Ocular Drug Delivery and Novel Formulations: A Review

 

Pawar Pravin, Yadav Adhikrao, Gharge Varsha*

Gourishankar Institute of Pharmaceutical Education and Research, Limb, Satara, India-415015

 

ABSTRACT:

Ocular drug delivery is one of the most challenging delivery tasks faced by Pharmaceutical researchers. Major barriers in ocular medication are the ability to maintain a therapeutic level of the drug at the site of action for a sustained duration. The ophthalmic preparations are available as sterile, buffered, isotonic solution. Various types of dosage forms are applied as the delivery system for the ocular delivery of drugs. The most prescribed dosage form is the eye drop solution as drops are easier to administer. Suspensions, gelled systems, ointment are also used for prolonged therapeutic action. Evaluation of ophthalmic preparations should be non-irritating to the ocular tissue. Homogenous i.e., particles uniformly dispersed, smooth, free from lumps and agglomerates. It should not cause blurred vision. Also it should not cause intolerable foreign body sensation. The formulation will be Sterile and adequately preserved or physically and chemically stable. New ocular drug delivery systems: Using eye drops to administer drugs needs frequent application. Prolonged drug release can be achieved using ophthalmic inserts, solid devices placed in the eye, but the inserts must then be removed when they are no longer needed. Different new drug delivery systems which are designed in such a way that they release the drug at predetermined and predictable rates thus eliminating the frequent administration of the drug for example ocular insert. The systems generally include controlled, delayed and or sustained release bioerodible implantable elements having multiple layers of different materials and/or different concentrations of materials. The elements generally include an inner layer, or core, including a therapeutic agent, and one or more outer layers made of polymeric materials, for example substantially pure polymeric materials. In the area of topical ocular administration, important efforts concern the design and the conception of new ophthalmic drug delivery systems able to prolong the residence time. The purpose of this review is to provide an update on the current knowledge within this field of ocular drug delivery.

 

 

 

 

INTRODUCTION:

The eye presents unique opportunities and challenges when it comes to delivery of pharmaceuticals. Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientists.¹ Utilization of the principal of controlled release as embodied by ocular inserts therefore offers an attractive alternative approach to the difficult problem of prolonging pre-corneal drug residence time.^2,3 Ocuserts are defined as sterile preparations with a solid or semisolid consistency, whose size and shape are especially designed for ophthalmic application.⁴ all types of ocuserts consists of three components namely, a central drug reservoir in which the drug is incorporated in a polymer, rate controlling membrane which ensures the controlled release of medicament from the drug reservoir, and an outer annular ring meant for easy handling and proper insertion. Ocuserts increases corneal contact time, prolongs duration of action, improves bioavailability, reduces the frequency of administration and thus achieves better patient compliance. Uniform ocular drug level eliminates systemic side effects and provides undisturbed sleep due to extended drug activity throughout the night. It is also possible to administer the drug to inflamed eye due to sustained release of the medicament from ocusert. Furthermore, ocuserts are advantageous in saving time to the healthcare professionals. The zero order kinetics characteristics a sustained release type of delivery system whereby the drug is held in a reservoir and is released into the tear film at constant rate to provide a constant concentration in the corner which provides greatly improved compliance.^5,6 These practical issues have stimulated the search for alternative methods for ocular drug delivery. Much of the work recently devoted to ocular inserts, which serves as the platform for the release of one or more active substances. It has become clear, however that the development of an ocular insert that reliably combines controlled release with absence of any irritation to the patient, poses a formidable technical challenge.⁷ A basic concept in ophthalmic research and development is that the therapeutic efficacy of an ophthalmic drug can be greatly improved by prolonging its contact with the corneal surface. Ophthalmic inserts offer many advantages over conventional dosages forms, like increased ocular residence, possibility of releasing drug at a slow and constant rate, accurate dosing, exclusion of preservatives and increased shelf life. Design, construction and technology of ocular insert in a controlled and sustained ocular delivery device are gaining rapid improvement to overcome this constraints.^{8, 9}

 

MECHANISM OF OCULAR DRUG ABSORPTION:

Topical delivery into the cul-de-sac is, by far, the most common route of ocular drug delivery. ^{10, 11}

Absorption from this site may,

1. Corneal.

2. Non-corneal

 

Barriers avoiding drug delivery

 

OCULAR PHARMACOKINETICS:

The drug pharmacokinetics from the eye follows the following paths

·        Transcorneal permeation from the lacrimal fluid into the anterior chamber.

