Ocular Implants

Kesarwani / IJDFR volume 2 Issue 5, Sep.-Oct. 2011

93 Kesarwani. / IJDFR volume 2 Issue 5, Sep.-Oct. 2011

Available online at www.ordonearresearchlibrary.org ISSN 2229-5054

INTERNATIONAL JOURNAL OF DRUG FORMULATION AND RESEARCH

OCULAR IMPLANTS: A NOVEL APPROACH TO OCULAR DRUG DELIVERY REVIEW

Ritesh Kumar Kesarwani*1, SL Harikumar2, AC Rana1, Chandan Kashyap2, Amanpreet Kaur2, Nimrata Seth1

1Rayat institute of pharmacy, Railmajra, distt. Nawanshahr, Punjab - 144533 2Rayat & bahra institute of Pharmacy, Sahauran, distt. Mohali, Punjab - 140104

Received: 23 Aug. 2011; Revised: 15 Sep. 2011; Accepted: 16 Oct. 2011; Available online: 5 Nov. 2011

INTRODUCTION

In the recent years, great efforts are being directed towards the fabrication of existing ophthalmic drug delivery systems, capable of solving problems related to poor bioavailability, dosing problem, pre-corneal elimination, poor water solubility etc. Ophthalmic diseases affect the quality of life of millions and millions of individuals. Although currently there are a number of therapeutic approaches for treating many of these ocular diseases, so there is a great opportunity to discover and develop better therapeutics that treat a greater number of ophthalmic diseases. A rapid expansion of new technology in ocular drugs to treat the challenging diseases in the anterior and posterior segments of the eye has recently emerged. This trend of working has led to development of Novel ophthalmic delivery system (NODS) to overcome these problems. The overall goal for this review is to focus on

Review- Article

ABSTRACT In the recent years, great efforts are being directed towards the fabrication of existing ophthalmic drug molecules, capable of solving problem related to poor bioavailability, dosing problem, pre-corneal elimination, poor water solubility etc. Approaching the ‘Ocular Implants’ as Novel Ophthalmic Delivery Systems (NODS) are leading to development in modern trend to treat, cure or prevent the ophthalmic diseases of various ophthalmic regions of eye by providing successful drug delivery for our working environment. ‘Ocular Implants’ are unit matrix or reservoirs system of drug and polymeric materials which can release the drug at pre-programmed rate without interference with the normal vision can serve with improved patient compliance. The overall goal for this review is to focus on new approaches for ‘Ocular implants’ with specific emphasis on new avenues of drug development for ocular drug delivery system. This review discusses the spectrum of potential applications, design and fabrications of ocular implants, polymer reviews, characterisation and developments in the techniques for in-vitro and in-vivo evaluation of ocular implants. Ocular drug delivery with implants had a profound impact in clinical ophthalmology, especially in the management of retinal diseases provides opportunities for targeting drugs to specific cells or intraocular compartments with improve patient compliance. Key words: corneal implant, in-situ gel, ocular implant, ophthalmic implant, scleral implant,

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new approaches for ‘Ocular implants’ with specific emphasis on new avenues of drug development for ocular drug delivery system. ‘Ocular implants’ are unit matrix or reservoirs system of drug and polymeric materials which can release the drug at pre-programmed rate without interference with the normal vision can serve with improved patient compliance [1]. Advantage over conventional dosage forms

The ocular implant in ophthalmic drug delivery establishes a new standard in front of Eye drug delivery. Several advantages offered by ocular implants, which can be summarized as follows:

(a) Ocular implants are a safe, flexible alternative to laser surgery.

(b) Ocular implants provide clear, maintenance-free ocular drug delivery without affecting the quality of our

vision.

(c) Ocular Implants show better patient compliance, resulting from a reduced frequency of administration

and lower incidence of visual side-effects.

(d) Ocular Implants are directly introduced in ophthalmic region of eye with elegantly minor (some time

major) surgery and reduce the chance of systemic absorption of ocular drug.

(e) Biodegradable corneal implants are bio-erodible and non toxic; show release of active drugs specifically

in eye [2].

(f) Ocular implant provides a release control mechanism suitable for providing a controlled passive release

of the pharmaceutical composition into the various ophthalmic regions of eye.

(g) Aseptic unit dosage form. (h) Exclusion of preservatives, thus reducing the risk of sensitivity reactions,

Hence, ocular implants are elegantly safe unique dosage form that provides patient comfort and enhance patient

compliance.

Drug Delivery through Ocular Implants: The Concept Ocular implants are unit dosing system of drug and polymeric materials, which can release the drug at pre-programmed rate without interference with the normal vision, can serve with improved patient compliance. Implants can be localized within the anterior or posterior segments (regions between Eye), promote better bioavailability and results in sustained release of active drug moiety after a simple surgical Implantation to treat a disease in a consistent and predictable fashion [3].

In order to optimise Ocular implant delivery systems, it is important to consider a number of factors, including effective implantation technique to promote good drug distribution in to the entire ocular region, prolonged contact time and ocular- compatible properties like non-irritability, limiting to post operative pain, reflex blinking and lachrymation. To optimise the route and site of implantation, many factors are considered: drug-water solubility, physicochemical properties, efficacy and toxicity, half-life, release rate and the anatomy & the pathology of the targeted tissues [4] [5].

A successful drug delivery may be achieved by a successful therapeutic strategy. The challenge of future therapeutic strategies in ophthalmology is the ability to integrate in optimized clinical practice and safe drug delivery of implants [6].



Fig. Anatomy of the Eye

Need of Implants With Respect To Conventional Ocular Dosage Forms Currently available ocular drug delivery methods include topical, systemic, periocular, subconjunctival, and intravitreal injections. All of these methods have limitations that may decrease the treatment effectiveness as inadequate intraocular penetration, side effects, inconstant intraocular drug levels and limited duration of action. Example, the bioavailability of ocular drugs topically applied in eye-drops is very poor (< 5%) and it is limited by protective function of the eye as lachrymation and blinking rate [7]. At other hand, Intravitreal injections are used to obtain adequate therapeutic levels at posterior segment of the eye. However, rapid clearance of drugs from the vitreous requires repeat dosing from several hours to several month intervals to maintain predictable therapeutic concentrations [8]. Therefore, repeated Intravitreal injections are often associated with complications such as vitreous haemorrhage, endophthalmitis, and retinal detachment. When macular diseases require long-term therapy, this practice is far from ideal [9]. Over this, ophthalmic implants provide continuous sustained drug delivery and more comfort to patient [10]. Hence, in order to improve drawbacks associated with conventional dosage form, it requires an alternative way of administration to enhance the bioavailability of the drug. ‘Ocular implants’ are the effective ocular delivery systems that have been commercialised recently or are under development all aim at enhancing drug bioavailability by providing prolonged or sustained delivery to the eye or by facilitating trans-corneal penetration for best patient compliance and affordability [11]. Approaches for Implantation of ocular implants:



Fig. Principal methods of ocular implant for local drug delivery to the eye.

(Source: Susan et al., 2008) [12]

The eye is a unique organ, both anatomically and physiologically, containing several widely varied structures with independent physiological functions. The complexity of the eye provides unique challenges to drug delivery strategies. Even Human eye has wide area of ocular implantation. Therefore, various approaches for ocular implantation are discussed with many researchers:

A. Anterior segment:

a. Corneal Route

Cornea provides vital space for implantation of corneal implants in ocular drug delivery system. A

corneal implant comprises a body formed of an optically clear, biocompatible material having the index of

refraction substantially identical to the refractive index of corneal tissue. This area may be sub-divided into

following ways:

i. Outer surface of cornea

In-situ gelling systems are most accepted implant technique, implanted by this route. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in-situ gel forming systems, which upon instillation as drops into the eye undergo a sol-gel transition in the cul-de-sac. This may result in better ocular bioavailability [13]. Recent innovations in front of the ocular drug delivery devices includes the Eye-instils produced by Med-Instill, Inc., which has a one-way-valve to ensure multiple dosing of sterile, and the OptiMyst device, which



dispenses medication as a mist rather than as a drop [11]. Over this, Intacus-corneal implants are used to treat Keratoconus & exhibits improved visual acuity [14].

ii. Within cornea

Corneal implants are fabricated to place ‘within’ the membranes of the cornea. The device (implant)

contains a distal end and a proximal end, and it is configured for laterally insertation within cornea. First basic

experimental studies was done by Robert Day in January, 1954, in which he designed both bioerodible and non-

bioerodible artificial intra-lameller implants. A successful in-vivo investigation in this study was performed in

rabbit and cat cornea [15].

