Treatise on Ocular Drug Delivery

Ocular globe is a very complex organ consisting of many tissues which protect optic nerve and photoreceptor cells. It sits in the skull cavity and is surrounded by fibrous muscle and lipoidal tissues. The eye is protected from external environment, infection and bright light by eyelids and eyelashes. Moreover, continuous tear production removes foreign objects from the eye. The anterior segment consists of a refractive system while the posterior segment consists of a visual light perceptive mechanism. Light rays entering the eye are focused onto the retina producing continuous images that are spontaneously transmitted to the brain. In this chapter, we discuss the anatomy and physiology of various ocular structures commencing from the anterior segment. Most of the aspects mentioned in this chapter describe the human eye unless otherwise specified.

Drug delivery to the eye has conventionally involved two basic methods of drug administration i.e. the topical route and the systemic route. Both of these orthodox methods of drug delivery face a number of barriers limiting their effectiveness in attaining therapeutic levels at the target site. The tight junctions, tear dilution and rapid clearance by the blood supply in both the anterior and posterior segments of the eye, act as the major barriers. To overcome these barriers, novel routes for drug delivery have been tried out by ophthalmologists that can bypass these barriers. The novel routes possess multiple advantages on the conventional routes such as increased drug concentration at the target site. Some of the routes are less invasive than the conventional routes and also cause fewer side effects. Some of these routes when used for delivering specialized formulations can also allow for better controlled/sustained/targeted drug delivery. In this chapter the comparisons between these conventional and novel routes of drug delivery have been made describing the advantages and disadvantages of each route.

Transport of therapeutic agents into the anterior segment of the eye is highly restricted by various anatomical and physiological barriers. Topical administration is the most convenient method of drug delivery for the treatment of anterior segment eye diseases. The global market for eye care products is approximately $12.5 billion and is growing at a rate of 9% every year. Eye drops account for 90% of all conventional ophthalmic formulations. However, it suffers from several disadvantages such as nasolacrimal drainage, loss in conjunctival blood circulation, tear dilution, normal tear drainage and reflux blinking. There is a need for alternate drug delivery systems which can address poor ocular absorption associated with conventional drug delivery systems. In this chapter, we have made an attempt to briefly describe various drug delivery systems employed in the treatment of anterior segment eye diseases such as nanoemulsions, collagen corneal shields, hydrogels, vesicular systems (liposomes and niosomes), iontophoresis, phonophoresis, punctal plugs and contact lenses.

Drug delivery for the treatment of posterior segment diseases has become a major challenge in the field of ophthalmology due to its restrictive barrier functionalities. Blood-ocular barriers act as a physical barrier between the local blood vessels, ocular tissues and fluids which restrict the passage of various solutes and fluids. Ocular barriers may be classified as static and dynamic barriers. Static barrier include sclera, Bruch’s membrane-choroid (BC), retinal pigment epithelium (RPE) and conjunctiva while dynamic barriers include drug clearance mechanism through blood and lymphatic vessels. Apart from above mentioned barriers, it is also imperative to understand the role of enzymes and transporters in drug disposition. Overall, it is essential to understand anatomy, physiology and disposition mechanisms of eye and interaction between drug molecules/formulation with various ocular tissues in order to design a successful drug delivery system.

Biodegradable polymers (both synthetic and natural) have been extensively explored for ophthalmic applications. These biomaterials are mainly biocompatible and biodegradable in nature. Moreover, different biodegradable polymers have different physico-chemical properties which can further be modulated to formulate desirable drug products. A wide range of ocular drug delivery systems such as implants, inserts, corneal shields, contact lenses, micelles, nanoparticles, microparticles, liposomes, dendrimers and stimuli sensitive hydrogels can be formulated with biodegradable polymers. Moreover, controlled drug delivery systems made up of biodegradable polymers can deliver a variety of therapeutic molecules including hydrophilic and hydrophobic small and macromolecules for prolonged periods to the targeted ocular tissues. In this chapter, we reviewed various synthetic and natural biodegradable polymers applied to ocular drug delivery.

