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Polymeric Systems for Ocular Inserts

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Abstract

Polymeric drug delivery to the ocular tissue has received increasing attention in the past decade. Obvious benefits of ocular polymeric drug delivery include; effective drug delivery, enhanced contact time of drug in cul-de-sac and sustained drug action. The advances in ocular drug delivery technology depend upon judicious and careful selection of polymers or their combinations, which affects release rate, mechanism and pharmacotherapy. The objective of this article is to review the different polymers, the rationale behind their use, modes of drug release and their future requirements for optimum ocular drug delivery.  This review focuses on recent literature regarding solid dosage forms, with special attention to various polymer systems used in its fabrication. Inserts made of various cellulose derivatives, polyvinyl alcohol, acrylic acid, hyluronic acid and many other polymer candidates show an interesting potential for future applications in the treatment of ocular diseases.

Key Words & Pharases: controlled drug delivery, polymer, ocuserts

Abbreviations:

CAP, cellulose acetate hydrogen phthalate; EC, ethylcellulose; HA, hyaluronic acid; HPC, hydroxypropylcellulose; HPMC, hydroxypropylmethylcellulose; IOP, intraocular pressure; MC, methylcellulose; NaCMC,sodium carboxymethylcellulose;; PAA, poly(acrylic acid); PEG, poly(ethylene glycol); PEO, poly(ethylene oxide); PLA, poly(d,l-lactic acid); PLGA, poly(d,l-lactide-co-glycolide); PVA, poly(vinyl alcohol); PVP, povidone;

Introduction

The renaissance of research activity in the field of polymer science is a direct result of importance of polymers in pharmaceutical research. Polymer research tremendously support development of new drug delivery systems. A polymer, natural or synthetic is a substance that is combined with a drug or other active agent to release drug in a predesigned manner 1,2 . The basic objective of controlled drug release is to achieve more effective therapies by eliminating the potential for both under- and overdosing. Other advantages are the maintenance of drug concentration within a desired range, fewer administrations, optimal drug use and increased patient compliance3.

Among anatomical locations, eye is one of the important sites that has been treated and studied for the optimum drug delivery by controlled drug delivery devices. Conventional dosage forms such as solutions, suspensions, gels and ointments are used but face incompetence due to rapid drug drainage from site of application and different physiological factors of the eye4,5. Polymeric inserts and discs have been developed to overcome such difficulties. Inserts allow for accurate dosing, reduced systemic absorption and better patient compliance resulting from reduced frequency of administration and lower incidence of systemic side effects. Moreover, inserts are least affected by nasolacrimal drainage and tear flow thus provide reliable drug release and longer residence in cul-de-sac6

Rationale of Polymer Application in Dosage Forms

The goal of controlled-release systems is to deliver a drug over a long period of time yielding high drug levels at the target tissue. Drug concentration of traditional ocular dosage forms follows the typical “peak and trough” profile4. In controlled drug delivery systems, drug level in the blood follow a “constant” profiles between the maximum and minimum for an extended period of time. Depending on the formulation and the application, this duration may vary from 24 hours to 1 month to 5 years (in case of certain implants). In recent years, controlled drug delivery formulations and the polymers used in these systems has turned more sophisticated, with the ability to do more than the simple extension of the effective release period of a drug. For example, current controlled-release systems can respond to changes in the biological environment and deliver or cease to deliver the drugs as per these changes. In addition, technologies like iontophoresis and electroporation have been integrated with polymer system with the objective to direct a formulation to specific cell, tissue, or site of action. While much of this work is still in initial stages, emerging technologies offer endless possibilities7,8.

Pre-requisite for the Polymers as an Ingredient of Ocular Formulation

Polymers were originally intended for non-biological uses and selected because of their desirable physical properties2, 9 . Other desired properties of a material to be used as a polymer are chemical inertness, absence of leachable impurities, appropriate physical structure with minimal undesired aging and readily processable material. Polymeric devices need to be biocompatible, inert, non-irritant to ocular tissues, mechanically strong, comfortable to the patient, capable of achieving high drug loading, safe from accidental release, simple to administer and remove and easy to fabricate and sterilize2,10.

