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.     

用于治疗糖尿病视网膜病变的抗血管新生药物

糖尿病视网膜病变是糖尿病的主要并发症,也是中老年人失明的重要原因之一。血管新生被普遍认为是糖尿病视网膜病变的治疗靶点。综述可用于治疗糖尿病视网膜病变的抗血管新生药物,包括抗血管内皮细胞生长因子药物、皮质类固醇激素、蛋白激酶C-β抑制剂和色素上皮衍生因子等的研究进展,为该类药物的深入开发和临床应用提供思路。     

Cubosomes and other potential ocular drug delivery vehicles for macromolecular therapeutics

Introduction: Many macromolecular therapeutics designed to treat posterior segment eye diseases (PSEDs) are administered through frequent ocular injection, which can further deteriorate eye health. Due to the high frequency of injection and the high cost of the therapeutics, there is a need to develop new ways in which to deliver these therapeutics: ways which are both safer and more cost effective.

Areas covered: Using the most common PSED, age-related macular degeneration, as an example of a debilitating ocular disease, this review examines the key barriers limiting the delivery of macromolecular therapeutics to the posterior segment of the eye and defines the key requirements placed on particulate drug delivery vehicles (DDVs) to be suitable for this application. Recent developments in macromolecular drug delivery to treat this disease as well as the remaining shortcomings in its treatment are surveyed. Lastly, an emerging class of DDVs potentially suited to this application, called cubosomes, is introduced.

Expert opinion: Based on their excellent colloidal stability and high internal surface area, cubosomes hold great potential for the sustained release of therapeutics. Novel production methods and a better understanding of the mechanisms through which drug release from these particles can be controlled are two major recent developments toward successful application.     

Models of retinal diseases and their applicability in drug discovery

Introduction: The impact of vision debilitating diseases is a global public health concern, which will continue until effective preventative and management protocols are developed. Two retinal diseases responsible for the majority of vision loss in the working age adults and elderly populations are diabetic retinopathy (DR) and age-related macular degeneration (AMD), respectively. Model systems, which recapitulate aspects of human pathology, are valid experimental modalities that have contributed to the identification of signaling pathways involved in disease development and consequently potential therapies.

Areas covered: The pathology of DR and AMD, which serve as the basis for designing appropriate models of disease, is discussed. The authors also review in vitro and in vivo models of DR and AMD and evaluate the utility of these models in exploratory and pre-clinical studies.

Expert opinion: The complex nature of non-Mendelian diseases such as DR and AMD has made identification of effective therapeutic treatments challenging. However, the authors believe that while in vivo models are often criticized for not being a ‘perfect’ recapitulation of disease, they have been valuable experimentally when used with consideration of the strengths and limitations of the experimental model selected and have a place in the drug discovery process.     

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.

     

Investigation of the Size Distribution for Diffusion-Controlled Drug Release From Drug Delivery Systems of Various Geometries

Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.     

Current and investigational pharmacotherapeutic approaches for modulating retinal angiogenesis

Retinal vascular development is a carefully orchestrated developmental process during which retinal and choroidal vasculature form to provide a dual vascular supply to the neurosensory retina and retinal pigment epithelium. The most common causes of vision loss in children and adults involve at least in part perturbation of the normal vascular physiology or development. Vascular endothelial growth factor has emerged as a key molecular regulator of retinal vascular development as well as retinal and choroidal neovascularization, which underlie the pathophysiology of many retinal diseases. Over the past decade, the advent of injectable pharmacotherapeutic agents into the vitreous cavity of the eye has revolutionized our management of neovascular age-related macular degeneration and other retinal diseases and has, for the first time, offered an opportunity to improve vision rather than just slow the progression of disease processes. The transient duration of these agents, however, requires chronic treatment with repeated intraocular injections and significant treatment burden for patients and the healthcare system. Novel treatments modulating retinal angiogenesis offer the promise of improved efficacy, decreased treatment burden and improved cost–effectiveness.     

VEGF inhibitors for the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.     

Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Photosensitisers for the photodynamic therapy of cancer and other diseases

Photodynamic therapy is a relatively recent addition to the clinic, primarily for the treatment of cancer but also for psoriasis, age-related macular degeneration and other diseases. Photodynamic therapy utilises a photosensitiser that targets the disease site to produce a photochemical reaction following delivery of light. The properties of the photosensitiser are critical to the outcome of the technique and numerous classes have been developed in the past decade, including porphyrins and related compounds, chlorins, phthalocyanines, naphthalocyanines, texaphyrins, core-modified porphyrins and various cationic dyes. The potential of this technique is apparent from the extensive number of patents that have been awarded over the past three years.     

Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

Introduction: Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases.

Areas covered: This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner.

Expert opinion: Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects.     