The refractive index of these implant material should be in the range of 1.36-1.39, which is substantially similar to that of cornea and it prevents edge effect. Some prosthetic corneal implants are also fabricated for modifying the corneal curvature and altering the corneal refractive power for correcting myopia, hyperopia, astigmatism and presbyopia. Such implants are formed of a micro-porous hydrogel material and the device is non- biodegradable and this can also be used for controlled release of active drug moiety in eye [16].

b. Non corneal Route for ocular implant in Anterior segment

i. Aqueous Humor

This is a transparent aqueous medium, also responsible for ocular hypertension. Continuous circulation

of aqueous humor naturally occurs in this region. This promotes passive release of active moiety through

implant system in ophthalmic region.

ii. Ocular lens

Ocular lens is most widely accepted as “intraocular lens implants” for sight accommodation. This may

also be utilised in implants for ophthalmic drug delivery.

iii. Sclera

Sclera is covering layer for entire Eye ball and provides continuous blood circulation in entire ophthalmic region. Hence, this is good site of choice for ocular implantation. These ocular Implants include trans-scleral solid devices placed by minor surgery, representing possibilities of increased residence time with slow release pattern of medication from sclera to vitreous cavity. A film-type scleral implant of indomethacin with Gellan gum matrix was introduced. Its pharmacodynamic studies showed a marked improvement in the various clinical parameters for more than three weeks [17]. In other hand, delivery of betamethasone with PVA-EVA episcleral implant was studied and localized over the sclera [18]. Later, Drug release from these episcleral implants was studied using Gd-DTPA and magnetic resonance imaging [19] [20]. The non-biodegradable intrascleral implant can be a useful drug carrier for intraocular delivery without severe retinal toxicity. The intrascleral site may be considered for effective intraocular drug distribution after implantation [21].



Fig. A variety of controlled-release systems at sclera. (a) An implantable non-biodegradable device suspended at the pars plana is used clinically with PVA, poly-(vinyl alcohol); EVA, ethylene vinyl acetate. (b) Biodegradable devices are implantable into the peribulbar space, at the sclera, or into the vitreous cavity in various shapes such as a disc (b1), a plug (b2), or rod, and pellet. [4]

Another absorbable scleral implant is reported and popular with the name of SKGel 3.5. It consists of reticulated sodium hyaluronate and phosphate buffer to produce a gel consistency. SKGel 3.5 is inserted in the scleral decompression space for controlled drug delivery in eye. These implants are commercialised by corneal laboratorie, France and have been popularized by Dr P.Sourdille. B. Posterior segment: Posterior segment of eye ball occupies more than 80% vital area for implantation of ophthalmic drug

delivery systems. This posterior region of Eye includes vitreous humor and retina. The drug implants have

greater acceptability at this region due to large surface area. It includes:

a. Vitreous Humor

Vitreal implants are most widely acceptable ophthalmic implant for drug delivery to Vitreous Humor.

The clear liquid implants or micro-suspension implants have greater acceptability for this region. The

“Intravitreal-injection” as ophthalmic implant is most direct approach to deliver drug at vitreous humor and

retina. However, this method of administration has been associated with serious side effects, like

endophthalmitis, cataract, haemorrhage, and retinal detachment [22]. These intravitreal implants can also deliver

into the posterior segment directly via pars plana [4]. Nevertheless, Intravitreal implant continues to be the mode

of choice for the treatment of acute intraocular therapy.

A polysulfone capillary fiber (PCF) based intravitrial ocular implant is reported with significant in-vitro and in-vivo release of carboxy fluorescein. Result indicates that the PCF devices are useful for the extended release of drug in the posterior segment of eye [23]. In another successful study, in-vivo study of intravitreal implant of hyaluronic acid esters, (known as hyaluronan implants) was studied for the treatment of posterior segment ocular diseases [24].



Various devices, giving zero-order release of Ganciclovir was clinically implanted in AIDS associated retinitis patients in phase I clinical trial. Steady state of Ganciclovir levels was observed. In another clinical trial a sustained release intravitreal implantable device for release of GCV was reported over 4 to 5 months. Eight patients with AIDS associated CMV retinitis were recruited in this study [25]. b. Retina

The implants used for retina are termed as “Retinal implant”. Due to large surface area of Retina, this is

area of choice of ocular implant in retinal diseases.

In an example, rod-shaped devices with drug-coating made up of poly butyl-methacrylate and poly ethylene-co-vinyl acetate were developed and implanted in the sub retinal space. These implants were used to deliver sirolimus or triamcinolone acetonide as a model drug [26].

Implantation of Ocular implant in ophthalmic region:

The techniques of Implantation of various Ocular implants in ophthalmic region, varies by site of implantation,

size of implant and pattern of its controlled release. In the focus of corneal implants implantation typically

performed by making a tunnel or pocket within the cornea (corneal flap), which leaves intact corneal layers or

within aqueous humor of anterior chamber. Commercially available device ‘micro keratome’ is used for corneal

prosthesis and this technique is termed as ‘corneal lamellar dissection’ [16]. In Scleral-implant, the surgery is

termed as ‘keratome surgery’. If the both eyes are treated, the implants must be placed at two separate times, to

decrease the risk of infection in both eyes at the same time.

Vitreal implants may be in viscous fluid, solid or semisolid dosage forms. They must be operated in class I atmospheric operating condition by open eye surgery or through sterilized micro needle. An Intravitreal implantation of solid plug type ocular implants is performed by ‘sclerotomy surgery’ near the limbus of eyes [24]. Delivery System Design for Ophthalmic implants: A successful design of a drug delivery system requires an integrated knowledge of the drug molecule and the constraints offered by the design of drug polymer devise. The delivery system can be designed as either a reservoir or a matrix type (see figure). Reservoir systems are non-eroding devices that give the best control of drug release-rate by virtue of a specific physical rate control feature. This feature can be as simple as an opening in the device, a porous screen or a coating through which the drug diffusion is retarded. It is easy to achieve a zero order constant rate of drug release using a reservoir system. Over this, matrix type devices are direct physical mixing of drug–polymer system.



Fig. The two primary styles of drug delivery devices,

(A) Reservoir and (B) Matrix-type.

Various designs of Delivery Systems of ocular implants: Type I : Tablet Type II : In-situ gel system Type III : Polymer Film (Non-Biodegradable, Biodegradable) Type IV : Pellets Type V : Helical type, Refillable system other compatible solid designs as implant 1. Tablets This is a matrix system fabricated under compression method. This matrix implant system is constituted with drug dispersed in the polymer. When the implant is placed in an aqueous environment (site of implantation) the polymeric structure dissolves, releasing the drug. The release rate follows first order kinetics, with an initial burst of drug followed by a rapid reduction in release [27].

Fig. Illustration showing a matrix tablet implant (left) with drug dispersed in the polymer.

“When the implant is placed in an aqueous environment (right), the polymeric structure dissolves, releasing the drug. The release rate (lower-left inset) follows first order kinetics, with an initial burst of drug followed by a rapid reduction in release [12].”

(Source: Susan S.L. et al., 2008)

Intra ocular tablet type implants of indomethacin drug were reported. In this, sodium alginate in combination with HPMC with or without calcium chloride was stidied for drug release pattern and toxicity [28]. 2. In-situ gel system: In situ gel systems are a unique way of drug implantation in ocular drug delivery. Upon instillation as drops into the eye in-situ-forming hydrogel polymers undergo in a sol-gel transition at the site of implantation. They form viscoelastic gel and this provides a response to environmental changes The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems, which upon



instillation as drops into the eye undergo a sol-gel transition in the cul-de-sac. This may result in better ocular availability of the drug [13]. There are various mechanisms of in-situ sol-gel transmission: A. Thermo coupled in-situ conversation B. pH triggered sol-gel transition C. Ionic-complexation A. Thermo coupled in-situ conversation: Temperature dependent sustained drug delivery can be achieved by use of a polymer that changes from sol to gel at the temperature of the eye. Temperature dependent systems include pluronics and tetronics. The poloxamers F127 are poly-ols with thermal gelling properties whose solution viscosity increases when the temperature is raised to the eye temperature (32-34C) from a critical temperature (16C). A recent development is studied of ophthalmic in situ gelling system using thermo reversible gelling polymer, Pluronic F 127 [29]. Another thermo-sensitive injectable hydrogel was recently prepared by grafting semi-telechelic poly(N-isopropylacrylamide) with amino group at hyaluronan [30]. B. pH triggered sol-gel transition: pH triggered systems show sol-gel transformation when the pH is changed to pH 7.4 by the tear fluid. pH triggered systems include- cellulose acetate hydrogen phthalate latex, (pH 5.0 to 7.4 forms sol to gel transformation), Carbopol (0.5% polyacrylic acid) (pH 4.0 to 7.4), Cellulose acetophthlate (CAP) is a polymer with potentially useful property in sustained drug delivery in eye. Since, latex forms free flowing solution at a pH of 4.4 which undergoes coagulation when the pH is raised by 7.4. pH triggered in-situ gelling system are low viscosity polymeric dispersion in water which undergoes spontaneous coagulation and gelation after instillation in conjuctival cul-de-sac [31- 34, 37]. C. Ionic Complexation: Change in electrolyte composition Ion activated system show sol to gel transformation in the presence of the mono or divalent cations (Na+, Ca2+ etc.) typically found in the tear fluids. Ion activated system include Gelrite® (Gomme gellan) and alginates. Gellan gum is an anionic extracellular polysaccharide secreted by Pseudomonas elodea. Gellan gum formulated as aqueous solution, forms clear gels in the presence of the mono or divalent cations. These system shows sol to gel transformation in the presence of ions [35, 36]. Instead of these, another mechanism is seen in in-situ sol-gel transmission, which is referred as “Phase-sensitive

sol-gel transition”.

