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The concept of ocular inserts as drug delivery systems: An overview Deivasigamani Karthikeyan1, Mithun Bhowmick1, Vijay Prakesh Pandey2,

Jothivel Nandhakumar1, Singaravel Sengottuvelu1, Sandeep Sonkar1, Thangavel Sivakumar1 1 Nandha College of Pharmacy, Erode - 638 052, Tamil Nadu, India 2 Department of Pharmacy, Faculty of Science and Technology, Annamalai University, Chitambaram, India Click here for correspondence address and email

Abstract Ocular diseases require localized administration of drugs to the tissues around the ocular cavity. The existing ocular drug delivery systems are fairly primitive and inefficient. However, the design of ocular system is undergoing gradual transition from an empirical to rational basis. In the recent years, there has been explosion of interest in the polymer based delivery devices. Utilization of the principles of controlled release as embodied by ocular inserts offers an attractive approach to the problem of prolonging pre-corneal drug residence times. In the present update, the authors discuss the basic concept of ocular inserts as drug delivery system and examine the few inserts, which are available in the market or are being developed by pharmaceutical companies for drug delivery. The article discusses soluble ocular drug insert (SODI), Ocusert, Collagen Shields, Ocufit, Minidisc and new ophthalmic delivery system (NODS) with special attention to biological/clinical performances, and potential for future applications and developments. Keywords: Basic concept, collagen shields, minidisc, NODS, ocufit, ocular diseases, ocusert, SODI How to cite this article: Karthikeyan D, Bhowmick M, Pandey VP, Nandhakumar J, Sengottuvelu S, Sonkar S, Sivakumar T. The concept of ocular inserts as drug delivery systems: An overview. Asian J Pharm 2008;2:192-200 How to cite this URL: Karthikeyan D, Bhowmick M, Pandey VP, Nandhakumar J, Sengottuvelu S, Sonkar S, Sivakumar T. The concept of ocular inserts as drug delivery systems: An overview. Asian J Pharm [serial online] 2008 [cited 2011 Mar 31];2:192-200. Available from: http://www.asiapharmaceutics.info/text.asp? 2008/2/4/192/45031

Introduction The eye as a portal for drug delivery is generally used for local therapy against systemic therapy to avoid the risk of eye damage from high blood concentrations of the drug, which is not intended. The unique anatomy, physiology, and biochemistry of the eye render this organ impervious to foreign substances, thus presenting a constant challenge to the formulator to circumvent the protective barriers of the eye without causing permanent tissue damage. Most ocular treatments like eye drops and suspensions call for the topical administration of ophthalmically active drugs to the tissues around the ocular cavity. These dosage forms are easy to instill but suffer from the inherent drawback that the majority of the medication they contain is immediately diluted in the tear film as soon as the eye drop solution is instilled into the cul-de-sac and is rapidly drained away from the pre-corneal cavity by constant tear flow and lacrimo-nasal drainage. Therefore, the target tissue absorbs a very small fraction

of the instilled dose. For this reason, concentrated solutions and frequent dosing are required for the instillation to achieve an adequate level of therapeutic effect. One of the new classes of drug delivery systems, polymeric film ocular drug delivery systems/ocular inserts, which are gaining worldwide accolade, release drugs at a pre-programmed rate for a longer period by increasing the pre-corneal residence time. [1],[3] 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). These inserts are 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. [4] History of ocular inserts The first solid medication (precursors of the present insoluble inserts) was used in the 19th century, which consisted of squares of dry filter paper, previously impregnated with dry solutions (e.g., atropine sulphate, pilocarpine hydrochloride). Small sections were cut and applied under eyelid. Later, lamellae, the precursors of the present soluble inserts, were developed. They consisted of glycerinated gelatin containing different ophthalmic drugs. [5] Glycerinated gelatin 'lamellae' were present in official compendia until the first half of the present century. However, the use of lamellae ended when more stringent requirements for sterility of ophthalmic preparations were enforced. Nowadays, growing interest is observed for ophthalmic inserts as demonstrated by the increasing number of publications in this field in recent years. Examples of the various types of inserts available or in development are presented in the [Table 1]. Advantages of ocular inserts Ocular inserts offer several advantages, [1],[2],[3] which can be summarized as follows: a. Increased ocular residence, hence a prolonged drug activity and a higher bioavailability with respect to standard vehicles; b. Possibility of releasing drugs at a slow, constant rate; c. Accurate dosing (contrary to eye drops that can be improperly instilled by the patient and are partially lost after administration, each insert can be made to contain a precise dose which is fully retained at the administration site); d. Reduction of systemic absorption (which occurs freely with eye drops via the naso-lacrimal duct and nasal mucosa); e. Better patient compliance, resulting from a reduced frequency of administration and a lower incidence of visual and systemic side-effects; f. Possibility of targeting internal ocular tissues through non-corneal (conjunctival scleral) routes; g. Increased shelf life with respect to aqueous solutions; h. Exclusion of preservatives, thus reducing the risk of sensitivity reactions; i. Possibility of incorporating various novel chemical/technological approaches.

Such as pro-drugs, mucoadhesives, permeation enhancers, microparticulates, salts acting as buffers, etc. The potential advantages offered by inserts clearly explain why an active interest has been dedicated to these dosage forms in recent years, and why efforts to introduce them on the pharmaceutical market continue. Of course, not all of the benefits listed above can be present in a single, ideal device. Each type of insert represents a compromise between the desirable properties inherent to solid dosage forms and negative constraints imposed by the structure and components of the insert itself, by fabrication costs, as well as by the physical/physiological constraints of the application site.

Disadvantages of ocular inserts The disadvantages [1],[2],[3] of ocular inserts are as follows: a. A capital disadvantage of ocular inserts resides in their 'solidity', i.e., in the fact that they are felt by the (often oversensitive) patients as an extraneous body in the eye. This may constitute a formidable physical and psychological barrier to user acceptance and compliance. b. Their movement around the eye, in rare instances, the simple removal is made more difficult by unwanted migration of the insert to the upper fornix, c. The occasional inadvertent loss during sleep or while rubbing the eyes, d. Their interference with vision, and e. Difficult placement of the ocular inserts (and removal, for insoluble types).

Mechanism of Drug Release The mechanism of controlled drug release into the eye is as follows: A. Diffusion, B. Osmosis, C. Bio-erosion. A. Diffusion In the Diffusion mechanism, [32],[33] the drug is released continuously at a controlled rate through the membrane into the tear fluid. If the insert is formed of a solid non-erodible body with pores and dispersed drug. The release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solutions. In a soluble device, true dissolution occurs mainly through polymer swelling. In swelling-controlled devices, the active agent is homogeneously dispersed in a glassy polymer. Since glassy polymers are essentially drug-impermeable, no diffusion through the dry matrix occurs. When the insert is placed in the eye, water from the tear fluid begins to penetrate the matrix, then swelling and consequently polymer chain relaxation and drug diffusion take place. The dissolution of the matrix, which follows the swelling process, depends on polymer structure: linear amorphous polymers dissolve much faster than cross-linked or partially crystalline polymers. Release from these devices follows in general Fickian 'square root of time' kinetics; in some instances, however, known as case II transport, zero order kinetics has been observed. B. Osmosis In the Osmosis mechanism, [33] the insert comprises a transverse impermeable elastic membrane dividing the interior of the insert into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane. There is a drug release aperture in the impermeable wall of the insert. The first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form. When the insert is placed in the aqueous environment of the eye, water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the