Drug Delivery Modules by Polymeric Devices 

There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release system11. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale (through pores in the polymer matrix) or on a molecular level (by passing between polymer chains). When a polymer and an active agent are mixed to form a homogeneous system, it is referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release11,12,13. For the reservoir systems, the drug delivery rate can remain fairly constant. In this design, a reservoir—whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix is surrounded by a film or membrane of a rate-controlling material. It is the structure of the polymer layer surrounding the reservoir that effectively limits the release of the drug. Since, this polymer coating is essentially uniform and of a nonchanging thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system14,15.

Recently some drug delivery systems have been developed in which only one side of the device deliver the drug16. All of the previously described systems are based on polymers that do not change their chemical structure beyond what occurs during swelling. However, a great deal of attention and research effort has been concentrated on biodegradable polymers. These materials degrade within the body as a result of natural biological processes, eliminating the need of removal from drug delivery system after release of the active agent17. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable and progressively smaller compounds. In some cases like polylactides, polyglycolides and their copolymers, the polymers will eventually break down to lactic acid and glycolic acid, enter the Kreb's cycle, and further broken down into carbon dioxide and water which is excreted through normal processes. Degradation may take place through bulk hydrolysis, in which the polymer degrades in a fairly uniform manner throughout the matrix18. The present work comprehends the various polymer systems studied for drug delivery through ocular inserts and their relevant outcomes for improving poor ocular bioavailability.

Introduction to Ocular Insert

Films, erodible and non-erodible inserts, rods and shields are the most logical delivery systems aimed at remaining for a long period of time in the front of the eye. These polymeric delivery systems sustain and control drug release and thus avoid pulsed entry characterized by a transient overdose, followed by a relative short period of acceptable dosing, which is in turn followed by a prolonged period of under dosing 19,20. From a therapeutical point of view, inserts have been a success in the improvement of accurate dosing, and drug bioavailability and by the reduction of systemic absorption, and consequently side effects. However, the inserts are not well tolerated or accepted by patients, due to difficulties encountered in the application, psychological factors, and possible interference with vision21, 22.

Inserts were developed more than 30 years ago to treat the symptoms of dry eyes. Inserts dissolve and/or erode on contact with the ocular surface and therefore need to be used in addition with other artificial tears to initiate the dissolving process. Although the sustained release effect is very pronounced, insert use is severely diminished by the high cost, as well as the difficulty in handling inserts in elderly people, and intense foreign body sensation. Considering the various mucoadhesion mechanisms, hydration or degree of swelling of the polymers involved play an important role .23 The contact time between the dosage form and the cul-de-sac determines the extent of swelling and interpenetration of the polymer chains. The swelling time is important for the assessment of the adhesiveness. Decreasing the swelling time results in an improvement of the interpenetration phenomena. During the last decade, notwithstanding the drawbacks encountered, and the low commercial success rate of inserts, but convinced about the therapeutical advantages offered by solid ocular dosage forms, many research groups directed their efforts to the development of better physiologically adapted and properly engineered devices with precise controlled drug release and bio/mucoadhesive properties.

Polymers Systems in Ocular Inserts

Polymers used in ocular inserts can be of natural, synthetic or semi synthetic in nature. Further, they can be either water soluble polymers with linear chains or water insoluble polymers joined by cross linking agents. Most commonly used polymer groups include nonionic polymer such as hydroxypropylmethylcellulose (HPMC); polycationics such as chitosan, DEAE-dextran and polyanionics like polyacrylic acid (PAA) derivatives e.g. carbopols, polycarbophils, carboxymethylcellulose24.

Earlier sustained release ocular dosage form includes lamellae or disks of glycerinated gelatin and sterile drug impregnated paper strip. The aqueous tear fluids dissolve the lamella and the drug is released for absorption25. The first controlled release topical dosage form OCUSERT(R) PILO was marketed in 1975 in the United States by Alza Corporation. A resrvoir containing pilocarpine and alginic acid is surrounded by hydrophobic ethylene/vinyl acetate copolymer membrane that controls the diffusion of pilocarpine from insert into the eye. The membrane may contain di(2-ethylhexy) phthalate to increases rate of diffusion. The pilocarpine offers a number of advantages over drop therapy for the glaucoma patient. It exposes a patient to only one-fourth to one-eighth the amount of pilocarpine as compared to drop therapy. This reduces local side effects and toxicity with continuous control of intraocular pressure that can even rise after using four times a day25.