In-situ gel offers-easy, accurate and reproducible administration of a dose, patient compliance, effective

alternative to conventional dosage form, can easily be instilled in liquid form, but are capable of prolonging the

residence time of the formulation on the surface of the eye ability to release drug in sustained manner, assist

enhancing ocular bioavailability, flexibility in design system with desirable rheological properties and drug

release rate [38].

3. Polymer Films: Polymer Films are the flexible, transparent system for various ocular implants used for ocular region. These are mostly designed as corneal implants, lens implant, sceleral implant or vitreal implant etc. A Film-type scleral implant of indomethacin with gellan gum was prepared by solvent casting method [17]. Another, film type ciprofloxacin Intravitreal matrix system was fabricated for sustained release drug delivery of



drug in entire ocular region [39]. A prosthetic corneal implant and method of manufacture was patented in US for sight accommodation treatment [16]. 4. Pellets: Pellets are the drug-polymer solid formulations used for intraocular implantation. The implantation may be occurring at various region of Eye. It must be ensure that the pallet implants must not interfere with vital visual role of Eye. Pellets are Reservoir or matrix type system and may be used for sustained delivery of active drug in ocular region. A pellet implant of ganciclovir was implanted into the vitreous of rabbit eyes to maintain therapeutic levels of drug for extended periods. These Pellet implant was well tolerated with no toxic effects attributable to the polymers used in the devices in the rabbit eye. They are proved useful in the clinical management of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome [40].

Fig. A polymer pellet implant for Intravitreal

Sustained-Release Ganciclovir [40]. An intravitrial delivery of ciprofloxacin was investigated through Preparation of Drug Reservoir Devices system. In this, free ciprofloxacin was compressed into 1.5mm diameter by 1.0mm pellets and coated with 5% solution of biocompatible poly lactic acid (PLA) [39]. 5. Other types: Some Recent Advantages are reported in ophthalmic implantation system for drug delivery. Some of them have very unique designs as Helical type scleral implant, refillable implant system etc. A Helical Intravitreal Triamcinolone Acetonide (drug) Implant is reported as noval approach to ocular implant system. A 6-Month Study in Rabbits shows the surgical feasibility and safety of a long-term Intravitreal sustained delivery system. Ocular examinations revealed excellent implant tolerability in animal model [9].



Fig. Example of Helical coil Prototype Ocular implant for sustained release [9].

(Source: Paulo A. et al., 2009)

Other Designs of transscleral delivery systems also includes a non-eroding reservoir system allowing for reinjection into the device [40]. Non-eroding metal coil with matrix coating controlling the drug release and fully erodible matrix design [41-43]. Fabrication Techniques of Implants: Various Methods of Implant Casting A. Punching Ocular implants can be fabricated through ‘tablet-compression’ in punching machine under high pressure for small thickness and minimum diameter in different shapes and sizes compatible for implantation. An Intra ocular tablet type implant of sodium alginate in combination with HPMC with or without calcium chloride was formulated [28]. B. Solvent pours casting technique An accepted technique by many researchers in fabrication of ocular implants is Solvent pour casting. The Polymer is dissolved in simulated tear fluid of pH 7.4 or other suitable media to form the drug reservoir by using magnetic stirrer in a beaker to get different concentrations of each polymer along with plasticizer [44]. After complete mixing the drug-Polymer formulations are poured on a ‘mercury surface’ contained in a petri dish (Anumbra). The solvent evaporation rate may be controlled by placing an inverted funnel over the petri dish. The film formation is noted by observing the mercury surface after complete evaporation of the solvent. After drying at room temperature for overnight, the dry film is removed from the mercury surface, stored between sheets of wax paper, and must keep in a desiccator until use. Films of different thickness may be prepared by changing the volume of polymer solution & plasticiser [45]. Elliptical, rod shaped, Disk, Circular rings, Oval, hexagonal, meniscus lens shaped circular flexible body members and other types of adjustable annular ring devices may easily casted as required [46]. C. Polymer Filming Implants can also fabricate through direct polymer filming-technique over aseptic glass plate without mercury-surface. A matrix type Intravitreal ciprofloxacin implant was fabricated for sustained release ocular drug delivery system from the bioerodible polylactic acid (PLA) and the nonerodible polyvinyl alcohol (PVA). Resulting slurries were poured onto a glass plate and dried to form a thin film. Discs were cut from these films using skin biopsy punches [39]. D. Extrusion method: In this oldest technique, preformulated semisolid polymer system is placed in a sound vessel known as metal injection moulding (MIM), with high pressure piston for ‘extrusion’ of implant. Further process is done for shapes & size uniformity, coatings of rate controlling polymer and polishing of implants during fabrication. This is suitable process for industrial production, but violated due to high influence rate in batch to batch uniformity [47].

F. Moulding through Zero gel ultraviolet Method Implants may be synthesized of hydrogel polymer with zero gel method through ultraviolet treatment or thermal curing of hydrophilic monomers and cross-linking agent of low molecular weight like diacrylates. These highly cross linked hydrogels are then machined into appropriate dimensions and hydrated in water at elevated temperature. Upon complete hydration, Polymer system is flash-frozen to temperature below - 40° C,



and then gradually warmed to a temperature of - 20° C to - 10° C and maintains the same temperature in order to generate porous structure via expansion of ice crystals. The frozen and annealed polymer is then quickly thawed to yield the micro-porous implant. Alternatively, the hydrated polymer device can be lyophilized and rehydrated to yield a micro-porous hydrogel Implant base [16].

G. Cross-linking with dissolving method To accommodate the variables during the implant fabrication, implants are fabricated by cross-linking method. There are two different methods in forward steps of cross-linking:

A. Cross-linking by Method I The previously prepared film type implant /patch is immersed in cross-linking solution (like calcium chloride solution) of defined concentration. Then the film type Implant is removed to dry at 40◦C in an oven, and cut into desired size-shape of implants. In an experiment, Cross-linking with calcium chloride, effectively show the potential release of indomethacin drug for extended period of time [17]. B. Cross-linking by Method II A graded volume of crosslinking solution is added to aqueous dispersions of polymer-plasticizer-drug mixture with gentle stirring and cast as dried. Then films are cut into desired implant size and stored in amber-colour glass vials in desiccators until further use. A Gellan based system for scleral implantation was prepared with this method and observed for suitable ophthalmological drug delivery [17].

Reason for surface cross-linking Calcium (Ca2+) is selected as a coordinating cation because of its relatively high gelation inducing ability and safety. In the Gellan based polymer system, cross-linking occurs by Calcium ions (Ca2+) present in Gellan that forms the backbone and provides strength to the network [48]. Time of exposure in cross-linking solution is directly responsible in drug release at site of ocular implantation due to filling of voids [17]. H. Other method In another interesting example, micro-porous hydrogel implant was made by starting with a known monomers or mixture of monomers dissolving in mixture of a low molecular weight polymer as filler which is soluble in said mixture and then polymerising the system. Resulted polymer is then converted into the required device shape (Implant) and extracted with an appropriate solvent to extract out the filled polymer and the result in a matrix hydrated to yield a microporous device ready to charge with respective medicament [16].

The novel interest with cross linking in in-situ gel formulations is subject of preparation by dissolving or dispersion systems with respective buffers, like citro phosphate buffer (pH 5.0) and with considerations of Rheological profile for in-situ gel [29]. Polymers used in Ocular Implant

An appropriate selection of the polymer matrix is necessary in order to develop a successful drug delivery

system. A polymeric system for ocular drug delivery should be selected not only to deliver the active moiety at

desired rate but also should be biocompatible and ocularly acceptable [5]. The polymer system could be non-

degradable or degradable. Non-degradable polymers can be used only if removal of implant is easy after

successful delivery of drug. Biodegradable polymers on the other hand do not require the removal, hence,

preferred for polymer selection in ophthalmic drug delivery. However, in later stage biodegradable polymers



degrades to smaller absorbable molecules, it is important to make sure that the monomers are non-toxic in

nature [49].

