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     

眼部给药系统的研究进展

目的介绍眼部给药系统的研究进展。方法查阅总结近年来眼部给药系统的最新研究成果,展望其发展前景。结果胶粒给药系统使不同阶段眼部疾病的治疗成为可能;靶向给药使得药物能够透过各种屏障到达眼部病变部位;原位凝胶显著延长了药物在眼部的滞留时间;可降解植入剂避免了释药后的二次手术;眼部电离子渗透技术大大降低了眼部治疗的创伤。结论随着临床医学、药物制剂学、高分子材料学的发展及新技术的应用,眼部给药系统在眼部疾病治疗中的应用更加广泛,具有很好的发展前景。     

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.     

A review on therapeutic contact lenses for ocular drug delivery

Contact lenses for ophthalmic drug delivery have become very popular, due to their unique advantages like extended wear and more than 50% bioavailability. To achieve controlled and sustained drug delivery from contact lenses, researchers are working on various systems like polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous scientists are working on different areas of therapeutic contact lenses to treat ocular diseases by implementing techniques like soaking method, molecular imprinting, entrapment of drug-laden colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercritical fluid technology, etc. Though sustained drug delivery was achieved using contact lens, the critical properties such as water content, tensile strength (mechanical properties), ion permeability, transparency and oxygen permeability were altered, which limit the commercialization of therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug integrity test), zero order release kinetics (prevent burst release), drug release during monomer extraction step after fabrication (to remove un-reacted monomers), protein adherence, drug release during storage in packaging solution, shelf life study, cost-benefit analysis, etc. are still to be addressed. This review provides an expert opinion on different methodology to develop therapeutic contact lenses with special remark of their advantages and limitations.     

Therapeutic implications of nanomedicine for ocular drug delivery

Delivering therapeutics to the eye is challenging on multiple levels: rapid clearance of eyedrops from the ocular surface requires frequent instillation, which is difficult for patients; transport of drugs across the blood–retinal barrier when drugs are administered systemically, and the cornea when drugs are administered topically, is difficult to achieve; limited drug penetration to the back of the eye owing to the cornea, conjunctiva, sclera and vitreous barriers. Nanomedicine offers many advantages over conventional ophthalmic medications for effective ocular drug delivery because nanomedicine can increase the therapeutic index by overcoming ocular barriers, improving drug-release profiles and reducing potential drug toxicity. In this review, we highlight the therapeutic implications of nanomedicine for ocular drug delivery.     

Nanomedicines for ocular NSAIDs: safety on drug delivery

The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. Poor bioavailability of drugs from ocular dosage forms is mainly due to precorneal loss factors (e.g., tear dynamics, nonproductive absorption, transient residence time in the cul-de-sac, and relative impermeability of the corneal epithelial membrane). There is a clear need for effective topical formulations capable of promoting drug penetration and maintaining therapeutic levels with a reasonable frequency of application—a strategy that can also result in enhancement of side effects that probably would not be acceptable. Delivery of a drug via a nanotechnology-based product fulfills three main objectives: enhancement of drug permeation, controlled release, and targeting. The inflammatory response of the ocular tissues is a common side effect associated with ophthalmic surgery. Together with steroidal agents, nonsteroidal anti-inflammatory drugs are used in eye surgery. In this review we focus on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as formulations incorporating anti-inflammatory drugs for ophthalmic application.From the Clinical EditorThis review focuses on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as novel high efficiency delivery systems of anti-inflammatory drugs in ophthalmic applications.     

Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye

ABSTRACT

Introduction: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency.

Area covered: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light-responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field.

Expert opinion: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications.     

Cyclodextrins in ophthalmic drug delivery

Most ocular diseases are treated by topical drug application in the form of aqueous eye drop solutions. Recent studies have shown that cyclodextrins are useful additives in ophthalmic formulations for increasing the aqueous solubility, aqueous stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. However, these studies have also shown that there are some basic differences between ophthalmic administration of cyclodextrins and administration of cyclodextrins via other routes. These differences have induced some limitations in the ophthalmic application of these most recently developed pharmaceutical excipients. The objective of this review is to summarize recent findings and applications of various cyclodextrins in ophthalmic drug delivery. Their mechanism of action in aqueous eye drop formulations is also discussed. Finally, the formulation of a couple of cyclodextrin containing eye drop solutions is described.     

Topical ocular delivery of fluoroquinolones

Introduction: Topical fluoroquinolones are used in ophthalmology to treat ocular infections. They are bactericidal and inhibit bacterial DNA replication by inhibiting DNA gyrase and topoisomerase. Fluoroquinolones possess two ionizable groups: a carboxylic group (pKa₁ = 5.5 – 6.34) and a heterocyclic group (pKa₂ = 7.6 – 9.3), in the nucleus, which acquire charge at pH above and below the isoelectric point (pI = 6.75 – 7.78). At isoelectric point, fluoroquinolones remain unionized and show enhanced corneal penetration but exhibit reduced aqueous solubility and the drug may precipitate from aqueous solution. Aqueous ophthalmic solutions of fluoroquinolones are obtained by using hydrochloride or mesylate salt which is acidic and irritating to the eyes. Hence, pH of the solution is kept between 5 and 7 to ensure aqueous solubility and minimum ocular irritation.