Cellulose polymers

Cellulosic polymers such as methyl cellulose; hydroxyethylcellulose (HEC); hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose(HPC) were introduced as viscolizers into artificial tear preparations over 40 years ago to retard canalicular drainage and improve contact time26. All cellulose-ethers impart viscosity to the solution, have wetting properties and increase the contact time by virtue of film forming properties.

Ciprofloxacin hydrochloride ocuserts using HPMC and ethyl cellulose, eudragit and microcrystalline cellulose have been prepared. Drug release was found to be better in terms of extent and amount27.  In case of tilisolol inserts, release of tilisolol from HPM was not affected by drug load but by amount of HPM. Controlled release has been observed with various beta-blockers from HPM inserts with improved ocular bioavailability and reduced toxicity and dosing frequency28. Soluble ocular inserts of ciprofloxacin hydrochloride were prepared with the aim of achieving once a day administration Drug reservoir was prepared using natural hydrophilic polymer viz. gelatin while rate-controlling membrane was prepared using hydrophobic ethyl cellulose. Authors conclude that the formulation has achieved target of present study such as increase residence time, prolong drug release, reduction in frequency of administration, and, thus may improve the patient compliance29. Diclofenac sodium inserts using hydroxypropylmethylcellulose, methyl cellulose, Polyvinylpyrrolidine in various proportions were formulated using a semi-permeable membrane and were observed to show the drug release for extended period of time30. Zero order release has been obtained successfully for once in a day in formulations of  Chloramphenicol ocuserts with HPMC, EC, Eudragit RL100 at various concentrations in vitro, in vivo studies31. Ciprofloxacin hydrochloride ocuserts based HPMC, MC and PVP in various proportions and combinations with ethyl cellulose as rate controlling membrane shows a good correlation and was found to extend the period of drug release up to 24 hrs during in vitro and in vivo studies32. HPC, HPMC, PVP and PVA were also used in different ratios to prepare the ocular films of pefloxacin mesylate with the objective to reduce the frequency of drug administration, patient compliance, controlled drug release and greater therapeutic efficacy ocular infections such as conjunctivitis, keratitis, kerato-conjunctivitis and corneal ulcers33. Various water soluble cellulose derivatives along with  polyvinyl alcohol were evaluated in preparing inserts by film casting and compression moulding. The release from these inserts was controlled by a diffusion mechanism. The release of indomethacin can be modified by using polymers with different solubility and viscosity grade, and by changing the blending ratio and the preparation method. Inserts made by compression moulding exhibit higher release rates.34 A lyophilisate based on hydroxypropylmethylcellulose (Methocel E50) deposited on a flexible poly(tetrafluoroethylene) carrier strip was developed to  measure the bioavailability of fluorescein after deposition of the lyophylisate in the cul-de-sac. Upon contact with the conjunctiva, the lyophilisate hydrated rapidly by the tear fluid. Compared to conventional eye drops, this new dosage form results in significantly higher cornea and aqueous humour concentrations for up to 7 h after application. No discomfort, good tolerability and excellent safety were reported .35

Polyvinyl Alcohol (PVA); alginic acid and derivatives

PVA was introduced into ophthalmic preparations in early 1960’s and reported to have a superior corneal contact time as a newtonian polymer solution. PVA lowers the surface tension of water reducing interfacial tension at an oil/water interface and enhance tear film stability. This film-forming property together with ease of sterlisation, compatibility with a range of ophthalmic drugs and an apparent lack of epithelial toxicity lead to use of PVA as a drug delivery vehicle and artificial tear preparation36. Polyvinylalcohol (PVA) has been used as a carrier to formulate polymeric inserts of pilocarpine nitrate and were found to enhance bio-availability in comparison to solutions37. Gamma scintigraphic studies shown increased precorneal residence time with PVA matrix upto 7 – 13 minutes in humans38. Indomethacin ophthalmic inserts with different types of polyvinylalcohols were formulated. The effect of physical reinforcement by heating and freeze thawing on drug release was studied using flow-through apparatus and modified Keshary–Chien cell. The study revealed that drug release was inversely proportional to low molecular weight PVA whereas the freeze thawing successfully retarded the drug release39. Cromolyn sodium ocular films were prepared by solvent casting technique using polyvinyl alcohol and sodium alginate with glycerin and polyethylene glycol 400 as plasticizers. The drug release pattern for all the formulation followed the zero order kinetics and non-fickian in nature. It was also concluded that sodium alginate and poly vinyl alcohol are good film forming agents and in the presence of plasticizer (PEG 400) they are promising controlled release ocular delivery systems for cromolyn sodium40. Ultrathin multicomposite capsular systems were selected to develop a sustained bioadhesive drug delivery system for delivery of Ciprofloxacin Hydrochloride in Cul-de-Sac for sustained and effective antimicrobial chemotherapy. The  colloidal calcium phosphate core and gluateraldehyde fixed RBCs were used as core on which alginate (negatively charged), polyallylamine hydrochloride (positively charged) and polyelectrolyte coating was deposited alternatively upto 10th layer. Based on corneal retention studies and tear drug concentration, the capsules can be considered for suitable and safe use for sustained ocular delivery of drugs41. In another work, sodium alginate as the gelling agent had been used to fabricate ciprofloxacin hydrochloride ophthalmic delivery system. The formulations were therapeutically efficacious and provided sustained release of the drug over an 8 hr period in vitro42.

