Contact lenses in ocular therapeutics

Drug delivery is a difficult task in the field of ocular therapeutics. Owing to the physiological and anatomical constraints of the eye, it is difficult to obtain the correct therapeutic concentration of a drug at the required site of action. This has led to clinicians recommending frequent dosing, which has resulted in noncompliance by patients and decreased cost effectiveness. To overcome these barriers, scientists have explored novel ocular delivery systems, such as in situ gels, ocuserts, nanoparticles and liposomes. A particularly novel form of such a delivery system are contact lenses, which are thin, curved plastic disks that are designed to cover the cornea and which cling to the surface of the eye owing to surface tension. In this article, we describe the introductory literature on ocular delivery using contact lenses, their classification and manufacturing process, and recent advances on drug delivery techniques using such lenses.     

Fabrication of a drug delivery system that enhances antifungal drug corneal penetration

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50?μL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4?h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.     

Enhancement of ocular drug penetration

Although new drugs have recently been developed within the field of ophthalmology, the eye's various defense mechanisms make it difficult to achieve an effective concentration of these drugs within the eye. Drugs administered systemically have poor access to the inside of the eye because of the blood-aqueous and blood-retinal barriers. And although topical instillation of drugs is very popular in ophthalmology, topically applied drugs are rapidly eliminated from the precorneal area. In addition, the cornea, considered a major pathway for ocular penetration of topically applied drugs, is an effective barrier to drug penetration, since the corneal epithelium has annular tight junctions (zonula occludens), which completely surround and effectively seal the superficial epithelial cells. Various drug-delivery systems have been developed to increase the topical bioavailability of ophthalmic drugs by enhancement of the ocular drug penetration. The first approach is to modify the physicochemical property of drugs by chemical and pharmaceutical means. An optimum promoiety can be covalently bound to a drug molecule to obtain a prodrug that can chemically or enzymatically be converted to the active parent drug, either within the cornea or after the corneal penetration. Along these same lines, the transient formation of a lipophilic ion pair by ionic bonding is also useful for improving ocular drug penetration. The second approach is to modify the integrity of the corneal epithelium transiently by coadministration of an amphiphilic substance or by chelating agents that act as drug-penetration enhancers. The third approach modifies the integrity of the corneal epithelium transiently by physical techniques including iontophoresis and phonophoresis. This paper reviews the absorption behavior and ocular membranes penetration of topically applied drugs, and the various approaches for enhancement of ocular drug penetration in the eye.     

Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

Biopharmaceutical considerations in topical ocular drug delivery

1. Despite the accessibility of the front of the eye, efficient delivery of drug to treat various ocular disorders is a challenge to the formulation scientist. The majority of ophthalmic medications are formulated as eye drops. Due to anatomical constraints, the volume that can be administered is limited to approximately 30 microL. This, together with the efficient clearance system that exists in the front of the eye, makes it difficult to maintain an effective pre-ocular drug concentration for a desired length of time. Various formulation strategies have been used to increase pre-ocular retention of eye drops. The most successful of these has been the inclusion of viscosity enhancing polymers, particularly those able to interact with the mucous layer on the eye surface or those that can undergo a transition from a solution to a gel under the conditions of the pre-ocular area. 2. When the target site is intra-ocular, drug must be absorbed from the pre-ocular region into the eye. The main route for absorption is across the cornea. However, absorption of drug across the cornea is inefficient due to its impermeable nature and small surface area. Thus, the intra-ocular bioavailability of topically administered medications is typically less than 10%. 3. Corneal permeability favours moderately lipophilic compounds. These compounds often have a low aqueous solubility. Problems in ocular drug delivery and formulation are compounded for poorly soluble drugs that must be formulated as suspensions. 4. Reformulation of ophthalmic suspensions as solutions has many advantages. This may be achieved by complexation using cyclodextrins. Solubilization using cyclodextrins can overcome many of the formulation problems. However, it is unclear as to their potential for improving ocular bioavailability, which is seemingly drug dependent and may be influenced by both the physicochemical properties of the drug and the complex formed.     

Nanotechnology in ocular drug delivery

Despite numerous scientific efforts, efficient ocular drug delivery remains a challenge for pharmaceutical scientists. Most ocular diseases are treated by topical drug application in the form of solutions, suspensions and ointment. These conventional dosage forms suffer from the problems of poor ocular bioavailability, because of various anatomical and pathophysiological barriers prevailing in the eye. This review provides an insight into the various constraints associated with ocular drug delivery, summarizes recent findings and applications of various nanoparticulate systems like microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers and cyclodextrins in the field of ocular drug delivery and also depicts how the various upcoming of nanotechnology like nanodiagnostics, nanoimaging and nanomedicine can be utilized to explore the frontiers of ocular drug delivery and therapy.     

Rapid in vitro test to predict ocular tissue permeability based on biopartitioning micellar chromatography.

