Ocular Drug Delivery System

IntroductionThe eye is a unique and precious organ. It is considered as the window of the soul. There are many eye ailments which affect this organ and one can loss the eye sight also. Therefore many ophthalmic drug delivery systems are available.

These are classified as conventional and newer drug delivery systems. Most commonly available ophthalmic preparations are eye drops and ointments, used topically rather systemically.

These dosage forms are easy to instill but suffer from the inherent drawback that the majority of the medication is immediately diluted in the tear film as soon as the eye drop solution is instilled into the cul-de-sac (a short road which is closed off at one end).

And is rapidly drained away from the precorneal cavity by constant tear flow and lacrimo-nasal drainage.

Therefore, the target tissue absorbs a very small fraction of the instilled dose.

Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy.

Application of nanotechnology has been very promising in the treatment of a gamut of diseases. Several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels are emerged as novel drug delivery systems for the eye.

Anatomy and Routes of Delivery of the eyeDrug delivery to the eye can be broadly classified into anterior and posterior segments:

Figure 1 : Structure of the eye

Anterior segment consists of front one third of eye that mainly includes pupil, cornea, iris, ciliary body, aqueous humor, and lens (Fig 1).

The posterior segment consists of the back two thirds of the eye that includes vitreous humor, retina, choroid, macula, and optic nerve (Fig 1).

Figure 2: Routes of delivery of the eye

Periocular route has been considered as the most promising and efficient route for administering drugs to posterior eye segment. Periocular refers to the region surrounding the eye. It is a broad term which includes peribulbar, posterior juxtascleral, retrobulbar, subtenon and subconjunctival routes (Fig 2).

Intravitreal injections have gained considerable momentum during the past two decades.

Various routes and dosage forms used:

• Topical Administration : solutions – eye drops, ointments, suspensions

• Intravitreal Injections : solutions, suspensions, implants

• SubTenon Injections : solutions, suspensions, implants

• Subconjunctival Injections : solutions, suspensions, implants

Drug Delivery to the Front of the Eye (Topical)

Dose in the Eye Absorption via cornea into Aq. Humor

Drainage and removal by

Naso-Lacrimal System, Blinking and tears

Absorption via Conjunctiva

Oculartissues

Systemic Circulation

Quick Loss

Drug Delivery to Front and Back of the Eye

Ocular Drug Design and Delivery: Challenges

For the therapeutic treatment of most ocular problems, topical administration is the preferred route. But it needs frequent dosing. For systemically administered drugs, only a very small fraction of the total dose reach the eye from the general circulatory system.

Problems with Delivery of Drugs:

Rapid drain out of the drug from the precorneal cavity by constant tear flow and lacrimo-nasal drainage.

Blood-retinal barrier (BRB) prevents high concentrations of drugs passage from the blood stream.

Most agents injected into the vitreous are cleared rapidly and are therefore ineffective.

Effective dose often toxic.

Subconjunctival and intravitreal injections carry a risk of infection.

Enhancement in BioavailabilityTopical bioavailability can be improved by maximizing precorneal drug absorption and minimizing precorneal drug loss.

1. Viscosity improver:

In order to prolong precorneal residence time and to improve bioavailability, attempts were made to increase the viscosity of the formulation.

The viscosity enhancers used were hydrophilic polymers such as cellulose, polyalcohol and polyacrylic acid, Sodium carboxy methyl cellulose etc.

2. Gels :Gel formation is an extreme case of viscosity enhancement through the use of viscosity enhancers. So the dosing frequency can be decreased to once a day. Cellulose acetate phthalate dispersion constituted a micro-reservoir system of high viscosity.3. Penetration enhancers:They act by increasing corneal uptake by modifying the integrity of comeal epithelium.Chelating agents, preservatives, surfactants and bile salts were studied as possible penetration enhancers. But the effort was diminished due to the local toxicity associated with enhancers.