Hyaluronic acid (HA); Polyacrylic Derivative (Bioadhesive- Mucoadhesive polymers)

Hyaluronic acid is a high molecular weight biological polymer consisting of linear polysaccharides present in the extracellular matrix. It is a nonimmunogenic glycosaminoglycan having several uses in ophthalmic therapy such as protecting corneal endothelial cells during intraocular surgery, replacing vitreous humor by acting as a tear substitute in the treatment of dry eye and increasing the precorneal residence time of various drugs21.

Hyaluronic acid benzyl ester films were studied for ocular drug delivery of predinisolone. Degree of esterification showed influence on drug release. Most hydrophilic polymers (with lowest degree of esterification) have shown fastest drug release and vice versa in in vivo studies performed in rabbits. Results showed sustained delivery of predinisolone with the use of hyaluronic acid ester43. Polyacrylic acid or Carbopol resins are acrylic acids based polymers which are available in the varying range of molecular weights which may be linear, branched or cross- linked. Carbopol 934P is a lightly cross-linked with molecular weight of approximately 3,000,000 Da. It is the only polymer used in pharmaceutical industry which is readily soluble in water. Many workers suggest that polyacrylic acid is one of the most psedoplastic polymers with bioadhesive properties44,45. Bioadhesive ophthalmic drug inserts for prolonged release of gentamicin sulphate were prepared using hydroxypropylcellulose, ethylcellulose and carbomer. Formulations prepared were in the form of solid dispersions. Coating of GS/EC granules with aqueous dispersion of celluloseacetatephthalate (CAP). The authors concluded that low irritation level and long efficacy time obtained with inserts containing GS/CAP solid dispersion make CAP an interesting candidate for the derivatization of hydro soluble compounds that need to be released at slow rate in the eye46. Monoesters of poly (vinyl methyl ether maleic anhydride) matrix containing timolol were prepared. The dissolution of these polymers and drug release were highly dependent on pH of the polymer surface. Here the effect of disodium phosphate with or without drug were studied. In vivo release and ocular and systemic absorption studies were compared with unbuffered matrices. Disodium phosphate with or without methaoxedrine at least doubled the concentration ratio of iris–cilliary body to plasma. The best cilliary-iris body/plasma concentration were achieved with buffered matrices containing methaoxedrine. Conjuctival vasoconstriction by methaoxedrine improves the ocular to systemic concentration ratio of timolol several folds. Compared to eyedrops, timolol administration in inserts reduced the systemic beta blocking activity significantly47. In vitro and in vivo evaluation of betoxalol hydrochloride  in ophthalmic dosage forms were carried out. An attempt was made to prepare gels and inserts of the drug. Carbopol – 940 was used to prepare gel whereas ethylcelllose and eudragit were used to prepare inserts. These dosage forms were evaluated for drug content uniformity and in vitro drug release study48. An  investigation of  the use of a polymer mixture containing Carbopol 974P and drum dried waxy maize starch to obtain prolonged drug release to the anterior eye segment was carried out. Two dosage forms with the composition were compared: a hydrated polymer dispersion and a minitablet. It was concluded that the acceptability of the minitablet is comparable to that of the polymer dispersion. Prolonging the release of Na-fluorescein to the anterior eye segment is only feasible with the dry preparation49. Chetoni et al. prepared rod-shaped mucoadhesive inserts from appropriate blendings of silicone elastomer, oxytetracycline hydrochloride and sodium chloride as release modifier. Mucoadhesion of the device depended on the composition and thickness of the interpenetrating polymer network present at the surface of the insert, which was realised by grafting of polyacrylic acid or polymethacrylic acid onto polydimethylsiloxane. In rabbits, the ocular retention of grafted devices was significantly higher when compared to ungrafted inserts. All grafted inserts tested ensured a prolonged drug release, and zero-order release kinetics. Oxytetracycline tear levels of 20–30 Ag/ml were measured for several days.This concentration is 10- to 30-fold above the MIC90 values for common ocular pathogens. 50