Drug delivery to the back of the eye currently relies largely on localized drug delivery systems. These systems provide high drug concentrations at the target sites and low concentrations in the systemic circulation, thereby improving the risk: benefit ratio of the therapeutic agent. Since localized drug delivery requires either a surgical procedure or an injection in or around the eye, drug delivery systems developed for the back of the eye are either self-sustaining or slow release systems. In this chapter, various drug delivery systems including non-degradable implants, biodegradable implants, encapsulated cell technology based implants, microparticles, nanoparticles, liposomes, micelles and hydrogels suitable for localized drug delivery to the back of the eye are discussed. Further, iontophoretic approaches are also briefly addressed.

Drug delivery to the eye is highly challenging due to the existence of protective anatomical barriers. Numerous vision threatening diseases affect the anterior and posterior segments of the eye. The topical route is the most common mode of drug administration for the treatment of eye diseases. Following topical administration, less than 5% of instilled dose may be absorbed primarily by corneal and secondarily by conjunctival pathway. However, the remaining portion of the drug is washed out by precorneal mechanisms such as tear turnover, nasolachrymal drainage and blink reflex. In addition, the physicochemical properties of the drug and lipoidal nature of the cornea limit ocular absorption. Various therapeutic strategies such as ultrasound, microneedle and prodrug modification are known to enhance drug concentrations at the target tissues. In this chapter, we made an attempt to discuss briefly these strategies and their role in enhancing bioavailability in the anterior and posterior ocular segments.

Ocular pharmacokinetics is a core component in the development of therapeutics for eye diseases. In this chapter, we provide a description of the following concepts and strategies that undergird when and where microdialysis may be a significant advance in the armamentarium of approaches for establishing PK/PD relationships in ophthalmology. We cover the following topics:

• Understanding the current limitations in PK/PD with conventional sampling approaches

• Progress report on advances in the use of microdialysis in ophthalmology

• Preclinical vs. clinical ocular PK cases studies

• Roadblocks to microdialysis in ophthalmology

o Probe design and probe recovery

o Bioanalytical limitations

o Invasiveness of probe implantation

o Analyte properties and perfusion flow rate

• Strategies for design of an ideal microdialysis experiment

• Next advances in microdialysis

The eye is protected from the external environment by various physiological and anatomical barriers. These barriers, through their protective actions, drastically diminish the ocular bioavailability of drugs. In the last decade, a number of innovations attempting to improve the ocular bioavailability of therapeutic agents have been reported. In the present chapter, some of the US patents and patent applications related to ocular drug delivery, published in the last decade, have been discussed. Additionally, an overview of US regulatory requirements and guidelines concerning transformation of innovations into commercial ophthalmic products have been presented.

Drug delivery to treat ocular diseases is one of the most challenging fields, due to complex anatomy of eye and its physiological barriers like precorneal loss and the presence of biological barriers, especially in the posterior segment of the eye. Although topical eye drop administration is usually preferred to treat disorders of the eye, the biological protecting factors lead to low ocular absorption and poor bioavailability (1– 10%). An efficient ocular drug delivery system, which can provide maximum precorneal residence time, overcome ocular barriers and sustain delivery of drugs following topical administration is desirable. Nanotechnology is an emerging field in drug delivery and considerable research is taking place towards the development of nanotechnology-based ocular drug delivery systems. Because of their ability to avoid various biological barriers and providing targeted and sustained drug delivery to various ocular tissues, nanotechnology-based formulations paved the approaches for efficient ophthalmic drug delivery for both the anterior and posterior segments of eye. This review discusses a variety of nanocarriers, such as nanoparticles, nanosuspension, liposomes, niosomes, discomes, micelles, dendrimers and microemulsion developed for the ocular delivery of many drugs. Some of them have shown promising results for improving ocular bioavailability. This review also attempts to extend the information on recently issued and filed patents on nanotechnology-based ocular drug delivery systems in the last few years.