Areas covered: This review gives an overview of various physicochemical and formulation factors affecting the ocular delivery of fluoroquinolones and strategies for getting higher ocular bioavailability for ocular delivery of fluoroquinolones. These strategies could be employed to improve efficacy of fluoroquinolones in eye preparation.

Expert opinion: Broad-spectrum antibacterials, such as the ophthalmic fluoroquinolones, are powerful weapons for treating and preventing potentially sight-threatening infections. The fourth-generation fluoroquinolones have quickly assumed an outstanding place in the ophthalmic applications. Especially valuable for their broad-spectrum coverage against Gram-positive and Gram-negative organisms, these agents have become the anti-infective of preference for many ophthalmologists. Moxifloxacin seems to be a promising powerful molecule among all fluoroquinolones for treatment of bacterial infections.     

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.     

Castor oil and mineral oil nanoemulsion: development and compatibility with a soft contact lens

Abstract

Context: The non-invasive ophthalmic therapy has a drawback: low residence time in the eye socket. Nanoparticles and contact lenses have been studied as promising ocular drug delivery systems.

Objective: To develop a nanoemulsion and evaluate its compatibility with a soft contact lens as a potential strategy for ocular delivery.

Materials and methods: The formulations were developed by spontaneous emulsification and fully characterized. Two drops of nanoemulsion were instilled on the surface of a commercial contact lens and its transparency was measured using a UV-Vis spectrophotometer. Before and after the instillation of the drops, the morphology (scanning electron microscopy – SEM) and ion permeability of the lenses were analyzed.

Results: The formulations had a mean particle size of 234?nm, polydispersity below 0.16, zeta potential of ?8.56?±?3.49?mV, slightly acid pH, viscosity ≈1.2?mPa?s^?1 and spherical-shaped particles. Nanoemulsion was non-irritant (hen’s egg test-chorioallantoic membrane), which was confirmed by the cytotoxicity studies in the SIRC cell cultures. After instillation, SEM analysis showed nanodroplets inside and on the surface of the lenses, although their transparency remained near 100%. No significant differences were found between lens ion permeability coefficients before and after instillation.

Conclusions: Formulations presented appropriate physicochemical characteristics and suitability for ocular application. The contact lens remained transparent and ion-permeable after association with the formulation.     

Controlled release of betamethasone from vitamin E-loaded silicone-based soft contact lenses

Context: Betamethasone (BMZ) is an effective drug which is commonly used as an eye drop for the management of ophthalmic inflammations. Due to low ocular bioavailability, it is necessary to prepare and optimize an ocular drug delivery system for BMZ.

Objective: In this study we tried to use vitamin E diffusion barrier for sustaining BMZ release.

Materials and methods: Three commercial contact lenses were soaked in vitamin E solutions and swelling percentage, diameter, transmittance, binding capacity and release amount and time were evaluated in comparison with non-vitamin E-loaded pure lenses.

Results: The results showed that vitamin E significantly decreased water content of contact lenses whereas, increased the lens diameter in both dry and wet states. It effectively blocked UV radiation which is harmful for the eye surface while had no significant effect on visible transmittance. BMZ loading capacity enhanced and release rate remarkably decreased after using vitamin E as a hydrophobic diffusion barrier.

Discussion and conclusions: This study revealed that vitamin E can be applied as a hydrophobic diffusion barrier for controlling and sustaining BMZ release from silicone-based soft contact lenses into the lachrymal fluid. It can also protect eye tissues as an antioxidant by blocking the UV radiation.     

Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis

Age-related macular degeneration, diabetic retinopathy, posterior uveitis, and retinitis due to glaucoma are leading causes of vision loss in the United States and other developed countries. Because these diseases are located in the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, since topically applied drugs rarely reach therapeutic levels in the affected posterior tissues such as the choroid and retina. Intravitreal injections can deliver drugs to the posterior segment without the side effects associated with systemic administration. However, the repeated and long-term injections often needed may cause complications, such as vitreous hemorrhage, retinal detachment, or endophthalmitis. Recent advances in ocular drug delivery methods and the development of novel biopharmaceutical agents could lead to new regimens for the treatment of disease of the posterior retina, choroids, and macula. This review will summarize recent literature concerning ocular drug delivery of bioactive compounds to the posterior segment of the eye with emphasis on transscleral iontophoresis.     