Gelfoam- Absorbable Gelatin Sponge

Gelfoam is a medical device intended for application to bleeding surfaces as haemostatic51. It is biocompatible, physically and chemically stable, sterlizable, compatible with drugs and relatively inexpensive. It is not soluble in water however it absorbs several times its weight of water and becomes soft and pliable. This is an important factor making it comfortable in eye. It is biodegradable and can be easily removed from eye at the end of dosing period52.

Gelfoam has been used for delivering pilocarpine to the eye. It was observed that a Gelfoam insert produced both prolonged and efficient miosis in rabbits. Gelfoam is a useful eye insert in the systemic delivery of sodium bovine insulin to rabbits. It also showed that absorption rate of the insulin from an eye device into systemic circulation is lower and of longer duration than the eye drops53,54. Gelfoam based ocular device containing phenylepherine and tropicamide was formulated and evaluated for papillary dilation in rabbits. In vivo study showed better and prolonged action by ocular inserts than the eye drops. The authors propose gelfoam as a versatile drug carrier for either local or systemic drug delivery via the ophthalmic route of administration55. The effects of Brij-78 on insulin delivery to rabbit via Gelfoam ocular insert has been studied that makes it feasible to obtain a prolonged systemic delivery of insulin within the desired therapeutic levels without risk of hypoglycemia56.

Poly (ethylene oxide) (PEO)

Poly(ethylene oxide)(PEO) exhibits good compressibility and thus is easy for the manufacturing of matrix tablets. In contact with an aqueous medium, poly(ethylene oxide) hydrates and gels superficially, the polyether chains of PEO forming strong hydrogen bonds with water. Drug release from poly(ethylene oxide) matrices is controlled by polymer swelling and erosion, or drug diffusion through the gel, or by both processes. Various release patterns can be achieved depending on the poly(ethylene oxide) molecular mass and physicochemical properties of the drug. Good mucoadhesive properties and lack of irritancy to the rabbit eye has been reported. It points that this polymer can be an interesting candidate material for controlled release erodible ocular inserts.

High molecular weight linear polyethylene oxide (PEO) in gel forming erodible inserts for ocular controlled delivery of ofloxacin has been tested in vitro and in vivo. Bioavailability increase has been ascribed to PEO mucoadhesion and /or increased tear fluid viscosity. The study was further extended to investigate the effect of PEO molecular weight (PEO MW) on insert characteristics that are relevant to therapeutic efficacy. Correlation between PEO MW and insert properties related to its therapeutic efficacy were evidenced57. Further, chitosan hydrochloride was also incorporated to ofloxacin erodible inserts based on PEO. Enhanced transcorneal penetration of the drug from the insert was observed which may be attributed to chitosan hydrochloride58. In order to enhance ocular absorption, drug loaded chitosan microspheres were added to poly(ethylene oxide) 400 and 900 inserts. The effect of the microspheres on the drug release mechanism and aqueous humour bioavailability was studied in rabbits. The higher the amount of microspheres present, the more the insert erosion rate was increased. Acceleration of hydration and swelling by chitosan and subsequent interaction with poly(ethylene oxide) resulted in chain disentanglement and dissolution. The enhancing effect of chitosan on drug release was not only ascribed to the acceleration of insert erosion but also to the increased contribution of parallel release mechanisms based on drug diffusion.59  