second compartment so that the drug is forced through the drug release aperture. C. Bioerosion In the Bioerosion mechanism, [33],[34] the configuration of the body of the insert is constituted from a matrix of bioerodible material in which the drug is dispersed. Contact of the insert with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix. The drug may be dispersed uniformly throughout the matrix but it is believed a more controlled release is obtained if the drug is superficially concentrated in the matrix. In truly erodible or E-type devices, the rate of drug release is controlled by a chemical or enzymatic hydrolytic reaction that leads to polymer solubilization, or degradation to smaller, water-soluble molecules. These polymers, as specified by Heller, [34] may undergo bulk or surface hydrolysis. Erodible inserts undergoing surface hydrolysis can display zero order release kinetics; provided that the devices maintain a constant surface geometry and that the drug is poorly water-soluble. Classification of Ocular Inserts The inserts have been classified, on the basis of their physico-chemical behavior, as soluble (S) or insoluble (I). Only the latter types can usually deliver drugs by a variety of methods at a controlled, predetermined rate, but need removal from the eye when 'empty'. Soluble (S) inserts, also generally defined by some authors [21] as erodible (E), are monolytic polymeric devices that undergo gradual dissolution while releasing the drug, and do not need removal. It should be pointed out that, as indicated in the article by Saettone [5] , the terms 'soluble' and 'erodible' are not interchangeable, and correspond to distinct chemical processes, even if a clear-cut distinction between the two mechanisms is sometimes difficult. True dissolution occurs mainly through polymer swelling, while erosion corresponds to a chemical or enzymatic hydrolytic process. [35] Hence, ocular inserts are classified as given below: I. Insoluble ocular inserts; II. Soluble ocular inserts; III. Bio-erodible ocular inserts. I. Insoluble ocular inserts Inserts made up of insoluble polymer can be classified into two categories: A. Reservoir systems; B. Matrix systems. A. Reservoir systems Each class of inserts shows different drug release profiles. The reservoir systems can release drug either by diffusion or by an osmotic process. It contains, respectively, a liquid, a gel, a colloid, a semisolid, a solid matrix, or a carrier containing drug. Carriers are made of hydrophobic, hydrophilic, organic, natural or synthetic polymers. They have been sub-classified into: 1. Diffusional inserts, e.g., 'Ocuserts'; 2. Osmotic inserts. 1. Diffusional insert or Ocuserts Ocusert system is a novel ocular drug delivery system based on porous membrane. The release of drug

from diffusional inserts/Ocusert is based on a diffusional release mechanism. It consists of a central reservoir of drug enclosed in specially designed microporous membrane allowing the drug to diffuse from the reservoir at a precisely determined rate. As pointed out by Urquhart, [29] the Ocusert pilocarpine ocular therapeutic system, developed by Alza Corporation, is notable for several reasons. This product was the first rate-controlled, rate specified pharmaceutical for which the strength is indicated on the label by the rate(s) of drug delivery in vivo , rather than by the amount of contained drug. It provides predictable, time-independent concentrations of drug in the target tissues, a feat impossible to achieve with conventional, quantity-specified, pulse entry ophthalmic medications. The near-constant drug concentration in ocular tissues markedly improves the selectivity of action of pilocarpine. A major advantage is that two disturbing side effects of the drug, miosis and myopia, are significantly reduced, while reduction of intraocular pressure (IOP) in glaucoma patients is fully maintained. Two types of Ocusert are available: the Pilo-20 and Pilo-40. The former delivers the drug at a rate of 20 g/h for 7 days, and the latter at a rate of 40 g/h for 7 days. This device, which is certainly well familiar to the readers of this review, has been exhaustively described and discussed in a series of specialized papers. [14],[17],[18],[19] Briefly, it consists of a reservoir containing pilocarpine alginate enclosed above and below by thin EVA (ethylene-vinyl acetate) membranes. The insert is encircled by a retaining ring of the same material, impregnated with titanium dioxide. The dimensions of the elliptical device are (for the 20 g/h system): major axis-13.4 mm, minor axis-5.7 mm, thickness-0.3 mm. The membranes are the same in both systems, but to obtain a higher release rate, the reservoir of the 40 g/h system contains about 90 mg of di (2-ethylhexyl) phthalate as a flux enhancer. 2. Osmotic insert The osmotic inserts are generally composed of a central part surrounded by a peripheral part and are of two types: Type 1: The central part is composed of a single reservoir of a drug with or without an additional osmotic solute dispersed throughout a polymeric matrix, so that the drug is surrounded by the polymer as discrete small deposits. The second peripheral part of these inserts comprises a covering film made of an insoluble semi-permeable polymer. The osmotic pressure against the polymer matrix causes its rupture in the form of apertures. Drug is then released through these apertures from the deposits near the surface of the device. [53] Type 2: The central part is composed of two distinct compartments. The drug and the osmotic solutes are placed in two separate compartments, the drug reservoir being surrounded by an elastic impermeable membrane and the osmotic solute reservoir by a semi-permeable membrane. The second peripheral part is similar to that of type 1. The tear diffuse into the osmotic compartment inducing an osmotic pressure that stretches the elastic membrane and contracts the compartment including the drug, so that the active component is forced through the single drug release aperture. [53] B. Matrix systems The second category, matrix system, is a particular group of insoluble ophthalmic devices mainly represented by contact lenses. It comprises of covalently cross-linked hydrophilic or hydrophobic polymer that forms a three dimensional network or matrix capable of retaining water, aqueous drug solution or solid components. The hydrophilic or hydrophobic polymer swells by absorbing water. The swelling caused by the osmotic pressure of the polymer segments is opposed by the elastic retroactive forces arising along the chains or crosslinks are stretched until a final swelling (equilibrium) is reached. 1. Contact lenses

Contact lenses are shaped structures and initially used for vision correction. Their use has been extended as potential drug delivery devices by presoaking them in drug solutions. The main advantage of this system is the possibility of correcting vision and releasing drug simultaneously. Refojo [36] has proposed a subdivision of contact lenses into 5 groups. a. b. c. d. e. Rigid Semi-rigid Elastomeric Soft hydrophilic Bio-polymeric

Rigid contact lenses have the disadvantage of being composed of polymers (e.g., poly methyl methacrylic acid) hardly permeable to moisture and oxygen, a problem which has been overcome by using gas permeable polymers such as cellulose acetate butyrate. However, these systems are not suitable for prolonged delivery of drugs to the eye and their rigidity makes them very uncomfortable to wear. For this reason, soft hydrophilic contact lenses were developed for prolonged release of drugs such as pilocarpine, [37] chloramphenicol and tetracycline [38] prednisolone sodium phosphate. [39] The most commonly used polymer in the composition of these types of lenses is hydroxy ethyl methyl metacrylic acid copolymerized with poly (vinyl pyrrolidone) or ethylene glycol dimethacrylic acid (EGDM). Poly (vinyl pyrrolidone) is used for increasing water of hydration, while EGDM is used to decrease the water of hydration. The soft hydrophilic contact lenses are very popular because they are easy to fit and are tolerated better. The drug incorporation into contact lenses depends on whether their structure is hydrophilic or hydrophobic. When contact lens (including 35 to 80% water) is soaked in solution, it absorbs the drug. Drug release depends markedly on the amount of drug, the soaking time of the contact lens and the drug concentration in the soaking solution. [53] II. Soluble ocular inserts These soluble inserts offer the advantage of being entirely soluble so that they do not need to be removed from their site of application, thus limiting the intervention to insertion only. They can be broadly divided into two types, the first one being based on natural polymers and the other on synthetic or semi-synthetic polymers. A. Natural polymers The first type of soluble inserts is based on natural polymer. [8] Natural polymer used to produce soluble ophthalmic inserts is preferably collagen. The therapeutic agent is preferably absorbed by soaking the insert in a solution containing the drug, drying, and re-hydrating it before use on the eye. The amount of drug loaded will depend on the amount of binding agent present, the concentration of the drug solution into which the composite is soaked as well as the duration of the soaking. As the collagen dissolves, the drug is gradually released from the interstics between the collagen molecules. B. Synthetic and semi-synthetic polymer The second type of soluble insert is usually based on semi-synthetic polymers (e.g., cellulose derivatives) [41] or on synthetic polymers such as polyvinyl alcohol. [41],[42] A decrease of release rate can be obtained by using Eudragit, a polymer normally used for enteric coating, as a coating agent of the insert [40],[41] . Saettone et al . [40] have observed in rabbits that Eudragit coated inserts containing pilocarpine induced a miotic effect of a longer duration, compared to the corresponding uncoated ones. However, the inherent problems encountered with these soluble inserts are the rapid penetration of the