4. Prodrugs:Prodrugs enhance corneal drug permeability through modification of the hydrophilic or lipophilicity of the drug. The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe ocular drug delivery system. Drugs with increased penetrability through prodrug formulations are - epinehrine, phenylephrine, timolol, pilocarpine and albuterol.

5. Cyclodextrins:

Cyclodextrins act as carriers by keeping the hydrophobic drug molecules in solution and delivering them to the surface of the biological membrane, where the relatively lipophilic membrane has a much lower affinity for the hydrophilic cyclodextrin molecules.

Optimum bioavailability can be achieved when just enough cyclodextrin (<15%) is added to the aqueous eye.

6. Bioadhesive polymers:The bioadhesive polymers adhere to the mucin coat covering the conjunctiva and the corneal surfaces of the eye, thus prolonging the residence time of a drug in the conjunctival sac. These polymers can be neutral, synthetic or semi synthetic. Polyacrylic acid, polycarbophil and hyaluronic acid are commonly used synthetic polymers.

NOVEL OCULAR DRUG DELIVERY SYSTEMS

One has to understand the physiological and biochemical factors involved in normal and pathological conditions for designing a successful ocular drug delivery system.

An ideal therapy requires selectively targeting of active agent to various diseases like CNV (cytomegalovirus), diabetic retinopathy and solid tumors in the eye.

1. Microemulsions:

Microemulsions are dispersions of water and oil facilitated by a combination of surfactant and co-surfactant in a manner to reduce interfacial tension. These systems are usually characterized by higher thermodynamic stability, small droplet size (100 nm) and clear appearance.

An oil-in-water system consisting of pilocarpine using lecithin, propylene glycol, PEG 200 as surfactant/co-surfactants, and isopropyl myristate as the oil phase has been designed, which is non-irritating to the rabbit animal model.

2. Nanosuspensions:

This can be defined as sub-micron colloidal system which consists of poorly water soluble drug, suspended in an appropriate dispersion medium stabilized by surfactants.

Nanosuspenisons usually consist of colloidal carriers like polymeric resins which are inert in nature. They help in enhancement of drug solubility and thus bioavailability.

Unlike microemulsions, they are also popular because of their non irritant nature.

3. Nanoparticles:

“Nanoparticles are defined as particles with a diameter of less than 1 μm, comprising of various biodegradable or non biodegradable polymers, lipids, phospholipids or metals”.

They can be classified as nanospheres or nanocapsules depending upon whether the drug has been uniformly dispersed or coated within polymeric material.Uptake and distribution of nanoparticles depend on the size of the nanoparticles. A solid lipid nanoparticulate system of tobramycin was developed for topical drug delivery.

4. Liposomes:Liposomes are lipid vesicles containing aqueous core which have been widely exploited in ocular delivery for various drug molecules. Liposomes containing GCV (Ganciclovir) were formulated by a reversed phase evaporation method and in vivo pharmacokinetic evaluation was performed in a rabbit model.

Ocular tissue distribution was higher in the sclera, cornea and vitreous humor from liposomal formulation. Acetazolamide was encapsulated in liposomal formulation for delivery via topical route.

5. Niosomes:

Niosomes are bilayered structural vesicles made up of non-ionic surfactant which are capable of encapsulating both lipophilic and hydrophilic compounds. In a recent approach to deliver cyclopentolate, niosomal formulation was developed. It released the drug independent of pH resulting in significant enhancement of ocular bioavailability A major advantage of this system was less systemic drainage because of the large size and large residence time in the cul-de-sac due to their disc shape.

6. Dendrimers:

“Dendrimers are macromolecular compounds made up of a series of branches around a central core. Their nanosize, ease of preparation, functionalization and possibility to attach multiple surface groups render them suitable alternative vehicle for ophthalmic drug delivery”.

Major drawbacks associated with these systems are blurred vision and formation of a veil leading to vision loss. Dendrimers consisting of poly (amidoamine) (PAMAM) have been widely employed in drug delivery.