Pluronics, Poloxamer F127

Sustained drug delivery can also be achieved by use of a polymer that changes from solution to gel at the temperature of the eye (33 to 34o C). An example of this type of polymer is poloxamer F127, which consists of linked polyoxyethylene and polyoxypropylene units. At room temperature, the poloxamer remains as a solution. When the solution is instilled onto the eye surface, the elevated temperature causes the solution to become a gel, thereby prolonging its contact time with the ocular surface. Pluronic F-127 based sustained release ocular inserts containing pilocarpine hydrochloride were used in different formulations excipients like hydroxypropylmethylcellulose, methylcellulose. The formulations were tested for their respective duration and intensity of miotic response using albino rabbit eye model. The effects produced were based on their ability to provide a substantial prolongation of drug action and improvement of bioavailability of pilocarpine as compared to conventional eye drops.  It was clear that ocular bioavailability can be increased more readily by varying both the rheological characteristics of delivery systems and using a smaller dose volume60. In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate were carried out. The viscosity of formulations containing thickening agents was in the order of PF-MC 3%>PF-HPMC 2%>PF-CMC 2.5%>PF127 15%. The slowest drug release was observed with 15% PF127 formulations containing 3% methylcellulose. In vivo study showed that the ocular bioavailability of TM (in albino rabbits) increased by 2.5 and 2.4 fold for 25% PF127 gel formulation and 15% PF127 containing 3% methylcellulose, respectively when compared with 0.5% TM aqueous solution61.Alginate and Pluronic-based solutions as the in situ gelling vehicles for ophthalmic delivery of pilocarpine were prepared and evaluated. The optimum concentration of alginate solution for the in situ gel-forming delivery systems was 2% (w/w) and that for Pluronic solution it was 14% (w/w). The mixture of 0.1% alginate and 14% Pluronic solutions showed a significant increase in gel strength in the physiological condition. Both in vitro release and in vivo pharmacological studies indicated that the alginate/Pluronic solution retained pilocarpine better than the alginate or Pluronic solutions alone62.

Collagen

Collagen is widely used for biomedical applications. It accounts for about 25 % of the total body protein in mammals and is the major protein of connective tissue, cartilage and bone. Importantly, the secondary and tertiary structures of human, porcine, and bovine collagen are very similar, making it possible to use animal-sourced collagen in the human body. Collagen shields are designed to be sterile, disposable, temporary bandage lenses that conform to the shape of the eye and protect the cornea. Their dissolution time on cornea ranges from 12-17 hrs and is controlled by varying degree of cross-link of the polymer.

Natural polymers like pepsin treated teopeptide and calf skin collagen has been used for in vitro studies, as a carrier for controlled release of pilocarpine nitrate. The results have indicated an initial boost release of drug, which becomes zero order at later stage. Collagen modification showed influence over drug release extent. Advocating the biological inertness structural stability and good biocompatibility of collagens, the author emphasize on using collagen as the most promising carrier for ocular inserts63. Study is to determine penetration of moxifloxacin 0.5% into human aqueous and vitreous via topical and collagen shield routes of administration. The findings of this investigation reveal that topically administered moxifloxacin (0.5%) can achieve relatively high aqueous concentrations. Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower. There are several advantages to this route of delivery that make it appealing in the immediate postoperative period. However, it was concluded that future studies will be needed to precisely define the role of fourth-generation fluoroquinolones and presoaked collagen shields in the prophylaxis or management of intraocular infections64 .

Eudragit

The polymer system appeared to be avoiding of any irritant effect on cornea, iris and conjunctiva up to 24 h after application seems to be a suitable inert carrier for ophthalmic drug65. Similarly, in another study, Eudragit RL100 polymer nanoparticle system loaded with cloricromene polymer matrix was prepared and characterized on the basis of physicochemical properties, stability and drug release features by topical administration in the rabbit eye and was compared with an aqueous solution of the same drug. The results indicated that the dispersion of cloricromene within Eudragit RL100 polymer system increased its ocular bioavailability and biopharmaceutical profile and was considerable in clinical practice66. Reservoir-type ocular inserts were fabricated with sodium alginate containing ciprofloxacin hydrochloride as the core (drug reservoir) that was sandwiched between the Eudragit and/or polyvinylacetate films. Better improvement was observed in artificially induced bacterial conjunctivitis in rabbit's eyes as compared to marketed eye drops and placebo. Drug concentration in the aqueous humor was found above the Minimum Inhibitory Concentration (MIC-90) against selected microorganisms67.