lachrymal fluid into the device, the blurred vision caused by the solubilization of insert components and the risk of expulsion due to the initial dry and glassy consistency of the device. [4] Ethyl cellulose, a hydrophobic polymer, can be used to decrease the deformation of the insert and thus to prevent blurred vision. [25],[42] As for the risk of expulsion, several authors have incorporated carbomer, a strong but well tolerated bio-adhesive polymer. [25],[43] The soluble inserts offer the additional advantage of being of a generally simple design, of being based on products well adapted for ophthalmic use and easily processed by conventional methods. The main advantage is decreased release rate, but still controlled by diffusion. III. Bio-erodible ocular inserts These inserts are formed by bio-erodible polymers (e.g., cross-linked gelatin derivatives, polyester derivatives) which undergo hydrolysis of chemical bonds and hence dissolution. [44],[45] The great advantage of these bio-erodible polymers is the possibility of modulating their erosion rate by modifying their final structure during synthesis and by addition of anionic or cationic surfactants. A cross-linked gelatin insert was used by Attia et al . [42] to increase bioavailability of dexamethasone in the rabbit eye. The dexamethasone levels in the aqueous humor were found to be four-fold greater compared to a dexamethasone suspension. However, erodible systems can have significantly variable erosion rates based on individual patient physiology and lachrimation patterns, while degradation products and residual solvents used during the polymer preparation can cause inflammatory reaction. In the following paragraphs, some important ocular inserts are discussed which are available commercially (SODI) or in advanced states of development (collagen shields, Ocufit, NODS, and Minidisc). Soluble ophthalmic drug insert Soluble ophthalmic drug insert (SODI) is a small oval wafer, which was developed by soviet scientists for cosmonauts who could not use eye drops in weightless conditions. SODI is together with the collagen shields, the first modern revival of the gelatin 'lamellae', which disappeared from pharmacopoeias in the late forties. The SODIs are the result of a vast collaborative effort between eminent Russian chemists and ophthalmologists, and led eventually (in 1976) to the development of a new soluble copolymer of acrylamide, N -vinylpyrrolidone and ethyl acrylate (ratio 0.25: 0.25: 0.5), designated ABE. [9] A comparison of medicated eye films prepared with different polymers, showed that ABE produced the highest concentration of drugs in rabbit ocular tissues. [10] After large-scale preclinical and clinical testing, the ABE copolymer was used for the industrial manufacture of the SODI in the form of sterile thin films of oval shape (9 x 4.5 mm, thickness 0.35 mm), weighing 15-16 mg, and color-coded for different drugs (over 20 common ophthalmic drugs, or drug combinations). After introduction into the upper conjunctival sac, a SODI softens in l0-15 s, conforming to the shape of the eyeball. In the next l0-15 min the film turns into a polymer clot, which gradually dissolves within 1 h while releasing the drug. The sensation of an 'extraneous body' in the eye disappears in 5-15 min. [11] Collagen shields Collagen is the structural protein of bones, tendons, ligaments, and skin and comprises more than 25% of the total body protein in mammals. This protein, which is derived from intestinal collagen, has several biomedical applications, the main of which is probably catgut suture.

Bloomfield et al . are credited for first suggesting, in 1977 and 1978, the use of collagen inserts as tear substitutes [7] and as delivery systems for gentamicin. [8] They compared the levels of gentamicin in tears, cornea, and sclera of the rabbit eye after application of a collagen insert, drops, an ointment or following subconjunctival administration. After 3 h, they found that the collagen insert gave the highest concentration of gentamicin in the tear film and in the tissue. Other treatments using collagen shields impregnated with gentamicin and dexamethasone have been described. [13] In rabbits, aqueous humor levels of dexamethasone and gentamicin achieved with collagen shields were compared to subconjunctival injections. The authors concluded that the use of collagen shields impregnated with gentamicin-dexamethasone was comparable to the subconjunctival delivery of these drugs over a 10-h period. Some drawbacks of these devices, however, need mentioning. To apply the collagen shield, the cornea is anaesthetized while the physician uses a blunt forceps to insert the hydrated or unhydrated shield. Contrary to medicated contact lenses, collagen shields often produce some discomfort and interfere with vision. In rabbits, collagen shields have been found to exacerbate ulcerations of alkali-burned corneas. [14] A new preparation referred to as collasomes consists of small pieces (1 mm x 2 mm x 0.1 mm) of collagen suspended in a 1% methylcellulose vehicle. Kaufman and co-workers [15] recently reported that collasomes provide the same therapeutic advantages of the shields (high and sustained levels of drugs and/or lubricants to the cornea), while not presenting their disadvantages. Ocufit The Ocufit is a sustained release, rod shaped device made of silicone elastomer, [16] patented in 1992 and currently developed by Escalon Ophthalmics Inc. (Skillman, NJ). It was designed to fit the shape and size of the human conjunctival fornix. Accordingly, it does not exceed 1.9 mm in diameter and 2530 mm in length, although smaller sizes for children and newborn babies are planned. The superiority of the cylindrical shape can be traced in an earlier paper by Katz and Blackman. They reported the effect of the size and shape of the inserts on tolerance and retention by human volunteers. [17] These workers found that expulsion of rod shaped units was significantly ( P < 0.01) less frequent than expulsion of oval, flat inserts. A typical example of a rod-shaped insert is the Lacrisert (Merck and Co., Inc.), a cellulosic device used to treat dry-eye patients. [18] The insoluble Ocufit reportedly combines two important features, long retention and sustained drug release. When placed in the upper fornix of volunteers, placebo devices were retained for 2 weeks or more in 70% of the cases. Moreover, active disease (bacterial, allergic and adenoviral conjunctivitis, trachoma, episcleritis, anterior uveitis, cornea1 ulcers or scars) did not overtly affect the ability of the patients to retain the inserts. Tetracycline-loaded inserts released in vitro 45% of the drug over the 14day period with an initial burst in the first day followed by a constant rate over the remaining period. The Minidisc ocular therapeutic system This monolytic polymeric device, originally described by Bawa et al . (Bausch and Lomb, Rochester, New York) [19] and referred to as Minidisc ocular therapeutic system (OTS), is shaped like a miniature (diameter 4-5 mm) contact lens, with a convex and a concave face, the latter conforming substantially to the sclera of the eye. The particular size and shape reportedly allow an easy placement of the device under the upper or lower lid without compromising comfort, vision or oxygen permeability. When compared with another standard insert, the Lacrisert, the Minidisc was reported to require less time and less manual dexterity for insertion. [21] Different versions of the device have been evaluated, such as, non-erodible hydrophilic, non-erodible hydrophobic and erodible.