·        Non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea.

·        Drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber.

 

 

·        Elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and sclemm's canal.

·        Drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier.

·        Drug distribution from the blood into the posterior eye across the blood-retina barrier.

·        Intra vitreal drug administration.

·        Drug elimination from the vitreous via E.g. posterior route across the blood-retina barrier.

·        Drug elimination from the vitreous via anterior route to the posterior chamber.

 

 

 

Anatomy and function of the eye

The eye is a spherical structure with a wall made up of three layers; the outer part sclera, the middle parts choroid layer, Ciliary body and iris and the inner section nervous tissue layer retina. The sclera is tough fibrous coating that protecting the inner tissues of eye which is white except for the transparent area at the front, and the cornea allows light to enter to the eye. The choroid layer, situated situated in the sclera, contains many blood vessels that modified at front of the eye as pigmented iris the coloured part of the eye (blue, green, brown, hazel, or grey)

 

The structure of the cornea:

The clear transparent bulge cornea situated at the front of the eye that conveys images to the back of the nervous system. The adult cornea has a radius of approximately 7-8mm that covers about one-sixth of the total surface area of the eye ball that is a vascular tissue to which provides nutrient and oxygen are supplied via lachrymal fluid and aqueous humour as well as from blood vessels of the junction between the cornea and sclera in fig.1 The cornea is made of five layers as epithelium, bowman’s layer, stroma, descemet’s membrane and endothelium that is main pathway of the drug permeation to eye. The epithelium made up of 5 to 6 layers of cells. The corneal thickness is 0.5– 0.7 mm in the central region. The main barrier of drug absorption into the eye is the corneal epithelium, in comparison to many other epithelial tissues (intestinal, nasal, bronchial, and tracheal) that is relatively impermeable ¹⁰The epithelium is squamous stratified, (5-6 layer of cells) with thickness of around 50-100 μm and turnover of about one cell layer every day. The basal cells are packed with a tight junction, to forming not only an effective barrier to dust particle and most microorganisms, and also for drug absorption. The transcellular or paracellular pathway is the main pathway to penetrate drug across the corneal epithelium. .the lipophilic drugs choose the transcellular route whereas the hydrophilic one chooses paracellular pathway for penetration (passive or altered diffusion through intercellular spaces of the cells). The Bowman’s membrane is an acellular homogeneous sheet with 8- 14μm thick situated between the basement membrane of the epithelium and the stroma. The stroma, or substania propria, composed of around 90% of the corneal thickness that contains about 85% water and about 200-250 collage nous lamellae. The lamellae provide physical strength while permitting optical transparency of the membrane. The hydrophilic solutes diffuse through the stroma’s open structure. The descemet’s membrane is secreted by the endothelium and lies between the stroma and the endothelium ¹¹

 

 

 

Conjunctiva:

The conjunctiva protects the eye and also involved in the formation and maintenance of the precorneal tear film. The conjunctiva is a thin transparent membrane lies in the inner surface of the eyelids and that is reflected onto the globe. The conjunctiva is made of an epithelium, a highly vascularised substantia propria, and a submucosa. The bulbar epithelium contains 5 to 7 cell layers. The structure resembles a pallisadeand not a pavemente corneal epithelium cells are connected by tight junctions, which render the conjunctiva relatively impermeable. The molecules up to 20,000 Da can cross the conjuctiva, while the cornea is restrict to molecules larger than 5000 Da. The human conjunctiva is about 2 and 30 times more absorption of drugs than the cornea and also proposed that loss of drug by this route is a major path for drug clearance. The highest density of conjunctiva is due the presence of 1.5 million globlet cell varying with age depended among the intersujects variability and age. The vernal conjunctivitis and atopic kerato conjunctivitis occurs due to the great variation in goblet cell density results only in a small difference in tear mucin concentration ^12,13

 

 

Figure1. Physiology of Eye

 

 

Figure 2. Flow chart of distribution of drug within ocular tissues after ophthalmic drug delivery

 

Ideal properties of controlled ocular drug delivery system:

Ideal properties of controlled ocular drug delivery system include controlled drug delivery at the desired targeted site, appropriate corneal penetration. Reduced dosing frequency, increased corneal contact and retention time. It bypasses various anatomical and physiological barriers such as tear secretion, naso-lacrymal drainage, enhanced patient compliance etc

 

 

Table 1:

NOVEL OCULAR DRUG DELIVERY SYSTEMS:

Nanotechnology based ocular drug delivery:

In a last few decades, many approaches have been utilized for the treatment of ocular diseases. Nanotechnology based ophthalmic formulations are one of the approaches which is currently being pursued for both anterior, as well as posterior segment drug delivery. Nanotechnology based systems with an appropriate particle size can be designed to ensure low irritation, adequate bioavailability, and ocular tissue compatibility. Several nanocarriers, such as nanoparticles, nanosuspensions, liposomes, nanomicelles and dendrimers have been developed for ocular drug delivery (Figure 3). Some of them have shown promising results for improving ocular bioavailability.