The drug permeability prediction across the ocular tissues is important in the development of new drugs and drug delivery strategies. Physicochemical characteristics of drugs, mainly acid-base character, hydrophobicity and the molecular size determine both their transport across the eye tissue barriers and their retention in biopartitioning micellar chromatography (BMC). An in vitro model able to describe and predict the whole cornea drug permeability is proposed. The model uses the retention of drugs in BMC and molecular weight (MW) as predictive variables. The relationships between drug retention data in BMC and their bibliographic permeability values in stroma, epithelium-plus-stroma and endothelium-plus-stroma are also studied. The results show that BMC can be a useful tool to select drug candidates according to their whole cornea permeability at the early stage of the drug discovery process.     

Newer approaches for optimal bioavailability of ocularly delivered drugs: review

Eye diseases can cause discomfort and anxiety in patients, with the ultimate fear of loss of vision and facial disfigurement. Many regions of the eye are relatively inaccessible to systemically administered drugs and, as a result, topical drug delivery remains the preferred route in most cases. Drugs may be delivered to treat the precorneal region for conjunctivitis and blepharitis, or to provide intraocular diseases such as glaucoma, uveitis, and cytomegalovirus retinitis. Most of the ophthalmic formulation strategies aim at maximizing ocular drug permeability through prolongation of the drug residence time in the cornea and conjunctival sac, as well as minimizing precorneal drug loss. The conventional topical ocular drug delivery systems show drawbacks such as increased precorneal elimination and high variability in efficacy. Attempts have been made to overcome these problems and enhance ocular bioavailability by the development of newer drug delivery systems. This review is concerned with classification, recent findings and applications and biocompatibility of newer drug delivery systems for the treatment of ocular diseases.     

Cell culture models of the ocular barriers.

The presence of tight barriers, which regulate the environment of ocular tissues in the anterior and posterior part of the eye, is essential for normal visual function. The development of strategies to overcome these barriers for the targeted ocular delivery of drugs, e.g. to the retina, remains a major challenge. During the last years numerous cell culture models of the ocular barriers (cornea, conjunctiva, blood-retinal barrier) have been established. They are considered to be promising tools for studying the drug transport into ocular tissues, and for numerous other purposes, such as the investigation of pathological ocular conditions, and the toxicological screening of compounds as alternative to in vivo toxicity tests. The further development of these in vitro models will require more detailed investigations of the barrier properties of both the cell culture models and the in vivo ocular barriers. It is the aim of this review to describe the current status in the development of cell culture models of the ocular barriers, and to discuss the applicability of these models in pharmaceutical research.     

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side‐effects. Conventional ophthalmic drug delivery systems such as topical eye‐drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood‐ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood‐ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate‐modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2219–2239, 2010     

New Techniques for Drug Delivery to the Posterior Eye Segment

Ocular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis.     

Delivery of therapeutics for deep‐seated ocular conditions – status quo

Objectives

There is a need for research into designing effective pharmaceutical systems for delivering therapeutic drugs to the posterior of the eye for glaucoma‐related pathology, macular degeneration, diabetic retinopathy, macular oedema, retinitis and choroiditis. Conventionally, eye drops have been extensively utilised for topical drug delivery to the anterior segment of the eye, but are less effective for delivery of therapeutics to the back of the eye due to significant barriers hampering drug penetration into the target intraocular tissue. This review explores some of the current and novel delivery systems employed to deliver therapeutics to the back of the eye such as those using liposomes, ocular implants, in situ gels, and nanoparticles, and how they can overcome some of these limitations.

Key findings

Issues such as blinking, precorneal fluid drainage, tear dilution and turnover, conjunctiva and nasal drug absorption, the corneal epithelium, vitreous drug clearance, and the blood–ocular barriers are reviewed and discussed.

Summary

Further studies are needed to address their shortcomings such as drug compatibility and stability, economic viability and patient compliance.

     

Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tear-flow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on beta-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches.     

眼部的给药屏障和给药途径

近年来,眼部药物递送系统越来越受到重视,本文综述了目前眼部给药的主要屏障包括角膜、结膜屏障,血房水屏障、血视网膜屏障等,以及一些新的给药途径和给药方法如结膜下、巩膜给药和离子电渗疗法等。以环孢素A为例介绍了一些克服眼部屏障的给药方法。尽管眼部给药系统目前已取得了进展,但药物递送到眼的后段仍有较大的难度,需要进一步开发更有效的眼部药物递送系统。     

Non-systemic delivery of topical brimonidine to the brain: A neuro-ocular tissue distribution study

To date, the risks of central nervous system (CNS) side effects of topically administered ophthalmic therapeutic agents are thought to be the consequence of systemic absorption of these drugs. This paper envisions the possibility of drug delivery to the CNS following ocular application through non-systemic routes. After single instillation of 50 μl of ³H-radiolabeled Alphagan® solution (0.2%) in the cul de sac of the right eye, three male albino rabbits (2–2.5 kg) were sacrificed at each time point (5, 15, 30 and 60 min). Both sides (eyes) specimens of aqueous humor, cornea, iris, lens, vitreous, conjunctiva, sclera, ciliary body, choroid, retina, optic nerve, optic tract and olfactory bulb were weighed, and blood samples were measured, before combustion in tissue oxidizer and radioactive liquid scintillation counting. Significant ³H-brimonidine levels were found in right and left optic nerves and tracts with extremely low corresponding drug levels in blood. Uveal tract (ciliary body, iris and choroid tissues) brimonidine levels were relatively high in the treated eye, and the highest among contralateral eye tissues. Our data provide the first case of good CNS availability after ocular application of conventional ophthalmic therapeutic agent, through non-systemic routes. Similar neuro-ocular pharmacokinetic studies should be adopted as a routine ocular therapeutics evaluation study.     