Poly(Lactic Acid) or Poly( Glycolic Acid )

Polymers such as poly(lactic acid) or poly ( glycolic acid ) undergo hydrolytic degradation in the body and become monomers of lactic acid or glycolic acid. These monomers can be metabolized and eliminated from the tissues. It is possible to incorporate drugs in the matrix of these polymers. The polymer containing the drug releases the drug for a sustained period and undergoes degradation simultaneously. These polymers have been used as materials of absorbable surgical sutures for many years and proved to be safe and biocompatible68. Feasibility of delivering drugs to the retina and vitreous as well as the subconjunctival space using the microspheres of biodegradable polymers has been reported. A suspension of the microspheres can be injected through a fine needle. These microspheres maintain the drug concentration of therapeutic level for several weeks to several months after the single administration. Effective drug delivery with biodegradable polymers will provide alternate treatments for numbers of ocular diseases including proliferative diseases (proliferative vitreoretinopathy), infectious diseases (endophthalmitis), inflammatory diseases (uveitis), vascular diseases such as diabetic retinopathy, retinal vein or arterial occlusion and  glaucoma. It has been shown that it is possible to target the drug to certain cells like the retinal pigment epithelium using the biodegradable microspheres 69. Efficient drug delivery system would be mandatory for success in regenerative medicine and transplantation procedure of the retinal tissues in the future. To evaluate the fibroinflammatory reaction induced by (PGLA) , a potentially useful depot drug delivery system for 5-fluorouracil (5-FU) was prepared. Polymer discs without 5-FU were inserted subconjunctivally in one eye of each of two guinea pigs and four pigmented rabbits (control group). The discs containing 20% 5-FU were inserted subconjunctivally in both eyes of nine pigmented rabbits (study group). After 4 weeks, the disc was disintegrated, but residual polymer was seen within multinucleated giant cells in the episcleral tissue. Granulation tissue and inflammatory responses were mild. Less inflammation and fibrosis occurred in the study eyes, although the pattern of response was similar in the two groups. The inflammatory response to PGLA was markedly less than that of implanted collagen shields, suggesting PGLA implant as a promising ocular drug delivery system for 5-FU after filtration surgery70.  Microparticles containing 5-fluorouracil (5-FU) were prepared using poly(DL-lactide-co-glycolide) with an oil-in-oil emulsion/solvent extraction technique. Particle characteristics including size distribution, 5-FU loading efficiencies, in vitro release and degradation were investigated. The 5-FU loaded microparticles approach with PLG might be a potential for the application of long-term delivery of hydrophilic drugs in the eye71. In one of the recent studies Timolol-loaded poly(D,L-lactide-co-glycolide; PLGA) films were prepared for achieving the long-term intraocular pressure (IOP) lowering effect on glaucoma treatment. The physicochemical properties and in vivo effects of films were determined and characterize the delivery system. Following a single-dose application in ocular hypertension rabbits, the prepared ocular films could achieve a long-term IOP lowering effect and maintain the IOP change (in comparison with baseline) of approximately 7 mmHg within 1 week. The aqueous humor levels of timolol were low within a range of 0.8-0.24 microg/mL for the initial 24 h and less than 0.15 mg/mL for 4–7 days. 72

Alginate and derivatives

Alginate is a linear co-polysaccharide isolated from brown seaweeds and certain bacteria. Chemically it is a (1-4)-linked block copolymer of â-D-mannuronate (M) and its C-5 epimer R-L-guluronate (G), with residues arranged in homopolymeric sequences of both types and in regions which approximate to the disaccharide repeating structure (MG)73,74(9,10). Commercially alginate is widely used as a gelling agent not only in foods but also in other industries such as pharmaceutical, biomedical, and personal care). As it is easy to prepare alginate ionotropic gels at mild conditions, it is possible to entrap drugs and living cells in alginate gels, which allow a wide application of alginate as scaffolds for tissue engineering, drug delivery systems, and cell encapsulation and transplantation.75,76 When sodium alginate solid matrices are brought in contact with an aqueous medium containing divalent ions e.g. tear fluid, the polymer tend to hydrate, forming a superficial gel, which eventually erodes as polymer dissolves. Drug release from such matrices may be controlled by polymer swelling or erosion or drug diffusion in hydrated gel or by these processes all together. All these properties and applications are ultimately dependent on the molecular architecture and gelling mechanism. Recently alginate-chitosan ocular inserts has been studied as an efficient means of delivering antibiotics(gatifloxacin).77

Current Trends and Future Challenges

The most exciting opportunities in controlled drug delivery lie in the arena of responsive delivery systems to deliver a drug precisely to a targeted site. Much of the development of novel materials in controlled drug delivery is focusing on the preparation and use of these responsive polymers with specifically designed macroscopic and microscopic structural and chemical features. Such systems include:

  • Copolymers with desirable hydrophilic/hydrophobic interactions.
  • Block or graft copolymers.
  • Complexation networks responding via hydrogen or ionic bonding.
  • Dendrimers or star polymers as nanoparticles for immobilization of enzymes, drugs, peptides, or other biological agents.
  • New biodegradable polymers.
  • New blends of hydrocolloids and carbohydrate-based polymers.