肝靶向微粒给药系统的研究进展

目的对近年来微粒给药系统在肝靶向治疗的研究进展做一综述。方法根据国内外文献资料进行整理归纳。结果纳米粒、微球、脂质体及微乳等微粒系统具有被动靶向于肝的趋势,利用肝细胞表面某些受体则可特异性靶向于肝达到主动靶向作用。结论微粒给药系统在肝靶向治疗领域具有重要意义。     

Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid

The aim of this study was to prepare spray dried inhalable powders containing isoniazid-loaded chitosan/tripolyphosphate (TPP) nanoparticles for sustained delivery of the drug to the lung. Nanoparticles were prepared by ionic gelation method. In-vitro drug release study indicated that the rate of drug release from nanoparticles was decreased by increasing the amount of chitosan. Entrapment of isoniazid into chitosan/TPP nanoparticles decreased minimum inhibitory concentrations (MIC) of the drug against mycobacterium avium intracellulare. Nanoparticles were spray dried using excipients such as lactose, mannitol and maltodextrin alone or with leucine. Results showed that the obtained powders had different aerosolization property. It was observed that by adding leucine, the particle size of microparticles deceased and the process yield and fine particle fraction (FPF) increased significantly. The in-vitro deposition data indicated that spray drying of isoniazid-loaded nanoparticles with lactose in the presence of leucine resulted in the production of inhalable powders with the highest FPF (45%).     

Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy

RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments.     

Biodegradable gentamicin delivery systems for parenteral use for the treatment of intracellular bacterial infections

Gentamicin is an aminoglycoside with a wide spectrum of antibacterial activity. However, as a highly water-soluble drug, it penetrates cells poorly. This constitutes a particularly important drawback for treating intracellular bacterial infections. This major hurdle may be solved by the use of vectors to deliver and target bioactive agents to the intracellular sites of infection. Thus, in the case of antimicrobials, drug delivery systems may help to increase their therapeutic index in intracellular locations. The development and evolution of pharmaceutical forms of gentamicin for the parenteral treatment of intracellular pathogens is reviewed in this paper.     

Alpha-lipoic acid: A possible pharmacological agent for treating dry eye disease and retinopathy in diabetes

Alpha-lipoic acid (ALA) is a naturally occurring dithiol micronutrient which acts as a cofactor for mitochondrial enzyme activity. Due to its potential antioxidant activity, it is considered as “universal antioxidant”. Previous studies reported the pharmacological benefits of ALA such as glycaemic control, improved insulin sensitivity and alleviation of diabetic complications such as neuropathy and cardiovascular diseases. Dry eye disease and retinopathy are prevalent in diabetic patients. Experimental studies demonstrated the beneficial effects of ALA in dry eye and diabetic retinopathy. ALA can prevent the dry eye by down regulating the expression of matrix metalloproteinase-9 in the corneal epithelial cells and activating the antioxidant status of the ocular surface. Furthermore, its direct antioxidant effect can also prevent oxidative stress-induced corneal surface erosion and lachrymal gland damage. ALA prevents diabetic retinopathy through inhibition of O-linked β-N-acetylglucosamine transferase and nuclear factor-kappa B activity and alleviation of oxidative stress. It can activate the nuclear factor erythroid-2-related factor 2 and AMP-activated protein kinase in retinal ganglion cells. Clinical trials conducted in pre-retinopathic diabetic patients showed ALA with genistein and vitamins could protect the retinal cells and decline the inflammatory effect in diabetic patients. However, studies are scant to explore its beneficial effects in dry eye disease and diabetic retinopathy. Therefore, this review article discusses an update on the role of ALA in dry eye disease and diabetic retinopathy, two ocular diseases prevalent in diabetic patients.     

Delivery of steroids into the eye for the treatment of macular edema

ABSTRACT

Introduction: Steroids have been in extensive use in ophthalmology since their discovery in 1948. Steroids are effective for the treatment of macular edema and may be delivered into the eye either topically, systemically, subconjunctivally, sub-Tenon, intravitreally and through injectable sustained release devices. Various steroid formulations and devices are commercially available. Each carries advantages and disadvantages, which requires the ophthalmologist to exercise careful medical judgment upon treatment selection.

Areas covered: This article focuses in steroid delivery into the eye for the treatment of macular edema, and reviews the current and future treatment options, summarizing their clinical efficacy and possible adverse effects.

Expert opinion: Steroids have an important role in the treatment of macular edema, regardless of its cause. Steroids are efficacious, low-cost, and much clinical experience has been accumulated regarding their use over the years. Prolonged systemic steroid use may be associated with severe systemic and local side effects, directly proportional to dosage and time. Intravitreal delivery of steroids has gained popularity as the medication is administered close to the target tissue, significantly reducing the possibility of systemic adverse effects. The biggest problem associated with intravitreal steroids still remains unacceptably high risk of glaucoma and cataract formation. Various controlled-release intravitreal delivery devices are currently commercially available, and more are in the pipeline. While they still carry the risk of local side effects, they are efficacious and can control macular edema for months and years after a single administration.