An ideal polymer system used for ocular implant must have the following properties:

✓Should be bio-compatible and non-toxic,

✓Should be non reactive with drug as well as system,

✓Should not cause any irritation or inconvenience to the patient,

✓Should facilitate stable and uniform rate and extent of drug release,

✓Should provide drug release in the bi-directional way,

✓Should provide the transmission of ophthalmic fluid through the fabricated system,

✓Should have good adherence property at site of implantation,

✓Should be free from high hydrophilic burst effect,

✓Should release the drug in a controlled as well as sustained release manner and,

✓Should not interfere with the normal vital ocular functions such as vision etc.

Non-biodegradable polymers were first used clinically for intraocular controlled release

of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis and uveitis [25, 50]. The

non-biodegradable polymer device has no initial adverse burst effect of drug, which is

superior to biodegradable types of devices [21].

Biodegradable polymers are promising materials for ophthalmic implants. Bio-degradable polymers provide advantages over non-degradable polymers; which undergo with hydrolysis of chemical bonds following its dissolution at the site and there leave no visual entity [51]. The great advantage in their erosion rate is achieved by modifying their final structure during synthesis by addition of anionic and cationic surfactants or cross-linking products. In the bio adhesive ocular implants, the adhesion of polymer materials is the two-step process: spreading of the bio adhesive material over the biological surface followed by hydration of the polymer and interpenetration of polymer chains into the mucus layer [52]. Poly-saccharides: Poly-saccharides are extremely advantageous compared to synthetic polymers being widely present in living organisms and often being produced by recombinant DNA techniques. Polysaccharides are usually non-toxic, biocompatible and show a number of peculiar physico-chemical properties that make them suitable for different applications in drug delivery systems [53]. Poly-saccharide forms three-dimensional, hydrophilic, polymeric networks with chemical or physical cross-links, capable of imbibing large amounts of water or biological fluids called as Hydrogels [54]. During the corneal prosthesis (i.e. implant within cornea) the desirable material includes various types of hydrogels because they are hydrophilic in nature and have the ability to transmitting fluid through the material [16].



Diffusion through polymer matrices system

fig. A figure illustrating transmission of fluid of ocular region through the hydrogel corneal implant.

Hydrogel implants of polysaccharides do operate to transmit nutrients, medicament and fluids in ocular region

to prevent tissue necroses. The implants made from hydrogel material should preferably a clear, permeably;

microporous with water content greater than 40% to 90% [55]. The microporous hydrogel material can be formed

from at least one, and preferably more, hydrophilic monomer, which is polymerised and cross-linked with at

least one multi- or di-olefinic cross-linking agent. The hydrogels preferably have micropores in the form of

irregular passageways. Such micropores should be in general having a diameter ranging from 50 to 1Å [16].

Lactic-acid and its derivatives:

Polylactide (PLA) and Poly(Lactide-co-Glycolide) (PLGA) are the most commonly used biodegradable and

non-toxic polymers for the application of ocular implants. These polymers have been used in biomedical

applications for more than 20 years. Lactic-acid (LA) based formulations are used to fabricate copolymer films

for implants with biodegradable property and have spherulitic morphology (looks like sphere) in optical

microscopy [56].

In spite of the several apparent advantages of PLA and PLGA based polymers, lactic-acid and derivative based

systems have limitation of high burst effect; thus they are used for initial fast release of drug in the media.

Among the polylactides, DL-PLA, which is co-polymer of D and L-lactide, degrades faster than L-PLA,

presumably due to lesser crystallinity. Similarly, the more hydrophobic end-capped PLGA polymers degrade

faster than the carboxyl-ended PLGA [57].

In a study, the ganciclovir (GCV) release rate from scleral implants was modified by blending poly-(D,L-lactide) of different molecular weights like PLA-70000, PLA-5000 and PLA-130000 and PLA-5000 at various ratios. An increase in the blended amount of PLA-5000 clearly accelerates the ganciclovir release and the onset of the second burst in the late phase of release tended to delay [58]. Gellan Gum: Gellan gum, a novel ophthalmic vehicle, is an anionic exo-polysaccharide produced by the aerobic fermentation of Pseudomonas elodea in batch culture. Gellan undergoes calcium-induced cross-linking to form a three-dimensional network, and this property makes it particularly attractive for the incorporation of biological moieties such as proteins. The Gellan film could be an ideal candidate in the development of protein delivery systems [17]. In-situ gel forming systems of Gelrite® was designed, which upon instillation as drops over cornea undergo a sol-gel transition in the cul-de-sac. It gels in the presence of mono or divalent cations present in the lachrymal fluid [13]. The gel strength of Gellan is weaker at Ca2+ cation concentration of below the stoichiometric equivalence of 0.5 [17].



It is also found that the concentrations of Gellan higher than 1% (w/v) or CaCl2 higher than 1 mM had resulted in gel formation in the solution. Therefore, the concentrations of CaCl2 or Gellan should be low enough to maintain the solution state for casting. A Gellan based film type insulin implant was fabricated. This device was implanted for insulin delivery in diabetic rats [48]. Sodium alginate: Alginate is a well known polysaccharide widely used due to its gelling properties in aqueous solutions. Alginate is extracted from marine brown algae and commercially produced by some bacteria [59, 60]. In-situ gel formation, temperature & pH dependent change or ionic complexation characters of Sodium alginate are great areas of interest for modern researchers. The kinetic of the gel formation is usually very fast and the resulting gel is strong enough to be suitable for biomedical applications in ophthalmology [61, 62]. An interesting pH and temperature dependent drug delivery system has also been observed by mixing methylcellulose (MC) with sodium alginate. At room temperature, the polymeric solutions can be easily mixed and loaded with the drug (18°C), but the obtained system turns into a gel with the increase of temperature upon entering the human body (36 -37°C), due to the thermo-gelling properties of methylcellulose. This property can be utilized for future ocular implant system [63]. Cross- linking of sodium alginate involves the interaction between cations and ‘G-residues’ in sodium alginate, resulting in the formation of an ‘egg-box’ structure. With increasing the concentration of Ca++, dense calcium alginate matrix results in controlled release of drug moiety. Intra ocular implants of sodium alginate in combination with HPMC with calcium chloride were formulated with indomethacin [28]. Hyaluronic acid: Hyaluronic acid is an unsulfated glycosaminoglycane and produced from streptococci [64]. Hyaluronic acid is also present in human connective tissues, where it plays an important role in many biological mechanisms [65]. In contrast to vitreous humour of eye, it is composed of hyaluronic acid, collagen and plasma proteins and the viscosity of the vitreous is provided by this hyaluronic acid component, which has a high affinity to form gel at low concentrations [66, 67]. The remarkable viscoelastic properties of hyaluronic acid and its complete lack of immunogenicity make it an attractive bio material [53]. A useful study of biocompatibility and bio-degradation rate of intravitreal implant were performed with three different hyaluronic acid esters: Hyaff 7, Hyaff 11 and Hyaff 11p75 for the treatment of posterior segment ocular diseases. The intravitreal plugs of both Hyaff 7 and Hyaff 11 undergoes slow dissolution process, respectively and the partial benzyl ester, Hyaff 11p75, is comparatively absorbed soon in vitreal region [24]. Hyaluronic acid and its derivatives are mucoadhesive in nature, capable of retaining the medication in the precorneal area by establishing physicochemical interactions with the mucin layer covering the corneal epithelium and hence, prolong residence time of formulation [68-73]. However, the insertion and removal of intraocular lens implants (IOLs) and surgical instruments found to cause some corneal endothelial cell damage. To prevent this hyaluronic acid as viscoelastic agent has been introduced into the anterior chamber to protect the corneal endothelium, whilst allowing the surgeon to easily insert and remove optical instruments and implants. Now, the viscoelastic agents can be easily prepared from a variety of materials including HPMC, collagen etc. [74]. A study was assessed for several soluble ophthalmic implant of bupivacaine and hyaluronic acid or sodium hyaluronate in terms of complete and long-lasting anaesthesia of the cornea [75]. Xyloglucan: Some of mucoadhesive polymers have found their way in lachrymal substitutes for treatment of dry eye conditions, as capable of retaining the medication in the precorneal area (i.e. precorneal implant) by establishing physicochemical interactions with the mucin layer covering the corneal epithelium a relatively recent discovery [73]. TSP® 0.5 (xyloglucan) is one of the example of these polymer system that may used for



precorneal implant. These formulations presumably owe their improved ocular retention to the presence of a mucoadhesive polymer [72]. The in-situ gelling formulations are more effective than aqueous buffer solutions while the rapid gelation was essential in preventing the loss of drug by drainage from the eye. Eudragit: Eudragit is used in ophthalmic drug delivery system to enhance the bioavailability of drug at the site of action. It exhibits some favourable behaviours, such as no toxicity, positive charge and controlled release profile, this makes it suitable member for ophthalmic application. Eudragit RLPM and RSPM are used as carrier materials in ocular formulation. Eudragit RSPM showes comparatively longer release than Eudragit RLPM in nanosuspensions injectable implant system, with excellent encapsulation efficiency [76].

