intraocular implants Implantable drug delivery systems can be classified into biodegradable and non- biodegradable. In both, drug release kinetics are determined by the polymer system used, drug physicochemical properties and diffusion of the drug through the polymer. Biocompatibility is an essential property or all systems. The inside of the eye is a viable location for implantation as evidenced by the use of intraocular lenses which are implanted to replace the clouded over natural lens during cataract surgery. 45  Intraocular implants Non-biodegradable intraocular implants Non-biodegradable systems are commonly ‘reservoir’ devices, whereby the drug core is coated by a semi- permeable polymer through which the drug can leave. Or the polymer coating may have an opening of a fixed area through which the drug can diffuse out. The other type of non- biodegradable system is the ‘monolithic’ type which is a homogeneous mix of drug and polymer. It is easier, however, to achieve zero-order kinetics from a reservoir system. 46  Intraocular implants Non-biodegradable intraocular implants Vitrasert® (ganciclovir 4.5 mg) is the first implantable intravitreal device to be available in the clinic and was approved by the FDA in 1996. Ganciclovir is embedded in a polyvinyl alcohol (PVA) and ethylene vinyl acetate (EVA) polymer based system. Drug is slowly released from this implant over 5–8 months. PVA is a hydrophilic polymer acting as the scaffold of the implant as well as controlling the rate of drug diffusion. EVA is hydrophobic polymer used to coat the implant to also control drug diffusion. 47  Intraocular implants Non-biodegradable intraocular implants Fluid goes into the implant and dissolves the drug; a saturated solution is formed within the core and drug molecules diffuse out of the system under a concentration gradient. The advantages of this system are that as long as a saturated drug solution remains in the core, the release rate will be constant. Moreover, no initial burst release of drug is observed. Intraocular insertion of the implant requires surgery and Further surgery is required to remove the implant devoid of drug. 48  Intraocular implants biodegradable intraocular implants Biodegradable systems are composed of polymers that are metabolized by enzymatic or non-enzymatic (e.g. hydrolysis) reactions in vivo into more soluble forms that can be safely eliminated by the body. Their main advantage over non-biodegradable systems is that they do not have to be removed from the body once the drug has been exhausted. 49  Intraocular implants biodegradable intraocular implants Ozurdex® (Allergan) is a dexamethasone (0.7 mg) bioerodible ocular implant with a six month duration of action. It is approved by the FDA or the treatment of macular oedema following retinal vein occlusion (RVO), diabetic macular oedema and uveitis. This implant is based on the copolymer poly(lactic-co-glycolic acid) (PLGA) which has been used for over 30 years in bio- degradable sutures for ophthalmic surgery. 50  Ocular drug delivery systems The objective of the ocular drug delivery is to a) Improve ocular contact time b) Enhancing corneal permeability c) Enhancing site specificity Role of polymers in ocular drug delivery Incorporation of polymers into an aqueous medium of drug could increase solution viscosity and reduces the solution drainage. Increasing the solution viscosity of pilocarpine from 1 to 100 cps by using methyl cellulose reduced the drug drainage and 2 fold increase in drug concentration in aqueous humour was obtained. Natural polymers such as sodium hyaluronate & chondroitin sulfate are being investigated as viscosity inducing agents. 51  Ocular drug delivery systems Ophthalmic inserts – It offers the potential advantage of improving patient compliance by reducing dosing frequency. The desired criteria for a controlled release ocular insert are: a) Comfort b) Ease of handling c) sterility d) Ease of manufacture. Controlled release systems for ocular use encompass both erodible & non-erodible systems. The non-erodible inserts are of 2 types: a) Ocusert system b) Contact lens 52  Ocular Inserts Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate. The rate of drug diffusion is controlled by: - The polymer composition - The membrane thickness - The solubility of the drug 53  Ocular drug delivery systems Ocusert systems – It is pre-programmed to release pilocarpine at constant rate of 20 or 40 μg/hr around the clock for 7 days for the treatment of glaucoma. Contact Lens – Therapeutic soft lenses are often used to aid corneal wound healing in patients with infection, corneal ulcers characterized by thinning of cornea. Erodible Inserts – Several erodible drug inserts have been prepared & tested for ocular use. Pilocarpine containing Carboxy methylcellulose (CMC) wafers, PVA disc or rod is a classical example. The three devices of erodible inserts have been marketed to date are: a) The Lacriserts b) Soluble ocular drug insert (SODI) c) Minidisc. 54  Ocular drug delivery systems Corneal collagen shields – Collagen is a protein that can be safely applied to the body and is used to promote wound healing and delivers a variety of medications to the cornea & ocular tissues. A study published in 1978 showed that wafer shaped collagen inserts impregnated with gentamicin produced highest level of drug in tear film & tissue in the rabbit eye compared to drops, ointment & conjunctival injection. 55