In vitro tests showed that the hydrophilic OTS (based on polyhydroxymethyl methacrylate) released sulfisoxazole for 118 h, while the hydrophobic unit (based on a proprietary Bausch and Lomb prepolymer) released gentamicin sulfate for more than 320 h. Clinical trials on placebo units demonstrated that the devices were well tolerated when placed either in the upper or lower conjunctival sac. In the eyes of healthy volunteers, the hydrophilic OTS released sulfisoxazole continuously for 3 days. [19] Further studies conducted on the hydrophobic Minidisc [20] showed that gentamicin sulfate was efficiently released in rabbit eyes for 14 days. The 'New Ophthalmic Delivery System' The 'New ophthalmic delivery system' (NODS), originally patented by Smith and Nephew Pharmaceuticals Ltd in 1985, is a method for delivering precise amounts of drugs to the eye within a water-soluble, drug-loaded film. [12] The device consists of a medicated flag (4 mm x 6 mm, thickness 20 m, weight 0.5 g) which is attached to a paper-covered handle by means of a short (0.7 mm) and thin (3-4 m) membrane. All components (flag, membrane, and handle) are made of the same grade of water-soluble polyvinyl alcohol (PVA). The devices are individually packaged and sterilized by gamma irradiation. For use, the flag is touched onto the surface of the lower conjunctival sac. The membrane proceeds to dissolve rapidly releasing the flag, which swells and dissolves in the lacrimal fluid, delivering the drug. This relatively simple device appears to offer most of the advantages specified earlier in the advantages of ocular insert, except the possibility of releasing drug at a slow, predetermined rate. [22] When evaluated in humans, the NODS produced an 8-fold increase in bioavailability for pilocarpine with respect to standard eye drop formulations. [23] The pre-corneal retention of experimental PVA matrices containing 99mTc-labelled sulphur colloid [12] or 99mTc-diethylene-triaminepentacetic acid [24] was studied in man using the gamma scintigraphy technique. In the latter study, the rate of clearance of the marker was investigated in relation to the duration of pharmacological effect of pilocarpine (also incorporated into the matrix). These studies showed the NODS system to have a t 1/2 of approximately 8 min for the film itself and 7 min for the water-soluble drug incorporated into the film, which compares to about 3 s for an aqueous solution of a water-soluble drug. Currently investigated ocular inserts containing anti-glaucoma, antibacterial, anti-inflammatory or antiviral drugs for ocular delivery are presented in [Table 2]. Conclusion The solid drug-releasing devices, in spite of the advantages demonstrated by extensive investigations and clinical tests, have not gained a wide acceptance by ophthalmologists. At this moment, the Ocusert systems are the only medicated inserts marketed in Western countries, and the acceptance of these devices has been, to the present date, far from enthusiastic. According to recent information the NODS project will not be further developed. [5] As said before, the commercial failure of inserts has been attributed to psychological factors, such as the reluctance of ophthalmologists and patients to abandon the traditional liquid and semi-solid medications, to price factors and to occasional therapeutic failures (e.g., unnoticed expulsion from the eye, membrane rupture, etc.). The manufacturers of ocular dosage forms appear to show a continued preference for dropperdispensed medications. Many drugs already in use have been reformulated in new longer acting liquid dosage forms, such as an ' in situ ' gelling preparation of timolol (Timoptic XE, Merck and Co., Inc.), Semisolid gel type preparations (i.e., Pilopine HS gel, Alcon Laboratories, Inc.),etc., do not seem to occupy an equally important position in the manufacturers' preferences.

Still, the prolonged, constant-rate release pattern achievable by inserts of the Ocusert and Ocufit type can be considered as the most desirable condition for long term therapy, both because of efficacy as well as the reduction of ocular and systemic side-effects. Shorter-acting devices, such as the collagen shields which could effectively deliver gentamicin-dexamethasone combinations, might prove useful for single application after intraocular surgery or other conditions. Although at this time the advantages of solid ocular dosage forms are understood and appreciated, marketing strategies prevent their further commercialization, unless, of course, their potential use could be extended to applications other than long-term glaucoma or trachoma treatment, or short-term medication after ocular surgery. Nevertheless, recent research suggests a renewed interest based on the efficacy of sub-conjunctival and intra-vitreal drug delivery devices. [57] References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Chien YW. Ocular drug delivery and delivery systems. In: Novel drug delivery systems. 2 nd ed. New York: Marcel Dekker; 1992. p. 269-70. Saettone MF, Salminen L. Ocular inserts for topical delivery. Adv Drug Del Rev 1995;16:95-106. Khar RK, Vyas SP. Targeted and Controlled drug delivery novel carrier systems. 1 st ed. New Delhi; CBS Publishers and Distributors; 2002. p. 384. Gurtler F, Gurny R. Patent literature review of ophthalmic inserts. Drug Dev Ind Pharm 1995;21:1-18. Saettone MF. Solid polymeric inserts/disks as ocular drug delivery systems. In: Edman P, editor. Biopharmaceutics of ocular drug delivery. Boca Raton: CRC Press; 1993. p. 61-79. Quigley HA, Pollack IP, Harbin TS Jr. Pilocarpine ocuserts: Long term clinical trials and selected pharmacodynamics. Arch Ophthalmol 1975;93:771-5. Bloomfield SE, Miyata T, Dunn MW, Bueser N, Stenzel KH, Rubin AL. Soluble artificial tear inserts. Arch Ophthalmol 1977;95:247-50. Bloomfield SE, Miyata T, Dunn MW, Bueser N, Stenzel KH, Rubin AL. Soluble gentamicin ophthalmic inserts as a drug delivery system. Arch Ophthalmol 1978;96:885-7. Khromow GL, Davydov AB, Maychuk YF, Tishina IF. Base for ophthalmological medicinal preparations and an ophthalmological medicinal film. US. Patent 3, 935, 303, 1976. Maichuk YF. Medicated eye films. Moscow: Med Export; 1985. p. 1-66. Maichuk YF. Polymeric ophthalmic inserts with antibiotics, Proceedings of the Conference of Ophthalmologists of the City of Moscow; 1967. p. 403-5. Lloyd R. U.K. Patent 2097680. Smith and Nephew Research, Ltd; 1985. Milani JK, Verbukh I, Pleyer U, Sumner H, Adamu SA, Halabi HP, et al . Collagen shields impregnated with gentamicin-dexamethasone as potential drug delivery device. Am J Ophthalmol 1993;116:622-7. Wentworth JS, Paterson CA, Wells JT, Tilki N, Gray RS, McCartney MD. Collagen shields exacerbate ulceration of alkali-burned rabbit corneas. Arch Ophthalmol 1993;111:389-92. Kaufman HE, Steinemann TL, Lehman E, Thompson HW, Varnell ED, Jacob-LaBarre JT, et al . Collagen-based drug delivery and artificial tears. J Ocul Pharmacol 1994;10:17-27. Darougar S. Ocular insert for the fornix, U.S. Patent 5,147, 1992,647. Katz IM, Blackman WM. A soluble sustained-release ophthalmic delivery unit. Am J Ophthalmol 1977;83:728-34. Lamberts DW, Pavan-Langston D, Chu W. A clinical study of slow-releasing artificial tears. Ophthalmology 1978;85:794-800. Bawa R, Dais M, Nandu M, Robinson JR. New extended release ocular drug delivery system: Design, characterization and performance testing of minidisc inserts. Proc Int Symp Control Rel Bioact Mater 1988;15:106a-b. Bawa R, Nandu M, Downie W, Robinson JR. Recent studies on the continuing characterization of