An ocular implant system was prepared from these inert polymer (Eudragit RS100 and RL100) and successful avoid any inflammation of cornea, iris, and conjunctiva up to 24 h after application [77]. The same conclusion could be drawn from another study in intraocular delivery concerning nanoparticles coated with Eudragit RS100 and RL100, which showed no particular sign of inflammation following 12 consecutive instillations as assessed by the Draize test and slit lamp examination [78-81]. Eudragit RS 100 is successfully reported as rate controlling membrane in controlled release in ophthalmic region and Eudragit RS100, Eudragit RL100 polymers can be used as drug carrier in preparation of ocular implants [46]. The release behaviour of eudragit microparticles was also studied [82]. Eudragit NE 30D and Eudragit L 100 are other forms of Eudragit polymer and May utilised as ‘rate controlling device’ in fabrication of ophthalmic formulations, but subject of ocular compatibility and toxicology study.

Poly Ethylene Glycol (PEG): The exploration of polyethylene glycolated (PEG) materials in biosciences

and pharmaceutics has grown rapidly and also accepted for ophthalmic drug delivery due to its ocular

compatibility. It is available in various molecular weight range 200, 300, 400 etc. Biodegradable Polymers, as

copolymers of polyethylene glycol (PEG) and polylactic acid (PLA) offers new tools to scientists for controlled

release formulations at delivery platforms.

Polyethylene glycol-coated cyanoacrylate nanoparticles, loaded with tamoxifen model drug were used for the

inhibition of intraocular inflammation in a rat model for treatment of autoimmune uveitis. These nanoparticles

as ocular implant induced a significant inhibition in extent of the uveitis in eyes without any detectable ocular

toxicity [83].

It is also used ‘as plasticiser’ in various ocular implants to provide desired flexibility to the implants material [17].

Poly-vinyl alcohol (PVA): Poly-vinyl alcohol (PVA) is non-biodegradable and biocompatible polymer used for sustained release matrix systems and hydrophilic, monolithic reservoir system in ocular drug delivery. PVA was first introduced clinically for intraocular controlled release of ganciclovir for the treatment of cytomegalovirus (CMV) retinitis. This reservoir-type device was composed of drug with coating polymers, polyvinyl alcohol (PVA) and ethylene vinyl acetate (EVA) [25, 50]. Another, ocular implant has also been investigated for long term intravitreal release of cyclosporine A. It bypasses the systemic circulation, avoiding the side effects associated with cyclosporine A, while administering therapeutic doses to eye over an extended period of time. The implant consists of a drug pellet coated with silicone attached to a poly vinyl alcohol (PVA) anchor strut [84, 85]. In another example, Vitreous implantation of PVA-silicone laminated fluocinolone



acetonide- a synthetic corticosteroid, was introduced for constant drug release over a 1 year period [86]. Further studies include a PLA intrascleral implant that was designed to sequester Betamethasone in which PVA is used as binder for scleral implant system [21]. Ethylene vinyl acetate copolymer (EVA): Ethylene vinyl acetate is non-biodegradable polymeric compound. EVA, isa membrane permeable polymer, not only acts as the framework for the implant devices but also regulates the rate of active drug permeation.

Studies on Ethylene vinyl acetate copolymer (EVA) coated intrascleral implant shows the cumulative release of Betamethasone drug from the implant. In study, the implant coated with higher concentrations of EVA solution showed a slower release of drug, hence the rate of drug release is proportional to the thickness of EVA coatings [21].

Hydroxyl propyl methyl cellulose (HPMC) or Hypromellose: HPMC (hypromellose), a nontoxic and non-irritant material, is most widely used as polymer in ophthalmic, topical and oral pharmaceutical formulations. HPMC is water-soluble, film forming polymer; used as an emulsifier, suspending agent, and stabilizing agent in ophthalmics. Depending upon the viscosity grade, 2–20% w/w is used for film-formation and 0.45–1.0% w/w is added as a thickening agent forming a viscous colloidal solution for vitreal implants [87-89]. In open atmosphere, HPMC absorbs moisture from surrounding air. This property makes it hydrophilic in nature. HPMC partially hydrates and forms pseudo gel consistency in system, controlling swelling of implant. Ones the protective gel layer is formed, two rate mechanisms predominate. Firstly, the pseudo gel permits additional water to penetrate in to the implant. Secondly, the outer gel layer fully hydrates and begins to be dissolved [90]. Intra ocular implants of sodium alginate in combination with HPMC are reported for sustained release of indomethacin. Study shows, an increase in concentration of HPMC in the implants causes a significant decrease in the release rate of drug [28]. Stability of the cyclodextrin-Drug complexe successfully increases with addition of HPMC in the formulation [91]. HPMC is also used as ‘viscosity increasing agent’ in in-situ ocular implants with Pluronic F-127 [29]. As viscoelastic agent HPMC plays an important role in ophthalmic surgery for protection of the corneal endothelium during cataract extraction for easy insertation and removal of ophthalmic implants [67, 74]. Chitosan: Chitosan is a cationic polyamine with a high charge density at pH <6.5; and so adheres to negatively charged surfaces and chelates the metal ions. Chitosan is characterised by a complete biocompatibility, non toxic, mucoadhesive and ability to produce solid or semisolid matrix for controlled release [92-94]. Chitosan is naturally bioerodible polymer & commercially produced by chemical treatment of crustacean’s shells such as shrimps and crabs [95]. Recently, chitosan was successfully used with 79% degree of acetylation in ophthalmic formulations and good member for ocular implants [95].

Poloxamer: Poloxamer 407 (P407) and poloxamer 188 (P188) copolymer (ethylene oxide and propylene oxide blocks) shows thermo-reversible properties, which is of the utmost interest in optimising drug formulation (fluid state at room temperature facilitating administration and gel state above sol–gel transition temperature at body temperature promoting prolonged release of pharmacological agents) [97]. Its gel forming consistency makes it good agent for ophthalmic in-situ drug delivery system [98, 99].



Other Polymers suitable for ocular implants: Several other polymers have been reported ocular compatibility and proposed for the formulation of modified release dosage forms and devices in the contrast of ocular implants. To draw up a complete list would be a very difficult task so some of them are Guar gum, Xanthan gum, Carraginan, Carbopol, Pullulan , Dextran, Polysulfone capillary fiber (PCF), Scleroglucan, Methyl cellulose, Ethyl Cellulose, Poly-(ethylene oxide) etc. Polymers show a variability and versatility, associated with their complex structures and physico-chemical characteristics. This provides very wide range of there applicability, and distinct delivery mechanism. Although, mixing of two or more polymers together in respective ratios results in combined polymeric properties and factors in fabrication of novel modified release system of ocular implants. Drug-Cyclodextrin complex polymer systems in ocular implants have great significance, as it is the subject of further researches.

Plasticizers in ophthalmic implants and its Effect: The plasticizers are used in polymeric systems to enhance the effective plasticity and their handling by filling void volumes in polymeric system. In ocular implant plasticizer is necessary to facilitate flexibility and uniform subdivision of implants in desired shape & size [17]. The numbers of examples of plasticizers are discussed by various researchers in the field of ocular implants, enlisted as follows: Glycerol * Propylene glycol * Polyethylene glycol (PEG) 200-400 * Dibutyl phthalate (DBP) [45] It is observed that at limited concentration, the tensile strength is significantly influenced by plasticisers. During the fabrication of films type implants, without glycerol the resultant films are too brittle to process. Because glycerol can hold water through its hydrogen bonding affinity and provides flexibility and mechanical integrity to the implant film [48]. Microbiological Aspects: Sterilization is major aspect for all parenteral (latin: para, enteron, away from alimentary canal) formulation, i.e. free from any viable microbes. Sterilization: The method of exposure to UV/gamma radiation and Ethylene oxide is widely accepted for sterilization of various ocular implants and no microbial growth should observe in formulation during sterility testing by direct inoculation method. When the fabrication of ocular implants is done with anti-microbial drugs, then the formulation must be effective against selected microorganism during in-vitro antimicrobial efficacy-studies. Each side of the implant is exposed to γ-radiation in film-type implant. The ocular implants must be previously sterilized before the in-vivo studies and clinical use. Evaluation Parameters for Ocular Implants:

The ocular implants are evaluated for drug-excipients interaction, physico-chemical characteristics, microbiological and in-vitro & in-vivo drug release studies.