 

 

Figure3. Nanotechnology based ocular drug delivery

Sr. No.	Formulation	Defination and Application	Example	Reference
1	Nanomicelles	Nanomicelles are the most commonly used carrier systems to formulate therapeutic agents in to clear aqueous solutions. In general, these nanomicelles are made with amphiphilic molecules. These molecules may be surfactant or polymeric in nature.	Ocular tolerability of nanomicelles was evaluated against Restasis® as control in New Zealand White (NZW) rabbits. A detailed 72 h study with Hackett-McDonald scoring with microscopic ocular examination was included for two voclosporin (0.02% and 0.2%) micellar and Restasis® formulations. Post 1 h-topical drop administration of Restasis® highest ocular irritation was observed relative to two micellar voclosporin formulations.	14
2	Nanoparticles	Nanoparticles are colloidal carriers with a size range of 10 to 1000 nm. For ophthalmic delivery, nanoparticles are generally composed of lipids, proteins, natural or synthetic polymers such as albumin, sodium alginate, chitosan, poly (lactide-co-glycolide) (PLGA), polylactic acid (PLA) and polycaprolactone.	melatonin loaded PLGA-PEG nanoparticles were most effective and demonstrated significant intraocular pressure (IOP) lowering effect compared with melatonin loaded PLGA nanoparticles and aqueous solution of equivalent concentration in the rabbit eye. It was speculated that the reduced zeta potential of nanoparticles fabricated from PLGA-PEG than the PLGA allowed better and longer interaction between the nanoparticles and eye surface leading to higher hypotensive effect for prolonged period.	15 -23
3	Nanosuspensions	Nanosuspensions are colloidal dispersion of submicron drug particles stabilized by polymer(s) or surfactant(s). It is emerged as promising strategy for delivery of hydrophobic drugs. For ocular delivery, it provides several advantages such as sterilization, ease of eye drop formulation, less irritation, increase precorneal residence time and enhancement in ocular bioavailability of drugs which are insoluble in tear fluid	compared ocular bioavailability of hydrocortisone (Hc) nanosuspensions prepared by precipitation and milling method with HC solution in rabbits post topical instillation. Nanosuspensions prepared by both the precipitation and milling method achieved significantly higher AUC (0–9 h) values of 28.06 ± 4.08 and 30.95 ± 2.2 μg/mL than that of HC solution (15.86 ± 2.7 μg/mL). A sustained drug action which was represented in terms of changes in intraocular pressure was maintained up to 9 h for the nanosuspensions compared to 5 h for the drug solution	24
4	Liposomes	Liposomes are lipid vesicles with one or more phospholipid bilayers enclosing an aqueous core (Figure 3). The size of liposomes usually range from 0.08 to 10.00 μm and based on the size and phospholipid bilayers, liposomes can be classified as small unilamellar vesicles (10–100 nm), large unilamellar vesicles (100–300 nm) and multilamellar vesicles (contains more than one bilayer)	liposomal formulations for ocular drug delivery are being exploited, few are in pre-clinical and clinical study stage and few are commercially available. Visudyne® and Tears again® are the examples of commercially available liposomal formulations for the treatment of ocular diseases. Visudyne® (QLT Ophthalmics, Inc., Menlo Park, CA, United States) is a liposomal formulation containing photosensitizer, verteporfin. It is used in photodynamic therapy for subfoveal choroidal neovascularization in age related macular degeneration, presumed ocular histoplasmosis and pathological myopia	25, 26
5	Dendrimers	Dendrimers are characterized as nanosized, highly branched, star shaped polymeric systems. These branched polymeric systems are available in different molecular weights with terminal end amine, hydroxyl or carboxyl functional group. The terminal functional group may be utilized to conjugate targeting moieties	demonstrated application of PAMAM dendrimers as ophthalmic vehicles for delivery of pilocarpine nitrate and tropicamide, for miotic and mydriatic activity. In this study, mean ocular residence time for fluorescein in saline and in PAMAM solutions were studied in rabbit eye. Fluorescein in 0.2% w/v Carbopol solution was used as reference bioadhesive polymer. The mean ocular residence time was significantly higher in case of PAMAM solutions and 0.2% w/v Carbopol solution compared to saline. Therefore, the use of dendrimers could be another option for increasing ocular residence time and therapy enhancing ocular bioavailability and achieving better therapeutic outcomes.	27, 28
6	In-situ gelling systems	In-situ hydrogels refer to the polymeric solutions which undergo sol-gel phase transition to form viscoelastic gel in response to environmental stimuli. Gelation can be elicited by changes in temperature, pH and ions or can also be induced by UV irradiation. For ocular delivery, research studies have been more focused toward development of thermosensitive gels which respond to changes in temperature	Several thermogelling polymers have been reported for ocular delivery which includes poloxamers, multiblock copolymers made of polycaprolactone, polyethylene glycol, poly (lactide), poly (glycolide), poly (N-isopropylacrylamide) and chitosan. These thermosensitive polymers form temperature dependent micellar aggregates which gellify after a further temperature increment due to aggregation or packing	29, 30
7	Contact lens	Intraocular implants are specifically designed to provide localized controlled drug release over a extended period. These devices help in circumventing multiple intraocular injections and associated complications[	Ocular implants are available as biodegradable and non-biodegradable drug releasing devices. Non-biodegradable implants offer long-lasting release by achieving near zero order release kinetics[110]. Polymers such as polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), and polysulfone capillary fiber (PCF) are being employed for fabricating non-biodegradable implants[108]. Vitrasert® and Retisert® are the examples of marketed non-biodegradable implants.	31, 32
8	Microneedles	Microneedle based technique is an emerging and minimally invasive mode of drug delivery to posterior ocular tissues. This technique may provide efficient treatment strategy for vision threatening posterior ocular diseases such as age related macular degeneration, diabetic retinopathy and posterior uveitis. This new microneedle based administration strategy may reduce the risk and complications associated with intravitreal injections such as retinal detachment, hemorrhage, cataract, endophthalmitis and pseudoendophthalmitis	For intraocular delivery of drugs Jason et al. investigated the application of microneedles surface coated with drugs[115]. Cadaver eyes were used to evaluate the role and scleral penetration of microneedle and intrascleral dissolution of microneedle surface coated drug (sulforhodamine). Results demonstrated that surface coated drug was rapidly dissolved in scleral tissue indicating high scleral sulforhodamine deposition within microneedle hole.	33, 34