minidisc inserts for ocular therapy. Proc Intern Symp Control Rel Bioact Mater 1989;16:213-4. 21. Bawa R. Ocular inserts. In: Mitra AK, editor. Ophthalmic Drug Delivery Systems. New York: Marcel Dekker; 1993. p. 223-59. 22. Richardson MC, Bentley PH. A new ophthalmic delivery system. In: Mitra AK, editor. Ophthalmic drug delivery systems. New York: Marcel Dekker; 1993. p. 355-67. 23. Kelly J, Molyneux PD, Smith SA, Smith S. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eye drop formulations. Br J Ophthalmol 1989;7:360-2. 24. Greaves JL, Wilson CG, Birmingham AT, Bentley PH, Richardson MC. Scintigraphic studies on the cornea 1 residence of a new ophthalmic delivery system (NODS): Rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine. Br J Clin Pharmacol 1992;33:603-7. 25. Gurtler F, Kaltsatos V, Boisrame B, Gurny R. Long acting soluble bioadhesive ophthalmic drug insert (BODI) containing gentamicin for veterinary use: optimization and clinical investigation. J Control Rel 1995;33:231-6. 26. Chetoni P, Di Colo G, Gandi M, Morelli M, Saettone MF, Darougar S. Silicone rubber/hydrogel composite ophthalmic inserts: Preparation and preliminary in vitro/in vivo evaluation. Eur J Pharma Biopharm 1998;46:125-32. 27. Simamora P, Nadkarni SR, Lee YC, Yalkowsky SH. Controlled delivery of pilocarpine.2. In vivo evaluation of Gelfoam device. Int J Pharm 1998;170:209-14. 28. Diestelhorst M, Grunthal S, Suverkrup R. Dry drops: A new preservative-free drug delivery system. Graefes Arch Clin Exp Ophthalmol 1999;237:394-8. 29. Urquhart J. Development of the Ocusert pilocarpine ocular therapeutic systems: A case history in ophthalmic product development. In: Robinson JR, editor. Ophthalmic Drug Delivery Systems, American Pharmaceutical Association, Washington DC: 1980. p. 105-16. 30. Hornof M, Weyenberg W, Ludwig A, Bernkop-Schnurch A. Mucoadhesive ocular insert based on thiolated poly(acrylic acid): Development and in vivo evaluation in humans. J Controlled Release 2003;89:419-28. 31. Sasaki H, Nagano T, Sakanaka K, Kawakami S, Nishida K, Nakamura J, et al . One-side-coated insert as a unique ophthalmic drug delivery system. J Controlled Release 2003;92:241-7. 32. Korsmeyer RW, Peppas NA. Macromolecular and modeling aspects of swelling-controlled systems. In: Roseman TJ, Mansdorf SZ, editors. Controlled Release Delivery Systems. New York: Marcel Dekker; 1983. p. 77-90. 33. Darougar; Sohrab, Darougar and Dayshad, Patent literature review of ocular inserts. United States Patent 6,264,971, Appl. No. 428967, Filed on November 4, 1999. 34. Heller J. Controlled release of biologically active compounds from bioerodible polymers. Biomaterials 1980;1:51-7. 35. Heller J. Controlled drug release from monolithic systems. In: Saettone MF, Bucci G, Speiser P, editors. Ophthalmic Drug Delivery, Biopharmaceutical, Technological and Clinical Aspects, Fidia Research Sereis. Vol. 11. Padua: Liviana Press; 1987. p. 179-89. 36. Refojo MF. Polymers in contact lenses: An overview. Curr Eye Res 1985;4:719-23. 37. Moddox YF, Bernstein HN. An evoluation of the bionite hydrophilic contact lens for use in a ocular drug delivery system. Ann Ophthalmol 1992;4:789. 38. Prans R, Brettschneider, Krjci L, Kahvodova. Hydrophilic contact lenses as a new therapeutic approach for the typical use of chloramphenicol and tetracycline. Opthalmologica 1972;165:62. 39. Hull DS, Edechauser HF, Hyndink RA. Ocular penetration of prednisolone and the hydrophilic contact lense Arch Ophthalmol 1974;92:413. 40. Saettone MF, Chetoni P, Torraca MT, Giannaccini B, Naber L, Conte U, et al . Application of the compression technique to the manufacture of Pilocarpine inserts. Acta Pharm Technol 1990;36:15-9. 41. Saettone MF, Torraca MT, Pagano A, Giannaccini B, Rodriguez L, Cini M. Controlled release of Pilocarpine from coated polymeric ophthalmic inserts prepared by extrusion. Int J Pharm

42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

1992;86:159. Attia MA, Kassem MA, Safwat SM. In vivo per formance of 3-H-dexamethasone ophthalmic film delivery system in the Rabbit eye. Int J Pharm 1988;47:21. Lee VH, Yong Li S, Sasaki H, Saettone MF, Chetoni P. Influence of drug release rate on systemic timolol absorption from polymeric ocular inserts in the pigmented rabbit. J Ocular Pharmacol 1994;10:421-9. Grass GM, Cobby J, Makoid MC. Ocular delivery of Pilocarpine from erodible matrices. J Pharm Sci 1984;73:618-21. Punch PI, Slatter DH, Costa ND, Edwards ME. Investigation of gelatin as a possible biodegradable matrix for Sustained delivery of gentamicin to the bovine eye. J Vet Pharmacol Ther 1985;8:335-8. Salminen L, Urtti A, Kujari H, Juslin M. Prolonged pulse-entry of pilocarpine with a soluble drug insert. Greafe's Arch Clin Exp Ophthalmol 1983;221:96. Saettone MF, Chetoni P, Torraca MT, Burgalassi S, Giannaccini B. Evaluation of muco- adhesive properties and in vivo activity of ophthalmic vehicles based on hyaluronic acid. Int J Pharm 1989;51:203. Urtti A, Salminen L, Miinalainen O. Systemic absorption of ocular pilocarpine is modified by polymer matrices. Int J Pharm 1985;23:147. Sendelbeck L, Moore D, Urqhart J. Comparative distribution of pilocarpine in ocular tissues of the rabbit during administration by eyedrop or by membrane-controlled delivery systems. Am J Ophthalmol 1975;80:274-83. Yamamoto Y, Kaga Y, Yoshikawa T, Moribe A. Ultra violet-hardenable adhesive. US Patent. 5145884 , 1992. Milani JK, Verbukh I, Pleyer U, Sumner H, Adamu SA, Halabi HP, et al . Collagen shields impregnated with gentaminic-dexamethasone as a potential drug delivery device. Am J Ophthalmol 1993;116:622-7. Pavan-Langston D, Langston RH, Geary PA. Idoxuridine ocular insert therapy: Use in treatment of experimental herpes simplex keratitis. Arch Ophthalmol 1975;93:1349. Rastogi SK, Vaya N, Mishra B. Ophthamic inserts: An overview. The Eastern Pharmacist, February 1996. p. 41-4. Hiratani H, Fujiwara A, Tamiya Y, Mizutani Y, Alvarez-Lorenzo C. Ocular release of Timolol from molecularly imprinted soft contact lenses. Biomaterials 2005;26:1293-8. Stephane M, Isabelle M, Belkacem H, Marie-Jose S, Patrick B, Yves T, et al . Pharmacodynamics of a new ophthalmic mydriatic insert in healthy volunteers: Potential alternative as drug delivery system Prior to cataract surgery, basic and clinical. Pharmacol Toxicol 2006;98:547-54. Natu MV, Sardinha JP, Correia IJ, Gil MH. Controlled release gelatin hydrogels and lyophilisates with potential application as ocular inserts. Biomed Mater 2007;2:241-9. Pijls RT, Lindemann S, Nuijts RM, Daube GW, Koole LH. Pradofloxacin release from the OphthaCoil: A new device for sustained delivery of drugs to the eye. J Drug Deliv Sci Technol 2007;17:87-91.