A. Characterization of delivery system

Characterisation must be performed to fulfil the qualitative & quantitative standards of the finished product.

These observations can be utilised for standardisation of batch and batch uniformity.

I. Preformulation Studies: Preformulation studies are carried out in order to find out the Drug-excipients

compatibility. The sample of drug and excipients are intimately mixed, in equal parts and screened by TLC

method or by using FTIR.

To check the quality of the drug and polymer, some quality checks are also performed, such as solubility,

melting point, Spectrophotometric absorption; Loss on drying etc.

X-ray Diffraction Studies: X-ray diffraction patterns of the pure drug and formulations are measured using an X-ray diffractometer with graphite monochromator [45].

II. Characterization of the finished product:

1. Thickness, weight, content uniformity and physical appearance: Calibrated micrometer, Balance,

Spectrophotometric method and optical microscopy may be used respectively. Physical Appearance test are

performed with ocular implants immersed in phosphate buffer pH 7.4 and stored at 37°C for 2 weeks. Then

observe under the optical microscopy.

2. Surface Topography:

Characterization of surface topography may be achieved by scanning electron microscopy (SEM) and

scanning force microscopy (SFM) [45].

Morphological characteristics of medicated and placebo ocular films implants, in the dry state and after

various intervals of dissolution are usually examined by SEM [17].

3. Tensile strength test: It ranges from 2.5 MPa to 53 GPa.

Mechanical properties of films implants are important due to long-term applications. Tensile tests reveal the strength of the three-dimensional network in these films. A small increase in film strength is observed by addition of 0.2 - 0.8% w/v gelatine. Glycerin and CaCl2 had similar effects by cross-linking. Although Gelatine, do not cross-links but forms a semi-interpenetrating network and thus increases the film strength [48].

4. Surface pHs :

The surface pH of the implants ranges from pH 7 to 7.4 indicating that the implants did not have an irritation potential, being identical with the pH of normal ocular fluids [101].

5. Drug Content uniformity test:

The drug concentration in per unit dose is analyzed spectrophotometrically, given elsewhere [102].

6. Percentage moisture absorption and loss:



The water absorption capacity of various film implant may determined at 84% RH. A rectangular piece of

film implant is cut using a glass template, weighed, and put in a glass chamber containing saturated solution

of potassium chloride (84% RH) with the help of a glass rod. After equilibrium is attained, the film is taken

out of chamber and weighed. The water absorption capacity of the film is calculated based on the change in

weight.

7. Viscosity and in-vitro gelling efficiency for in-situ formulation:

In-situ as well as liquid formulations are evaluated for in-vitro gelling efficiency and viscosity in order to

rheological considerations. The in-vitro gelling efficiency may determined by placing a drop of sample in

test-tube containing 2 ml of simulated tear fluid (used for corneal implant system) freshly prepared and

equilibrated at 37°C. The visual assessment of gel formation is carried out simultaneously and the time

required for gelation is noted. The viscosity of the systems is measured using Brookfield viscometer (or other

compatibles) for comparative evaluation [29].

8. Sterility testing:

Sterility testing is performed to assure the sterilization of ocular implants and no microbial growth must be

observed in any ocular implant. Sterility testing is done by direct inoculation method.

9. Stability Studies:

Stability studies are carried out, according to ICH guidelines by storing replicates of ocular implants packed in aluminium foil in humidity chamber, with at 40 ±0.5°C and 75 ±5% RH. Samples are withdrawn at 0, 30, 60, 90 and 180th day and period of implant degradation is checked. Ocular implants are also evaluated for their physical characteristics (viz. thickness, weight, and folding endurance) during stability studies and analyzed for drug content. Samples are stored at 37°C, 65°C and 80°C for further studies [48].

B. In-vitro Drug release studies:

There are various methods reported used in in-vitro release studies of ocular implants by various researchers.

In-vitro drug release studies may performed by number of following methods:

i. Bi-chambered donor receiver compartment model:

This release technique is also referred as ‘Diffusion cell studies’. The implant is placed inside the donor compartment. In order to simulate, 0.7 ml of phosphate buffer pH 7.4 is placed and maintain same level throughout the study in the donor compartment. Semi permeable membrane is used to mimic in-vivo conditions like corneal epithelial barrier. The entire surface of the membrane is in contact with reservoir compartment which contains phosphate buffer pH 7.4 and stirred continuously using a magnetic stirrer [40].

At periodic intervals, defined quantity of sample is withdrawn from the sampling pool and replaced with equal volume of phosphate buffer pH 7.4. The drug content is analyzed by UV–visible spectrophotometer using phosphate buffer pH 7.4 as blank. The release data obtained is fitted into ‘Korsemeyer Peppas and Higuchi diffusion model’ to find the mechanism of release from the ocular implants [103]. Gorle et al., 2009 carried out in-vitro drug release studies using bi-chambered donor receiver compartment model for their ophthalmic formulation by using commercial semi permeable membrane of regenerated cellulose (Sigma Dialysis Membrane) [96].



ii. Dissolution studies by Static method:

The drug release study from the prepared implants is determined using a static dissolution set-up developed.

In this method individually weighed implants are placed in stainless steel mesh holder of dimension 2 x 4 x 6

mm and suspended in amber coloured vials containing phosphate buffer (pH 7.4) and placed in incubation on

shaking water-bath at 37 ± 1°C. At pre-determined time intervals dissolution medium is completely

withdrawn and replaced with pre-warmed buffer to ensure sink conditions. The withdrawn samples are

analyzed for drug content using spectrophotometre or by using HPLC method [17, 28, 58].

In a study, drug release of ciprofloxacin reservoir and matrix type pellet implants was successfully

investigated through Static-method. The entire media was periodically assayed by HPLC and replaced with

fresh, preheated media [39].

iii. Dissolution studies by Continuous flow throw apparatus:

The dissolution cell consists of two circular plates, made up of acrylate. The plates are held together by

means of screws. The bottom plate has a groove, fitted with #80 mesh supporting the implant. An outlet tube

is provided for collecting the eluate. The top plate has a hole for inlet of dissolution medium (phosphate

buffer pH 7.4). The entire setup is connected from the top by a silicone tubing of 1 mm internal diameter to a

peristaltic pump. The flow rate of medium is controlled at 0.8 ml/hr and the eluate is collected in amber

colure vials and analysed spectrophotometrically for drug content [28].

iv. Dissolution studies for in-situ ocular implant formulations:

The in-vitro release patterns of in-situ liquid implants are studied by using modified dissolution test

apparatus due to its rheological consistency [104, 105]. Freshly prepared dissolution media such as simulated

tear fluid (pH 7.4) is used for study. Cellophane membrane, previously soaked overnight in the dissolution

medium at 37 ±1°C, is tied to one end of a specially designed glass cylinder. 2 ml of the formulation is

accurately pipette out into the cylinder and is suspended in dissolution medium maintained at 37 ±1°C in

such a way that the membrane just touched the surface of the receptor medium. The dissolution medium is

magnetically stirred. 10 ml aliquots are withdrawn periodically replacing same with fresh dissolution

medium and is spectrophotometrically analyzed [28].

C. Animal Model Studies (In-vivo studies)

In-vivo ocular pharmacodynamic studies are subjected to perform by various animal models. Approval for use

of animals in the study is mandatory from the animal ethical committee. Number of animal models is used for

ocular drug delivery studies worldwide such as Rabbits, Cats, Monkey, Dog, Goat etc.. Rabbit is most accepted

as an experimental animal because of number of anatomical and physiological ocular similarities and also due

to larger eye-size.

Environmentally controlled (temperature 22 ±1°C, humidity 40–60% RH, light 6:00 a.m.–6:00 p.m.) animal care facilities for 1 week before must be carried out. Animal under observation must be healthy and young. These animals are housed in restraining boxes in experimental duration and fed with standard diet & water as



much as required. Free leg and eye movement is allowed [48]. All animals must be treated according to institutional guidelines on the use of animals in research. Statistical Evaluation: Experimental results are expressed as mean ± standard deviation (SD). The student ‘t’-test is also performed to determine the level of significance. In case of multiple comparisons of groups, analysis of variance (ANOVA) must be performed [17, 106].

Fig. In vivo and in vitro release of betamethasone from a non-biodegradable disc, implanted in intrascleral pocket. In-vivo release tends to be faster than that in-vitro in stable linear pattern [21]. (Source: Okabe et al., 2003).

Establishment of in-vitro and in-vivo correlation:

To assess the effectiveness of the ophthalmic formulations, the optimized formulations are subject to in-vivo studies and stability studies. In-vitro drug release data must be treated accordingly for zero-order, first-order, Korsemeyer Peppas model and Higuchi kinetics to access the mechanism of drug release.