 

 

CONCLUSION:

Ocular drug delivery systems provide local as well as systemic delivery of the drugs. The limitations of existing medical therapies for ocular disorders include low drug bioavailability, no specificity, side effects, and poor treatment adherence to therapy. These limitations may be overcome through the use of sustained- release intraocular drug delivery systems. In the area of topical ocular administration, important efforts concern the design and the conception of new ophthalmic drug delivery systems able to prolong the residence time. Drug molecules are being encapsulated into nanosized carrier systems or devices and are being delivered by invasive/non-invasive or minimally invasive mode of drug administration. Several nanotechnology based carrier systems are being developed and studied at large such as nanoparticles, liposomes, nanomicelles, nanosuspensions and dendrimers. Few of these are commercially manufactured at large scale and are applied clinically. Nanotechnology is benefiting the patient body by minimizing the drug induced toxicities and vision loss. Also, these nanocarriers/devices sustain drug release; improve specificity, when targeting moieties are used, and help to reduce the dosing frequency. However, there is still need of developing a carrier system which could reach targeted ocular tissue, including back of the eye tissues, post non-invasive mode of drug administration. With the current pace of ocular research and efforts being made and put in, it is expected to result in a topical drop formulation that retains high precorneal residence time, avoids non-specific drug tissue accumulation and deliver therapeutic drug levels into targeted ocular tissue (both anterior and posterior). In near future, this delivery system may replace invasive mode of drug administration to back of the eye such as periocular and intravitreal injection.

 

ACKNOWLEDGEMENTS:

I solicit my deep sense of appreciation and love to my wonderful FATHER and MOTHER consider my self-privilege to have seen an entity of almighty in them. I consider myself as luckiest person being my sister RUPALI always there besides me during my ups and downs in my life and also thank to my teacher who will guide me for writing this review article. I am immensely thankful to G.I.P.E.R Limb Satara for their providing all facilities required for my work.

 

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Received on 20.08.2018                Accepted on 28.10.2018               

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