Non-Ionic Surfactant Based Vesicle 'Niosome' As A Potential Ocular Drug Delivery System - An Overview

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Abstract:
The common principle for the success of pharmacotherapy is that the suitable drug should be present at the site of action in an effective concentration for a desired period of time. In ophthalmic treatment the site of action may be any ocular tissue, depending on where the disorder is located. Hence the drug should be targeted to many different sites within the eye. Poor bioavailability of drugs from ocular dosage form is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. Though the topical and localized application are still an acceptable and preferred way to achieve therapeutic level of drugs used to treat ocular disorders but the primitive ophthalmic solution, suspension, and ointment dosage form are no longer sufficient to combat various ocular diseases. The use of niosomes in combating the ophthalmic disorders is gaining momentum in the present scenario. This article reveals the importance in using niosomes as a potential ocular drug delivery system and highlights the need for the successful formulation, method of preparation and its characterization etc. to meet the future challenges and thereby rendering the dosage form for ocular therapy more effective. Keywords: Ocular drug delivery system, Niosomes, Niosomes preparation, Non-ionic surfactant vesicle

Introduction:
Ocular diseases were widely noticed since the inception of human race and animals. Reference to diseases of the eye in dogs and cattle has been found in 4000-year-old papyri of Ancient Egypt. Between 450 and 510 AD1,eight chapters devoted to the eye diseases of the horse and related therapies were translated from Greek by Publius Vegetius Renatus in Artis Veterinariae sive Mulomedicinae. Most veterinary topical ophthalmic drugs and delivery systems (solutions, suspensions and ointments) are derived from human ocular formulations, since in animals the main diseases are similar (e.g. inflammation, keratoconjunctivitis sicca, glaucoma) and exhibit similar pathologies to those of the human eye. In human, various disease states such as keratitis, glaucoma, iritis and cataract affect the anterior segment of the eye. Similarly, the posterior segment of the eye is affected by disease states such as diabetic retinopathy, viral and bacterial infections, malignancies, proliferative vitreal disorders and macular degeneration2. The tendency today is to find ocular delivery systems that are patient-friendly. Most ocular diseases are treated with a topical application of drug solutions administered as eye-drops. The relative percentages are 62.4% for solution, 8.7% suspensions and 17.4% ointments3. These conventional dosage forms account for nearly 90% of the currently accessible marketed formulations4. One of the major problems encountered with the topical delivery of ophthalmic drugs is the rapid and extensive precorneal loss caused by the high tear fluid turnover5 as well as the relatively large volume of the administered eye drop (~50 l versus 7 l of cornea1 tear film), lead to a high rate of lacrimal drainage. Due to the resulting elimination rate, the precorneal half life of drugs applied by these pharmaceutical formulations is considered to be between about 1-3 min. As a consequence, only the very small amount of about l-3% of the dosage actually penetrates through the cornea and is able to reach intraocular tissues6, 7, 8 Anatomical and physiological parameters in the human eyes9 were summarized in Table No.1. The poor productive absorption, on the other hand, results in a high amount of drug that is drained into the nose or into the gut. Especially the nose but also the gut is very efficient absorption organs of the body. This in turn leads to an extensive systemic absorption and may result in unwanted side effects and toxicity of the drug8. Lacrimation and blinking are actually efficient protective mechanisms which keep the eye free from foreign substances10, but they prevent efficient ocular therapy. As a consequence, the ocular residence time of conventional eye drops is limited to a few minutes11, 12 and the ocular absorption of a topically applied drug is reduced to approximately l-10%13, 14.Furthermore, drug uptake occurs as a massive pulse entry followed by a

rapid decline. The drug is mainly absorbed systemically via conjunctiva and nasal mucosa15, which may result in some undesirable side effects12 Although these problems have been recognized for a long time, surprisingly little effort has been made by drug companies to improve the situation, and only very few alternative ocular drug delivery systems are on the market. To overcome these problems, various ophthalmic vehicles such as ointments16, 17, suspensions18, 19, 20, micro- and nanocarrier systems21,22,23, Inserts24,
25, 26

, and liposomes21, 27, 28, 29 have been investigated.

Vesicular System
In recent years, vesicles have become the vehicle of choice in drug delivery. Lipid vesicles were found to be of value in immunology, membrane biology, diagnostic techniques, and most recently, genetic engineering.30 Vesicles can play a major role in modeling biological membranes, and in the transport and targeting of active agents. Vesicular systems not only help in providing prolonged and controlled action at the corneal surface but also help in providing controlled ocular delivery by preventing the metabolism of the drug from the enzymes present at the tear/corneal epithelial surface. Moreover, vesicles offer a promising avenue to fulfill the need for an ophthalmic drug delivery system that has the convenience of a drop, but will localize and maintain drug activity at its site of action. The penetration of drug molecules into the eye from a topically applied preparation is a complex phenomenon. The rate of drug penetration depends not only on the physicochemical properties of the drug itself, such as its solubility31, and particle size, in case of suspensions
32

but also on those of its vehicle33. In vesicular dosage forms, the drug is encapsulated in lipid vesicles,

which can cross cell membrane. Vesicles, therefore, can be viewed as drug carriers and as such they change the rate and extent of absorption as well as the disposition of the drug. Vesicular drug delivery systems used in ophthalmics broadly include liposomes and Niosomes. Drug delivery systems using colloidal particulate carrier such as liposomes34 have distinct advantages over conventional dosage forms. This carrier can act as drug reservoir, and modification of its composition or surface can adjust the drug release rate and/or the affinity for the target site. Liposomes can carry hydrophilic drugs by encapsulation or hydrophobic drugs by partitioning of these drugs into hydrophobic domains. The first study to utilize liposomes for ophthalmic therapy was reported by Smolin et al.35 They compared the therapeutic efficacy of idoxuridine in solution and liposomal form in the treatment of acute and chronic herpetic keratitis in the rabbit eye.

Niosomes In Lieu Of Liposomes Reasons


One of the most significant problems associated with the use of liposomes as adjuvant is the susceptibility of phospholipids to oxidative degradation in air. This requires that purified phospholipids and liposomes have to be stored and handled in an inert (e.g. nitrogen) atmosphere36. Phospholipid raw materials are naturally occurring substances and as such require extensive purification thus making them costly37. Alternatively, phospholipids can be synthesised de novo, however this approach tends to be even more costly than using naturally occurring lipids.Because of liposomes above mentionioned drawbacks, alternative nonionic surfactants have been investigated. This involves formation of liposome-like vesicles from the hydrated mixtures of cholesterol and nonionic surfactant such as monoalkyl or dialkyl polyoxyethylene ether36. Niosomes are unilamellar or multilamellar vesicles capable of entrapping hydrophilic and hydrophobic solutes38. From a technical point of view, niosomes are promising drug carriers as they possess greater stability and lack of many disadvantages associated with liposomes, such as high cost and the variable purity problems of phospholipids39. Another advantage is the simple method for the routine and large-scale production of niosomes without the use of unacceptable solvents. Cholesterol, 5-cholesten-3-ol is used in combination with nonionic surfactant for the formation of niosomes.

Points To Meet Successful Niosomes Formulation


The fundamental requirements for the success of successful niosomes used in ocular delivery may be summarized as follows40, 41. Physician acceptance, User acceptance, Ease of handling and application, Patient comfort, Lack of expulsion during application, Lack of toxicity, Noninterference with vision and oxygen permeability, Reproducibility of

release kinetics, Applicability to a variety of drugs, Sterility, Stability, Ease of manufacture, Reasonable price and Duration of action.