Complications in Implantation of Ocular Implants:

The complications during implantation of various ocular implants lead to poor patient compliance. Vitreous hemorrhage, rhegmatogenous retinal detachment, endophthalmitis, and cystoids macular edema are well known complications reported. These problems should be surmounted, as postoperative complications it may interfere with visual acuity loss despite treatment [4]. Some other complications are reported by various researchers in different routes of ocular implantation: [101]

• Cataract formation • Retinal detachment • Endopthalmitis • Sometimes ‘general anaesthesia’ is achieved during surgical implantation. • Chance of ocular infection in surgical implantation. • Sometimes, poor drug -penetration into ocular tissues. • • Drug release, if not well modulated, may result in burst effect with high release in short periods. • Low drug loading and poor physico-chemical stability in non-erodible ocular implants • Displacement of device due to breaking of device in the contrast of solid implant like scleral plug or pellet. • Visual disturbances



Over to this, an expert hand can minimise the risk associated with these surgical implantation.

Discussion In the area of ocular administration important efforts concern the conception & design of new Bioerodible or non-Bioerodible implantable system to various parts of eye to prolong the residence time. The uses of implants which are solid devices to be placed sclerally or inside the corneal region by minor surgery represent possibilities to achieve increased residence time. If the drug kinetics can be controlled, target tissue concentration of drug can be maintained in the therapeutically appropriate range; and harmful side effects associated with intracorneal & intravenous administration can be reduced. Continuous long term administration can eliminates the discomfort associated with multiple dosing and improve patient compliance. The potential advantages in light of disadvantage must be viewed if it does not biodegradable, the device may

require surgical removal. The implant polymer must be biocompatible, carrying no tissue irritation and if it is

biodegradable, its breakdown product must be non-toxic. The device must be adequately design to eliminate

possible dumping of the dose.

Conclusion

Ocular drug delivery with implants had a profound impact in clinical ophthalmology, especially in the management of retinal diseases that can lead to blindness. Ocular implants have been engineered to avoid the barriers that often impede the delivery of drug via traditional methods. Matrix implants, with drug release generally lasting less than three months, are being investigated to treat acute eye diseases, while reservoir implants, with drug release lasting up to five years, are used for chronic eye diseases. The investigation and clinical use of ocular drug implants requires a multidisciplinary approach including biomedical, materials, and chemical engineers interacting with ophthalmologists. This team approach will facilitate the development of ocular implants with prolonged residence time for drug release, thus providing more treatment options to reduce the severity of sight-threatening ocular diseases.

Acknowledgement We thank the patients who have participated in the clinical trials reviewed in this article, our many postdoctoral and student collaborators, who have conducted laboratory work on ophthalmic implant studies over the past decade, and Dr. SL Harikumar, Chandan Kashyap and Amanpreet Kaur for help with the manuscript.



References

1. Pundit J.K., Sing S., Muthu M.S., Annual Indian academy of neurology, 2006, 9, 207-216.

2. Wnek G.E., Bowlin G.L., Encyclopaedia of biomaterials and biomedical engineering, London 1996, 3, 1981-1996.

3. Mitra A.K., Ophthalmic Drug Delivery Systems, New York, 2003.

4. Yasukawa T., Yuichiro O., Eiji S., Yasuhiko T., Hideya K., Adv. Drug Del. Rev., 2005, 57, 2033–2046.

5. Kamath K.R. and Park K., Adv. Drug Del. Rev., 1993, 11, 59–84. 6. Chien Y.W., Ocular drug delivery systems: novel drug delivery systems, New York, 1992, 2, 269-

270.

7. Saettone M.F., Pharmatech Business Briefing, 2002; 167-171. 8. Bochot A., Couvreur P., Fattal E., Prog. Retin. Eye Res., 2000, 19, 31–147. 9. Paulo A., Mello F., Dilek G., Nathan R. F., Beeley, Eugene, Signe R., Ophthalmic Surgery Lasers & Imaging,

2009, 40, 160-168. 10. Thomas Y., Abbot F.C., Martin B.W., Ocular Therapeutics: Eye On New Discoveries, New York,

2008, 1, 16. 11. Walter L. Z. and Timothy R.S., Ophthalmic Drug Therapy – Challenges And Advances In Front-Of-

The-Eye Delivery, mystic pharmaceuticals, Inc., 2007, 44-45. 12. Susan S.L., Peng Y., Michael R. R., Encyclopedia of Biomaterials and Biomedical engineering, New

York, 2008,1, 1981-1995.

13. Balasubramaniam J., Kant S. and Pandit J.K., Acta Pharm. 2003, 53, 251-261. 14. Kristopher A., Optometry, 2004, 75, 6, 370-371. 15. Robert Day, Trans Am Ophthalmol Soc., 1957, 55, 455–475. 16. Nigam A., Canyon T., Calif, Corneal Implant and method of manufacture, U.S. Patent 6102946,

2000.

17. Balasubramaniam J., Kumar M.T., Pandit J.K. and Kant S., Drug. Deliv., 2004, 11, 371-379. 18. Kato A., Kimura H., Okabe K., Okabe J., Kunou, Ogura, Invest. Ophthalmol. Visual Sci., 2004, 45,

238–244. 19. Kim H., Robinson M.R., Lizak M.J., Tansey G., Lutz R.J., Invest. Ophthalmol. Visual Sci., 2004, 45,

2722–2731. 20. Sakurai E., Nozaki M., Okabe K., Kunou N., Kimura H., Ogura Y., Invest. Ophthalmol. Visual Sci.,

2003, 44, 4845–4852. 21. Okabe K., Kimura H., Okabe J., Kato A., Kunou N., Ogura Y., Invest. Ophthalmol. Visual Sci.,

2003, 44, 6, 2702–2707. 22. Geroski D.H., Edelhauser H.F., Invest Ophthalmol Vis Sci., 2000, 41, 961-964. 23. Rahimy M.H., Peyman G.A., Chin S.Y., Golshani R., Aras C., Borhani H., Thompson H., Journal of

Drug Targeting, 1994, 2, 289-298. 24. Teresio A., Filippo M., Francesco C., Claudio B., Melina, Luigi A., Carmelo F., Alfredo R.,

Biomaterials, 2001, 22, 195-200.

25. Sanborn G.E., Anand, R., Torti R.E., Nightingale S.D., Stanley X., Yates B., Ashton P and Smith T.J., Arch. Ophthalmol., 1992,110, 188-195.

26. Beeley N.R., Stewart J.M., Tano R., Lawin L.R., Chappa R.A., Qiu G., Anderson A.B., Varner S.E., J. Biomed. Mater. Res., 2006, 76 A, 690–698.

27. Gary E., Wnek, G., Bowlin l., Encyclopedia of Biomaterials and Biomedical engineering, vol. 1, Informa Healthcare USA, 2008.

28. Balasubramanium J., Srinath A, Pandit J.K., Ind. J of Pharm Sci., 2008, 70, 216-221.



29. Shastri D.H., Patel L.D., Parikh R.K., Journal of young pharm., 2010; 2(2): 116-120. 30. Dong I.H., Sang B.L., Moo S.C., Young M.L., Macromolecular Research, 2006, 14, 1, 87-93. 31. Basavaraj K. Nanjwade, Manjappa A., Murthy R.S, Asian Journal of Pharmaceutical Sciences,

2009, 4, 189-199. 32. Manjappa A.S., Basavaraj K. Nanjwade F., Manvi R.S., Murthy R., Drug Development Research,

2009, 70, 417–424.

33. Gurny R., Pharm. Acta Helv, 1981, 56, 130–132. 34. Gurny R., Boye T., Ibrahim H., J. Contr. Rel., 1985, 2, 353–361. 35. Rozier A., Manuel C., Groove J., Plazonet B., Int. J. Pharm., 1989, 57, 163–168. 36. Sanzgiri Y. D., Maschi S., Crescenzi V., Calligaro L., Topp E. M., Stella V. J., J. Contr. Rel., 1993,

26, 195–201. 37. Nittur J.R., Kunchu K., Gounder T., Mani T., Int J of Pharm Sci Review and Research, 2011, 7, 08-

14. 38. Rathor K.S., Nema R.K., Sisodia S.S., Rathor D.S., in-situ gel forming ocular drug delivery, national

seminar, Rajasthan collage of pharmacy, jaipur, Augast 2009. 39. Hainsworth D. P., Conklin J.D., Bierly J.R., Doreen A., Paul A., Journal of ocular pharmacology

and therapeutics,1996, 12, 183-191. 40. Thomas J., Pearson A., Blandford D.L., Brown J.D., Kenneth A. et al., Arch ophthalmol, 1992, 110,

255-258. 41. Weiner A., Sinnett K., Johnson S., Tack for intraocular drug delivery and method for inserting and

removing the same, US Patent 5466233, 1995. 42. Varner S.E., Barnes A.C., DeJuan E.,Humayun M., Shelley T., Devices for intraocular drug delivery.