Small, ocular solid dosage forms, in particular gel-forming minitablets and erodible inserts, show interesting in vivo performances and allow for therapeutic levels to be obtained over an extended period of time in the tear film and anterior chamber. Sustained release can be modulated by the composition and manufacturing procedure. Mucoadhesive minitablets or inserts are promising ocular drug delivery systems to treat external and intraocular eye infections, and diseases that require frequent eye drops instillation in order to maintain therapeutic drug levels. The new biomaterials, tailor-made copolymers have excellent potential for drug delivery but the formulations based on them have still to go a long way to find their path in actual clinical practice. Successful development of these novel formulations will obviously require assimilation of a great deal of emerging information about the chemical nature and physical structure of these new materials. However the attempts based on these principles are surely a route to better drug Bioavailability through the stubborn sites (as eye) for drug delivery.

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Figure1. Chemical Structure Of Some Selected Polymers Used In Ocular Insert

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Table 1. Some Drugs And Polymers Studied And Incorporated In Ocular Inserts.

image

About Authors:

Ritu Mehra Gilhotra

Ritu Mehra Gilhotra  
School of Pharmacy, SGV University, 84/232, Pratap Nagar, Sanganer, Jaipur, India
Mishra D. N

Mishra D. N.
Dean, Department of Pharmaceutical Sciences,
Guru Jambheshwar University, Hisar-125001, Haryana, India

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7 Comments

pharmacistsahu's picture

Really a nice article.

Deepak Sahu

Deepak Sahu
Submitted by pharmacistsahu on Wed, 04/08/2009 - 09:08
Vishva priya Bharadwaj's picture

Really your work is very nice. With the help of this article I clear about the ocusert and the role of polymers. Your presentation is also very good.
vishva priya bhardwaj

Submitted by Vishva priya Bh... on Sat, 04/11/2009 - 07:03
manish mathur's picture

This article is really appreciable and contents are good enough.This article gives sufficient knowledge about controlled delivery system and polymers. Also a good information about drugs used in ocular inserts. Readers will certainly get benefitted through this article.
Manish Mathur
Lekh Raj

Submitted by manish mathur on Wed, 04/15/2009 - 09:09
dabhimahesh's picture
dabhimahesh says:

Relatively good work.

Dabhi Mahesh
Asst. Professor,
Department of Pharmaceutical Sciences,
Saurashtra University,
Rajkot-360 005,
GUJARAT, INDIA.

Dabhi Mahesh Department of Pharmaceutical Sciences, Saurashtra University, Rajkot-360 005, GUJARAT, INDIA.
Submitted by dabhimahesh on Thu, 05/28/2009 - 07:12
pharmacistsahu's picture

hi mahesh how ru, still you r busy with projects. dear plz send me the project on quetiapine

Deepak Sahu

Deepak Sahu
Submitted by pharmacistsahu on Tue, 06/02/2009 - 04:37
dabhimahesh's picture
dabhimahesh says:

Hiiii

Project is in pipeline and still work is not completed.

Dabhi Mahesh
Asst. Professor,
Department of Pharmaceutical Sciences,
Saurashtra University,
Rajkot-360 005,
GUJARAT, INDIA.

Dabhi Mahesh Department of Pharmaceutical Sciences, Saurashtra University, Rajkot-360 005, GUJARAT, INDIA.
Submitted by dabhimahesh on Fri, 06/26/2009 - 11:12
pharmacistsahu's picture

for your article i want to say only few words

Book love... is your pass to the greatest, the purest, and the most perfect pleasure that God has prepared for His creatures.

The toughest thing about success is that you've got to keep on being a success. Talent is only a starting point in this business. You've got to keep on working that talent. Someday I'll reach for it and it won't be there.

PERFECTION is our goal, excellence will be tolerated.

your article is really worthy for all students

Deepak Sahu

Deepak Sahu
Submitted by pharmacistsahu on Tue, 06/02/2009 - 04:43