Prerequisites Of Controlled Ocular Delivery Systems42


1 To overcome the side effects of pulsed dosing produced by conventional therapy. 2.To provide sustained and controlled release. 3.To increase the ocular bioavailability of drug by increasing corneal contact time. These can be achieved by effective coating or adherence to corneal surface, so that the released drug effectively reaches the anterior chamber. 4.To provide targeting within the ocular cavity so that prevents the loss to other ocular diseases. 5.To circumvent the protective barriers like drainage, lacrimation and diversion of exogenous chemicals into the systemic circulation by the conjunctiva. 6.To provide comfort and compliance to the patient and yet improve the therapeutic performance of the drug over conventional systems. 7.To provide the better housing of the delivery system in the eye so as the loss to other tissues besides cornea is prevented.

Advantages Of Niosomes In Ocular Drug Delivery30, 42, 43


1.Niosomes are quite stable structures, even in the emulsified form. They require no special conditions such as low temperature or inert atmosphere for protection or storage. 2.They are chemically stable as compare to liposomes. 3.They can entrap both hydrophilic and hydrophobic drugs. 4.Nontoxic, biodegradable, biocompatible and non-immunogenic. 5.Flexible in their structural characterization (composition, Fluidity and size). 6.They can improve the performance of drug molecules via delayed clearance from circulation, better bioavailability and controlled drug delivery at the desired site. 7.A number of non- ionic surfactants have been used to prepare vesicles viz. polyglycerol alkyl ether, glucosyl dialkyl ethers, crown ethers, ester linked surfactants, polyoxyethylene alkyl ether, Brij, and a series of spans and tweens. 8.Relatively low cost of materials makes it suitable for industrial manufacture. 9.Handling and storage of surfactants require no special conditions. 10.No tissue irritation and damage as caused by penetration enhancers. 11.They prevent the metabolism of drugs from the enzymes present at tear / corneal epithelium interface. 12. Provide a prolonged and sustained release of drug.

Retrospect Of Niosome
Niosomes were first reported in the seventies as a feature of the cosmetic industry by Vanlerberghe et al44, Handjani-vila et al.,45 ; Van Abbe46 explained that the non inonic surfactants are preferred because the irritation power of surfactants decreases in the following order: cationic > anionic > ampholytic > non-ionic. Green and Downs47, Keller et al.48, Burstein49, Kaur and Smitha50 reported that an increased ocular bioavailability of water soluble , entrapped in niosomes , may be due to the fact that surfactants also act as penetration enhancers as they can remove the mucus layer and break functional complexes. Handjani-Vila et al.45 reported that vesicular systems were formed when a mixture of cholesterol and single alkyl chain, non-ionic surfactants was hydrated. The resultant vesicles, termed as niosomes can entrap solute. Okhata et

al.51 suggested vesicle formation by some members of dialkylpoly oxyethlene ether non-ionic surfactant series. Singh and Mezei52 stated that niosomes are a suitable delivery system for both hydrophilic and lipophilic drugs. Baillie et al.35 reported that niosomes are osmotically active and relatively stable. Lasic53 stated that the assembly into closed bilayers is rarely spontaneous and usually involves some input of energy such as physical agitation or heat. The result is an assembly in which the hydrophobic parts of the molecule are shielded from the aqueous solvent and the hydrophilic head groups enjoy maximum contact with same. The non-ionic surfactant vesicles have been reported successfully by Saettone et al.54 as ocular vehicle for cyclopentolate. Carafa et al.55 stated that niosomes are the non-ionic surfactant vesicles and like liposomes are bilayered structures, which can entrap both hydrophilic and lipophillic drugs either in an aqueous layer or in vesicular membrane, made up of lipids. Vyas et al.56 prepared both niosomes and discomes of water-soluble drug timolol maleate and found that discomes entrapped comparatively a higher amount of drug (25% as compared to 14% in case of niosomes). Moreover, an increase in ocular bioavailability was found to be approximately 3.07-fold compared to 2.48-fold in case of niosomes with respect to timolol maleate solution. Carafe et al.57 reported that niosomes are biodegradable, biocompatible, and non-immunogenic. Indu P. Kaur et al.43 gave an impression on vesicular system in ocular drug delivery. Deepika Aggarwal et al.58 studied the improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system. Deepika Aggarwal et al.59 studied the ocular absorption of acetazolamide by microdialysis sampling of aqueous humor. Ghada abdelbary60 and Nashwa el-gendy investigated the feasibility of using non-ionic surfactant vesicles as carriers for the ophthalmic controlled delivery of a water soluble local antibiotic, Gentamicin sulphate.

Method Of Preparation Of Niosomes61,62


To date, different methods have been reported on preparation of niosomes by Azmin et a., Baillie et al., Chopineau et al., Handjani- Vila et al., Kiwada et al., Niemec et al., Talsmea et al., Wallach and Philippot, Yoshioka et al. Small unilamellar vesicles (SUV, size -0.025-0.05 m) are commonly produced by sonication, and French Press procedures. Ultrasonic electrocapillary emulsification or solvent dilution techniques can be used to prepare SUVs. Multilamellar vesicles (MLV, size >0.05 m) exhibit increased-trapped volume and equilibrium solute distribution, and require hand-shaking method. They show variations in lipid compositions. Large unilamellar vesicles (LUV, size >0.10 m), the injections of lipids solubilised in an organic solvent into an aqueous buffer, can result in spontaneous formation of LUV. But the better method of preparation of LUV is Reverse phase evaporation, or by Detergent solubilisation method. However, the more commonly used laboratory methods of niosome preparation and drug loading identified in the literature are listed below. 1. The ether injection method is essentially based on slow injection of surfactant : cholesterol

solution in ether through a 14 gauge needle at the rate of approximately 0.25 ml/min into a preheated aqueous phase maintained at 60C. The mechanism whereby relatively larger unilamellar vesicles are formed however is not understood, presumably it could be ascribed to the slow vapourization of solvent resulting into a ether gradient extending across the interfacial lipid / surfactant monolayer at ether-water interface. The latter subsequently may result into the formation of a bilayer sheet, which eventually folds on itself to form sealed vesicles. 2. Surfactant and cholesterol mixture is dissolved in diethylether in a round bottomed flask. The ether is evaporated under vacuum at room temperature in a rotary evaporator. Upon hydration the surfactant swells and is peeled off the support in to a film, like lipids in lipid based film. Swollen amphiphiles eventually fold to form vesicles. 3. The formation of oil in water (o / w) emulsion from an organic solution of surfactants / lipids and an aqueous solution of the drug. The organic solvent is then evaporated to leave niosomes dispersed in

the aqueous phase. In some cases, a gel results which must be further hydrated to yield niosomes. ( reverse phase evaporation) 4. The injection of melted lipids / surfactants into a highly agitated heated aqueous phase in which presumably the drug is dissolved or the addition of a warmed aqueous phase dissolving the drug to a mixture of melted lipids and hydrophobic drug. To this method, do not require the use of organic solvents, which are expensive, difficult to remove in their entirety and hazardous. 5. The addition of the warmed aqueous phase to a mixture of the solid lipids / surfactants. This also does not require the use of organic solvents. 6. Niosomes may also be formed from a mixed micellar solution by the use of enzymes. A mixed micellar solution of C16 G2, DCP, polyoxyethylene cholesteryl sebacetate diester (PCSD) converts to a niosome dispersion when incubated with esterases. PCSD is cleaved by the esterases to yield polyoxyethylene, sebacic acid and cholesterol. Cholesterol in combination with C16 G2 and DCP then yields C16 G2 niosomes. 7. The homogenization of a surfactant / lipid mixture followed by the bubbling of nitrogen gas through this mixture. Apparently the homogenization step may be omitted from the procedure with out affecting particle size, although a longer bubbling time was required.