2nd Ophthalmic Drug Development and Delivery Summit

The Second Annual Ophthalmic Drug Development and Delivery Summit was held on 19 – 20 September 2006 in San Diego, CA, US. The 2-day symposium, having a highly focused theme, was packed with cutting-edge science, insightful overviews and networking opportunities. With a total of 11 recognized specialists presenting reviews and recent results in the advancement of ocular drug development and delivery, the invited expert speaking faculty presented the latest preclinical and clinical developments in novel ophthalmic therapies and drug delivery technology. The talks included various case studies from primary investigators and pharmaceutical companies touching upon key topics: updates on current clinical trials, study design issues, sustained delivery to the eye, views of the vitreous space as a drug reservoir, new developments in dry and wet age-related macular degeneration and diabetic retinopathy, formulation for optimal drug delivery, differences and similarities in developing drugs for the eye compared with other targets, pharmacokinetics, novel ocular delivery methods and devices, delivery of proteins and peptides, focal drug delivery, non-invasive drug delivery to the eye, neuroprotection challenges, in vitro and in vivo models for glaucoma and angiogenesis for early efficacy estimation, and toxicology. Overall, the 2-day annual symposium continues to grow as an efficient platform for fostering discussion on a range of scientific topics and challenges and avenues for building collaborative partnerships in ophthalmic drug development.     

Contact lenses as a platform for ocular drug delivery

Introduction: Most ophthalmic drugs are delivered through eye drops even though only about 1 – 5% of the drug reaches the target tissue and the patient compliance is not good. Drug-eluting contact lenses could significantly increase bioavailability, reduce side effects and improve patient compliance.

Areas covered: Recent research on drug-eluting contact lenses has focused on increasing the release duration through molecular imprinting, dispersion of barriers or nanoparticles, increasing drug binding to the polymer, sandwiching a PLGA (poly[lactic-co-glycolic acid]) layer in a lens and developing novel materials. This review covers all these studies with a specific focus on the transport mechanisms and advantages and disadvantages of each approach.

Expert opinion: The main reason for prior failures was the short duration of release from the lenses. The new technologies can provide extended drug release for hours to days. The in vivo animal and clinical studies have proven the safety and efficacy of drug-eluting contact lenses, while showing considerable improvements compared to eye drops. The future appears to be promising but several challenges remain such as processing and storage issues, regulatory hurdles, high costs of clinical studies, potential lack of acceptance by the elderly, etc.     

Review of ocular drug delivery

Successful treatment of eye diseases requires effective concentration of drug at the eye for sufficient period of time. Conventional ocular drug delivery including eye drops, systemic administration, ophthalmic ointments, is no longer sufficient to combat ocular diseases. This article reviews the constraints with conventional ocular therapy, and explores various novel approaches, to improve the ocular bioavailability of drugs to the anterior chamber of the eye.     

Recent Perspectives in Ocular Drug Delivery

Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. 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. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. All the authors contributed equally to this work.     

Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery

Poor ocular bioavailability of drugs (<1%) from conventional eye drops (ie, solution, suspension, and ointments) is mainly due to the physiologic barriers of the eye. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. In our current work, we develop and evaluate a new colloidal system, that is, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles for sparfloxacin ophthalmic delivery, to improve precorneal residence time and ocular penetration. Nanoparticles were prepared by nanoprecipitation technique and characterized for various properties such as particle size, zeta potential, in vitro drug release, statistical model fitting, stability, and so forth. Microbiological assay was carried out against Pseudomonas aeruginosa using the cup-plate method. Precorneal residence time was studied in albino rabbits by gamma scintigraphy after radiolabeling of sparfloxacin by Tc-99m. Ocular tolerance of the developed nanosuspension was also studied by the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method. The developed nanosuspension showed a mean particle size in the range of 180 to 190 nm, suitable for ophthalmic application with zeta potential of –22 mV. In vitro release from the developed nanosuspension showed an extended release profile of sparfloxacin according to the Peppas model. Acquired gamma camera images showed good retention over the entire precorneal area for the developed nanosuspension compared with that of a marketed formulation. The marketed drug formulation cleared very rapidly from the corneal region and reached the systemic circulation through the nasolacrimal drainage system, as significant radioactivity was recorded in kidney and bladder after 6 hours of ocular administration, whereas the developed nanosuspension cleared at a very slow rate (P < .05) and remained at the corneal surface for longer duration, as no radioactivity was observed in the systemic circulation. HET-CAM assay with 0 score in 8 hours indicates the nonirritant property of the developed nanosuspension. The developed lyophilized nanosuspension was found to be stable for a longer duration of time than the conventional marketed formulation with a good shelf life.From the Clinical EditorPoor ocular bioavailability of drugs (<1%) from conventional eye drops is mainly due to the eye physiological barriers. In this study, a new colloidal system, PLGA nanoparticle for sparfloxacin ophthalmic delivery was demonstrated to improve precorneal residence time and ocular penetration. The developed lyophilized nanosuspension was found to be stable for longer duration of time than conventional marketed formulations.