US Patent 6719750, 2004. 43. Ogura Y., Ikada Y., Biodegradable scleral plug, US Patent 5707643, 1998. 44. Sultana Y., Aqil M., Ali A., Acta Pharm., 2005, 55, 305-314.

45. Rao P.R., Ramakrishna S., Diwan P.V., Pharm Dev Technol, 2000, 5: 465-472. 46. Tanwar Y.S., Patel D., Sisodia S.S., DARU, 2007, 15 (3), 139-145.

47. Shiah J.G., Bhagat R., Blanda W.M., Nivaggioli T., Peng L., Chou D., Weber D., ocular implant made by a double extrusion process, US Patent 20080286336, 2008.

48. Jing Li, Kamath K., Dwivedi C., Journal of Biomaterials Applications, 2001, 15, 321-343. 49. Lipinsky C., American Association of Pharmaceutical Sciences, Annual Meeting 1998. 50. Musch D.C., Martin D.F., Gordon J.F., Davis M.D., Kuppermann B.D., N. Engl. J. Med., 1997, 335,

83–90. 51. Grass G.M., Cobby J., Makoid M.C., J Pharm Sci., 1984, 73, 618-621.

52. Mathiowitz E., Chickering D., Lehr C.M., Bioadhesive drug delivery systems. Fundamentals, novel approaches and development. New York, 1999.

53. Tommasina C., Pietro M., Carlotta M., Franco A., Journal of Controlled Release, 2007, 119, 5–24.

54. Peppas N.A., Bures P., Leobandung W., Ichikawa H., Eur. J. Pharm. Biopharm., 2000, 50, 27–46. 55. Kim S.W., Bae Y.H., Okano T., Pharm Res., 1992, 9, 283-290. 56. Yasukatsu M., Atsuyoshi N., Ioannis A., Norioki K., Kazuko H., Noboru Y., Seiichi A., Polymer

Journal, 2000, 32, 307-15.

57. Shive M.S., Anderson J.M., Adv. Drug Del. Rev., 1997, 28, 5-24. 58. Noriyuki K., Yuichiro O., Tsutomu Y., Hideya K., Hideki M., Yoshihito H., Yoshito I., Journal of

Controlled Release, 2000, 68, 263–271. 59. Donati I., Holtan S., Morch Y.A., Borgogna M., Dentini M., Skjak G., Biomacromolecules, 2005, 6,

1031–1040. 60. Hartmann M., Dentini M., Draget K.I., Skjak B., Polym., 2006, 63, 257–262. 61. Draget K.I., Smidsrod O., Skjak B., Biopolymers, 2002, 6, 215–244. 62. Rehm B., Biopolymers, 2002, 5, 179–212.



63. Liang H.F., Hong M.H., Ho R.M., Chung C.K., Lin Y.H., Chen C.H., Sung H.W., Biomacromolecules, 2004, 5, 1917–1925.

64. Prehm P., Biopolymers, 2002, 5, 379–406. 65. Morra M., Biomacromolecules, 2005, 6, 1205–1223. 66. Goa K.L., Beneld P., Drugs, 1994, 47, 536-66. 67. Andrew W.L., Richard G.A., Stephen P.D., Biomaterials, 2001, 22, 769-785. 68. Robinson J.R., Mucoadhesive ocular drug delivery systems, Germany, 1990. 69. Zimmer A.K., Chetoni P., Saettone M.F., Zerbe H., Kreuter J., J. Control. Release, 1995, 33, 31–46. 70. Kaur I.P., Smitha R., Drug Dev. Ind. Pharm., 2002, 28, 353–369. 71. Kaur I.P., Kanwar M., Drug Dev. Ind. Pharm., 2002, 28, 473—493. 72. Mark A.B., Recent Patents on Drug Delivery & Formulation, 2009, 3 (2), 229-265. 73. Herrero V.R., Fernandez C.A., Frutos G., Cadorniga R., J Ocul Pharmacol Ther., 2000, 16, 419-428. 74. Liesegang T.J., Surv Ophthalmol., 1990, 34(4), 268-293. 75. Isabelle M., Stephane M., Irene J., Jacqueline O., Catherine T., Guy S., Yves T., Robert C., Said E.l.,

Alain G., Jean F., Bergmann, British Journal of Clinical Pharmacology, 2004, 59(2), 220–226. 76. Khopade A.J., Jain N.K., Pharmazie., 1995, 50, 812-14. 77. Pignatello R., Bucolo C., Ferrara P., Maltese A., Puleo A., Puglisi G., Eur. J. Pharm. Sci., 2002, 16,

53–61. 78. Pignatello R., Ferro M., Puglisi G., AAPS Pharm Sci Tech., 2002, 3(2), 35–45. 79. Pignatello R., Bucolo C., Spedalieri G., Maltese A., Puglisi G., Biomaterials., 2002, 23, 3247-3255. 80. Pignatello R., Bucolo C., Puglisi G., J Pharm Sci., 2002, 91, 2636-2641. 81. Bucolo C., Maltese A., Maugeri F., Busa B., Puglisi G., Pignatello R., J. Pharm. Pharmacol., 2004,

56, 841-846. 82. Duarte A.R., Roy C., Vega-Gonzalez A., Duarte C.M., Subra P., Int J

Pharm., 2007, 332,132-139. 83. Kozak Y., Andrieux K., Villarroya H., Klein C., Thillaye G., Naud M.C., Garcia E., Couvreur P.,

Eur. J. Immunol., 2004, 34, 3702–3712. 84. Pearson A.P., Jaffe G.F., Martin D.F., Arch Ophthalmol., 1996, 114, 311-317. 85. BenEzra D., Maftzir G., Courten C., Br. J Ophthalmol, 1990, 74, 350-352. 86. Jaffe G.J., Yang C.H., Guo H., Denny J.P., Lima C., Ashton P., Invest. Ophthalmol.Visual Sci.,

2000, 41, 3569–3575. 87. Needleman I.G., Smales F.C., Biomaterials, 1995, 15, 617–624. 88. Patel D., Smith A.W., Grist N., Barnett P., Smart J.D., J Control Release, 1999, 61, 175–183. 89. Woodley J., Clin Pharmacokinet, 2001, 40, 77–84. 90. Majumdar S., Balasubramaniam J., Barat R., Pandit J.K., Indian drugs, 2001, 38, 240-247. 91. Loftsson T., Stefansson E., Frioriksdottir H., Kristinsson J.K., Proc Int Symp Control Rel Bioact

Mater., 1996, 23, 453–454. 92. Miyazaki S., Nakayama A., Oda M., Takada M., Attwood D., Biol Pharm Bull., 1994, 17, 745–747. 93. Giunchedi P., Juliano C., Gavini E., Cossu M., Sorrenti M., Eur J Pharm Biopharm., 2002, 53, 233–

239. 94. Fini A., Orienti I., Am J Drug Deliv., 2003, 1, 43–59. 95. Gebelein C.G., Dunn R.L., Progress in Biomedical Polymers. New York, 1990. 96. Gorle A.P. and Gattani S.G., Chem. pharm. bull., 2009, 57(9), 914—919. 97. Gilles D., Jean L.G., Florence A., Jean C.C., Pharmaceutical Research, 2006, 23(12), 2709-2728. 98. Cao F., Zhang X., Ping Q., Drug Deliv, 2010, 17(7), 500-507.

99. Kim E.Y., Gao Z.G., Park J.S., Li H., Han K., Int J Pharm., 2002, 233, 159-167. 100. Castle J.E., Zhdan P.A., Journal of Physics D: Applied Physics, 1997, 30, 722. 101. Thilek K.M., Pandit J.K., Balasubramaniam J., J Pharm Pharmaceutical Sci, 2001, 4(3), 248-254. 102. Rojas F.S., Ojeda C.B., Analytica Chimica Acta, 2009, 635, 22-44. 103. Kaur I.P., Singh M., Kanwas M., Int. J. Pharm., 2000, 199, 119—127.

http://www.springerlink.com/content/?Author=Gilles+Dumortier

http://www.springerlink.com/content/?Author=Jean+Louis+Grossiord

http://www.springerlink.com/content/?Author=Florence+Agnely

http://www.springerlink.com/content/?Author=Jean+Claude+Chaumeil

http://www.springerlink.com/content/0724-8741/



104. Tabbara K.F., Arch Ophthalmol., 2001,119, 338-42. 105. Lin H.R., Sung K.C., Journal of Control Release, 2000, 69, 379-88. 106. Freund R.J., Littell R.C., Spector P.C., SAS System for Linear Models, SAS Institute Inc., Cary,

North Carolina, USA, 1986.

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