Characterization Of Niosomes Involved In Ocular Drug Delivery


Entrapment efficiency58, 61, 63, 64 Entrapment efficiency largely depends on the preparation method. Non-ionic surfactant vesicles prepared by ether injection method demonstrate higher entrapment efficiency as compared to those prepared by hand shaking method. The Analysis of entrapment efficiency can be done by dialysis or ultracentrifugation methods. The niosome entrapped drug could be separated from the free drug by dialysis method. Fill the prepared noisome into the dialysis bags and dialyze the free drug for 24 hrs into 100 ml of phosphate buffer saline, pH 7.4. The absorbance (A) of the dialysate can be measured against phosphate buffer saline using UV spectrophotometer and the absorbance (A) of the corresponding blank niosome would be measured under the same condition. The concentration of free drug could be obtained from absorbance difference (A = A-A) based on standard curve. The entrapment efficiency of the drug is defined as the ratio of the mass of niosome associated drug to the total mass of drug. In the ultracentrifugation method, the prepared niosomal suspension will be subjected for centrifugation at high rpm for 30 mins to 60mins. Analyse the clear supernatant liquid by using spectrophotometer and calculate the amount of un-entrapped drug. Amount of entrapped drug can be obtained by subtracting amount of un-entrapped drug from the total drug incorporated. Percent entrapped = [Entrapped drug (mg) / Total drug added (mg)] X 100 Size, Shape and Morphological characterization64 Vesicular structure of surfactant based vesicles can be visualized and established using freeze fracture electron microscopy while photon correlation spectroscopy could be successfully used to determine mean diameter of the vesicles. Electron microscopy can be used for morphological studies of vesicles while master sizer based on laser beam is generally used to determine size distribution, mean surface diameter and mass distribution of niosomes. Drug release studies64 The release of drug from niosomes is determined using the membrane diffusion technique. Suspend an accurately measured amount of drug niosomal formulation in 1ml phosphate buffer saline and transferred to a glass tube covered at its lower end by a soaked cellulose membrane. Suspend the glass tube in the dissolution flask of a dissolution apparatus containing 75 ml phosphate buffer saline and rotate it at 50 rpm. Keep the temperature at 37 C. Draw the aliquots of the dialysate at predetermined time and replenish

immediately with the same volume of fresh simulated fluid. Analyze the withdrawn samples using spectrophotometer. Physical stability study64 Physical stability study is required to investigate the leaching of drug from niosomes during storage. Seal the prepared niosomes in 20 ml glass vials and store at a temperature of 2 - 8C for a period spread over 60 90 days. Withdraw samples from each batch at definite time intervals and determine the residual amount of the drug in the vesicles after separation from un-entrapped drug by ultracentrifugation or dialysis method. Zeta potential analysis68 The presence of surface charge in vesicular dispersions is critical. Aggregation is attributed to the shielding of the vesicle surface charge by ions in solution and there by reducing the electrostatic repulsion. Vesicle surface charge can be estimated by measurement of particle electrophoretic mobility and is expressed as the zeta potential which can be calculated using the Henry equation. = E4 /

Where, = zeta potential, E = electrophoretic mobility, = viscosity of the medium, = dielectric constant. Microviscosity of bilayer membrane63 The microviscosity of niosomal membrane can be determined by fluorescence polarization (P) and can be calculated according to the following equation. P = ( IP G Iv ) / (Ip + GIv ) Where, Ip and Iv are the fluorescence intensity of the emitted light polarized parallel and vertical to the exciting light, respectively and G is the grating correction factor. The fluorescence intensities Ip and Iv are measured at various temperatures with spectrofluorophotometer. The microviscosity of vesicular membrane could be measured by DPH (1, 6 diphenyl-1,3,5-hexatriene) (fluorescent probe) method. DPH normally exists in hydrophobic region in the bilayer membrane. According to this technique, the mobility of DPH could be monitored as a function of temperatures. Fluorescence polarization correlates to microviscosity near the probe. High fluorescence polarization means high microciscosity of the membrane. Increase of cholesterol contents result in an increase of microviscosity of the membrane indication more rigidity of the membrane. However, membrane formed with stearyl chain surfanctants will be more rigid even without cholesterol. The bilayer membrane with very low microviscosity could not stably carry water soluble substances in the vesicles. Rheological properties65 The viscosity of ophthalmic products is most important parameter because It is generally agreed that an increase in vehicle viscosity increases the residence time in the eye, although there are conflicting reports in the literature to support the optimal viscosity for ocular bioavailability products formulated with a high viscosity are not well tolerated in the eye, causing lacrimation and blinking until the original viscosity of the tear is regained. Drug diffusion out of the formulation into the eye may also be inhibited due to high product viscosity. Finally, administration of high viscosity liquid products tends to be more difficult. The rheological properties of niosomes can be studied using Ostwald- U- tube at 25 C. Dilute the samples with water to the required concentrations and leave it to equilibrate for 1 hr. Relative viscosity can be calculated by comparing efflux time with that of water. Ocular irritancy of niosomes64 The potential ocular irritancy and/or damaging effects of the formulations under test could be evaluated by observing them for any redness, inflammation, or increased tear production. The healthy rabbits weighing 2.5-3 kg should be selected. Introduce the test and control samples into the left and right eyes respectively, once a day for a period of 40 days. Separate the eyes, fix them and cut vertically, dehydrate, clear,

impregnate in soft and hard paraffin, section at 8m thickness with the microtone and stain with haemotoxylin and eosin. Corneal histological examinations can be completed after photographing the stained sections using optical microscopy. Intraocular pressure58, 64, 67 Adult male normotensive rabbits weighing 1.5 2 kg can be used for the study. Measure the IOP using a tonometer after instilling a drop of a local anaesthetic in both the eyes immediately prior to the instillation of the drug. Change in IOP (IOP) for each eye is expressed as follows, IOP = IOPdosed eye IOPcontrol eye. Aqueous humor analysis59, 66 The albino rabbits weighing 2.5 kg can be used for the study. Keep the rabbits under anesthesia throughout the experiment by intramuscularly injecting 50/50 mixture of ketamine hydrochloride (30 mg/kg) and xylazine hydrochloride (10 mg/kg). To reduce the discomfort further, anaesthetize the eyes using one to two drops of oxybuprocaine. Insert the 25 G needle across the cornea, just above the corneoscleral limbus, so that it traverses through the center of the anterior chamber to the other end of the cornea. Collect the samples and can be stored at - 20C until analysis carried out. Measure the levels of drug in the aqueous humor samples by using HPLC with UV detector.

Future Prospects
Currently the available conventional dosage forms for ophthalmic use induce the absorption of drugs only to the extent of 1-3% through the cornea. The main aim of ophthalmic preparation is to give the maximum drug absorption through prolongation of the drug residence time in the cornea and conjunctival sac as well as to slow drug release from the delivery system and minimize precorneal drug loss. The non ionic surfactant vesicles fulfill all the requirements for the controlled ocular delivery system and in addition, it has the advantage of drug to be administered in the form of a drop, which increases patient compliance. There is very good scope for the non-ionic surfactant vesicles in ocular drug delivery system. However, indepth knowledge about the physicochemical characteristics of the drug molecule and expected interaction and implications of entrapping the same into a vesicular system is important.

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S. No 1 2 3 4 5 6 7 8 9 10 Normal tear volume Tear secretion rate

Parameters

Value 7.0l 1.2 l/min 1.45 min


1

Solution drainage rate constant Corneal surface area Conjunctival surface area Palpebral conjunctiva surface area Bulbar conjunctiva surface area Corneal thickness Volume of aqueous humor in anterior chamber Aqueous humor secretion rate, as a percentage of volume of aqueous humor in anterior chamber

1.04 cm2 17.65 cm2 8.82 cm2 7.78 cm2 0.52 mm 261310 l 12%/min

11 12

Distribution volume in anterior chamber Clearance in anterior chamber

1503000 l 130 l /min