Non-systemic delivery of topical brimonidine to the brain: a neuro-ocular tissue distribution study

To date, the risks of central nervous system (CNS) side effects of topically administered ophthalmic therapeutic agents are thought to be the consequence of systemic absorption of these drugs. This paper envisions the possibility of drug delivery to the CNS following ocular application through non-systemic routes. After single instillation of 50 microl of 3H-radiolabeled Alphagan solution (0.2%) in the cul de sac of the right eye, three male albino rabbits (2-2.5 kg) were sacrificed at each time point (5, 15, 30 and 60 min). Both sides (eyes) specimens of aqueous humor, cornea, iris, lens, vitreous, conjunctiva, sclera, ciliary body, choroid, retina, optic nerve, optic tract and olfactory bulb were weighed, and blood samples were measured, before combustion in tissue oxidizer and radioactive liquid scintillation counting. Significant 3H-brimonidine levels were found in right and left optic nerves and tracts with extremely low corresponding drug levels in blood. Uveal tract (ciliary body, iris and choroid tissues) brimonidine levels were relatively high in the treated eye, and the highest among contralateral eye tissues. Our data provide the first case of good CNS availability after ocular application of conventional ophthalmic therapeutic agent, through non-systemic routes. Similar neuro-ocular pharmacokinetic studies should be adopted as a routine ocular therapeutics evaluation study.     

Ophthalmic drug delivery considerations at the cellular level: drug-metabolising enzymes and transporters

Ophthalmic drugs typically achieve < 10% ocular bioavailability. A drug applied to the surface of the eye may cross ocular–blood barriers where it may encounter metabolising enzymes and cellular transporters before it distributes to the site of action. Characterisation of ocular enzyme systems and cellular transporters and their respective substrate selectivity have provided new insight into the roles these proteins may play in ocular drug delivery and distribution. Altered metabolism and transport have been proposed to contribute to a number of ocular disease processes including inflammation, glaucoma, cataract, dry eye and neurodegeneration. As ocular enzyme and transport systems are better characterised, their properties become an integral consideration in drug design and development.     

Ophthalmic drug delivery considerations at the cellular level: drug-metabolising enzymes and transporters

Ophthalmic drugs typically achieve < 10% ocular bioavailability. A drug applied to the surface of the eye may cross ocular-blood barriers where it may encounter metabolising enzymes and cellular transporters before it distributes to the site of action. Characterisation of ocular enzyme systems and cellular transporters and their respective substrate selectivity have provided new insight into the roles these proteins may play in ocular drug delivery and distribution. Altered metabolism and transport have been proposed to contribute to a number of ocular disease processes including inflammation, glaucoma, cataract, dry eye and neurodegeneration. As ocular enzyme and transport systems are better characterised, their properties become an integral consideration in drug design and development.     

An updated patent review on ocular drug delivery systems with potential for commercial viability

The eye due to its special attributes is an effortlessly accessible location for topical drug administration. Topical administration not only provides local targeting of drugs but also offers a better control over the systemic delivery. Bioavailability of drugs from ocular dosage forms is dependent to the precorneal loss factors (physiological and anatomical constraints of eye) thus, very small fraction of the drug is absorbed through ocular route. The effective dose of medication administered ophthalmically may be altered by changing the formulation. Various research reports have been documented for ocular drug delivery, both on academic level as well as commercial level resulting in augmented increase in the numbers of patents in this field. The primary objective of the present review is to provide an overview of the ocular drug delivery systems with special emphasis on the intellectual aspects of these systems. This paper also attempts to extend the information on ocular drug delivery systems already existing in the literature by focusing on the update on the patents granted as well as applications published for these systems during the last decade.     

Topical and systemic drug delivery to the posterior segments

The posterior segments of the eye are exquisitely protected from the external environment. This poses unique and fairly challenging hurdles for drug delivery. It is somewhat dogmatic that topical ocular delivery is insufficient to achieve therapeutic drug levels in the posterior segments. However, some drugs are currently challenging this dogma. In this review we investigate the constraints and challenges of drug delivery to the posterior segment. Additionally, we outline several potential absorption pathways that may potentially be exploited to deliver drug to the back of the eye. Data on several compounds that achieve therapeutic posterior segment concentrations after topical dosing is presented. Finally, the issues surrounding systemic delivery to the posterior segment are reviewed.