7. Cyclodextrins:

“Cyclodextrins (CDs) belong to a group of cyclic oligosaccharides capable of forming inclusion complexes with many guest molecules. Through CD complexation, aqueous solubility of hydrophobic drugs can be enhanced without changing their molecular structure and their intrinsic ability to permeate biological membranes”.

These complexes have been proven to increase corneal permeation of drugs like dexamethasone, cyclosporine and so on.

8. Contact Lenses:Traditionally used soaked contact lenses provide a drug release for a few hours. Current challenges in this mode of drug delivery are to sustain release for longer period and also to incorporate sufficient drug amounts in the lens matrix. Recently, surfactant loaded polyhydroxy ethyl methacrylate (p-HEMA) gel has shown sustained release of cyclosporine-A.

The bioavailability of the formulation was found better than the topical eye drops.

9. Intraocular Implants:

Implants have been widely employed to extend the release in ocular fluids and tissues particularly in the posterior segment. Implants can be broadly classified into two categories based on their degradation property:

(a) biodegradable and (b) non-biodegradable.

With implants, the delivery rate could be modulated by varying polymer composition. Implants can be in the form of solid, semi-solid or particulate based delivery systems.

10. Hydrogel Systems:

The progress has been made in gel technology to the development of droppable gel. They are liquid upon instillationand undergo phase transition in the ocular cul-de-sac to form visco-elastic gel and this provides a response to environmental changes. Three methods have been employed to cause phase transition in the eye surface. These are change in pH, change in temperature and ion activation.

I. pH: In this method gelling of the solution is triggered by a change in the pH. CAP latex cross linked polyacrylic acid and derivatives such as carbomers are used. They are low viscosity polymeric dispersion in water which undergoes spontaneous coagulation and gelation after instillation in the conjunctival cul-de-sac.

II. Temperature: In this method gelling of the solution is triggered by change in the temperature. Sustained drug delivery can be achieved by the use of a polymer that changes from solution to gel at the temperature of the eye.

III. Ionic strength: In this method gelling of the solution instilled is triggered by the change in the ionic strength. Example is Gelrite.Gelrite is a polysaccharide, low acetyl gellan gum, which forms a clear gel in the presence of mono or divalent cations. The concentration of sodium in human tears is 2.6 g/l is particularly suitable to cause gelation of the material when topically installed into the conjunctival sac.

11. Iontophoresis:Ocular iontophoresis has gained significant interest recently due to its non-invasive nature of delivery to both anterior and posterior segment. It requires a mild electric current which is applied to enhance ionized drug penetration into tissue. This mode of delivery can overcome the potential side effects associated with intraocular injections and implants mentioned earlier. Examples of antibiotics successfully employed are gentamicin, tobramycin and ciprofloxacin by this system.

12. Microneedle:

Recently, researchers have attempted microneedle to deliver drug to posterior segment as an alternative to topical route. An evaluation of coated solid metal microneedle to deliver the drug was carried out both in-vitro and in-vivo.

Microneedle had shown excellent in-vitro penetration into sclera and rapid dissolution of coating solution after insertion. In-vivo drug level was found to be significantly higher than the level observed following topical drug administration. This mode of drug delivery was also successful in the delivery of pilocarpine.

13. Gene Delivery:

Recently, various strategies have been adopted to deliver nucleic acids to a specific site within the eye. Designing delivery system for antisense ODNs (oligodeoxynucleotides), aptamers or siRNAs is a challenging task for researchers in ocular delivery field because of high molecular weight, size, surface charge, solubility of the active drug and intrinsic complexities associated with the structure of ocular tissues like retina and cornea. Recently, FDA has approved Vitravene®, an ODNs for the treatment of CMV in AIDS patients and Macugen® (pegaptanib sodium injection) which is an aptamer for the treatent of “wet” AMD.