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Advanced Drug Delivery Reviews (v.58, #11)
Challenges and obstacles of ocular pharmacokinetics and drug delivery by Arto Urtti (pp. 1131-1135).
Modern biological research has produced increasing number of promising therapeutic possibilities for medical treatment. These include for example growth factors, monoclonal antibodies, gene knockdown methods, gene therapy, surgical transplantations and tissue engineering. Ocular application of these possibilities involves drug delivery in many forms. Ocular drug delivery is hampered by the barriers protecting the eye. This review presents an overview of the essential factors in ocular pharmacokinetics and selected pharmacological future challenges in ophthalmology.
Keywords: Pharmacokinetics; Eye; Drug delivery; Epithelial barriers; Posterior segment
Drug transport in corneal epithelium and blood–retina barrier: Emerging role of transporters in ocular pharmacokinetics by Eliisa Mannermaa; Kati-Sisko Vellonen; Arto Urtti (pp. 1136-1163).
Corneal epithelium and blood–retina barrier (i.e. retinal capillaries and retinal pigment epithelium (RPE)) are the key membranes that regulate the access of xenobiotics into the ocular tissues. Corneal epithelium limits drug absorption from the lacrimal fluid into the anterior chamber after eyedrop administration, whereas blood–retina barrier restricts the entry of drugs from systemic circulation to the posterior eye segment. Like in general pharmacokinetics, the role of transporters has been considered to be quite limited as compared to the passive diffusion of drugs across the membranes. As the functional role of transporters is being revealed it has become evident that the transporters are widely important in pharmacokinetics. This review updates the current knowledge about the transporters in the corneal epithelium and blood–retina barrier and demonstrates that the information is far from complete. We also show that quite many ocular drugs are known to interact with transporters, but the studies about the expression and function of those transporters in the eye are still sparse. Therefore, the transporters probably have greater role in ocular pharmacokinetics than we currently realise.
Keywords: Transporter; Corneal epithelium; Retinal pigment epithelium; Retinal capillaries; Ocular drug delivery; Ocular pharmacokinetics
Transscleral drug delivery to the posterior eye: Prospects of pharmacokinetic modeling by Veli-Pekka Ranta; Arto Urtti (pp. 1164-1181).
Basic biological research has provided new approaches to treat severe diseases of the retina and choroid, such as age related macular degeneration. Although it is possible to deliver drugs from a subconjunctival drug depot to the retina and choroid, the barriers and kinetics of this route of drug administration are not well known. In this review we investigate the pharmacokinetic aspects of transscleral drug delivery into the posterior eye with emphasis on pharmacokinetic modeling. The existing simulation models related to the transscleral drug delivery are reviewed and future directions for the model development are discussed. In addition, a new simulation model for the transscleral drug delivery based on permeability data is introduced. This compartmental model contains several ocular tissues (sclera, choroid, retinal pigment epithelium and vitreous) and it takes into account the clearance of the drug via choroidal circulation. The model is used to simulate the vitreous delivery of macromolecules based on the available data on FITC-dextran 70Â kDa.
Keywords: Ocular drug delivery; Pharmacokinetic simulation; Permeability; Sclera; Choroid; Retina; Vitreous
Intraocular implants for extended drug delivery: Therapeutic applications by J.L. Bourges; C. Bloquel; A. Thomas; F. Froussart; A. Bochot; F. Azan; R. Gurny; D. BenEzra; F. Behar-Cohen (pp. 1182-1202).
An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.
Keywords: Drug delivery; Ocular implants; Particulate drug delivery systems; Nanoparticles; Microparticles; Polymers; Liposomes
Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA by Elias Fattal; Amélie Bochot (pp. 1203-1223).
Nucleic acids have gained a lot of interest for the treatment of ocular diseases. The first to enter in clinic has been Vitravene® an antisense oligonucleotide for the treatment of cytomegalovirus (CMV) infection and more recently, research on aptamers have led to the marketing of anti-vascular endothelial growth factor (VEGF) inhibitor (Macugen®) for the treatment of age-related macular degeneration (AMD). The siRNAs appear very promising as they are very potent inhibitors of protein expression. Despite their potential, nucleic acids therapeutic targets of nucleic acid-based drugs are mainly located in the posterior segment of the eye requiring invasive administration which can be harmful if repeated. Their intracellular penetration in some cases needs to be enhanced. This is the reason why adequate delivery systems were designed either to insure cellular penetration, protection against degradation or to allow long-term delivery. A combination of both effects was also developed for an implantable system. In conclusion, the intraocular administration of nucleic acids offers interesting perspectives for the treatment of ocular diseases.
Keywords: Antisense oligonucleotides; Aptamers; siRNA; Intravitreal administration; Cationic polymers; Cationic lipids; Nanoparticles; Microparticles; Liposomes; Dendrimers; Iontophoresis
Non-viral ocular gene therapy: Potential ocular therapeutic avenues by C. Bloquel; J.L. Bourges; E. Touchard; M. Berdugo; D. BenEzra; F. Behar-Cohen (pp. 1224-1242).
Non-viral vectors for potential gene replacement and therapy have been developed in order to overcome the drawbacks of viral vectors. The diversity of non-viral vectors allows for a wide range of various products, flexibility of application, ease of use, low-cost of production and enhanced “genomic� safety. Using non-viral strategies, oligonucleotides (ODNs) can be delivered naked (less efficient) or entrapped in cationic lipids, polymers or peptides forming slow release delivery systems, which can be adapted according to the organ targeted and the therapy purposes. Tissue and cell internalization can be further enhanced by changing by physical or chemical means. Moreover, a specific vector can be selected according to disease course and intensity of manifestations fulfilling specific requirements such as the duration of drug release and its level along with cells and tissues specific targeting. From accumulating knowledge and experience, it appears that combination of several non-viral techniques may increase the efficacy and ensure the safety of these evolving and interesting gene therapy strategies.
Keywords: Gene therapy; Eye disease; Gene delivery; Gene replacement
Current status of gene delivery and gene therapy in lacrimal gland using viral vectors by Shivaram Selvam; Padmaja B. Thomas; Sarah F. Hamm-Alvarez; Joel E. Schechter; Douglas Stevenson; Austin K. Mircheff; Melvin D. Trousdale (pp. 1243-1257).
Gene delivery is one of the biggest challenges in the field of gene therapy. It involves the efficient transfer of transgenes into somatic cells for therapeutic purposes. A few major drawbacks in gene delivery include inefficient gene transfer and lack of sustained transgene expression. However, the classical method of using viral vectors for gene transfer has circumvented some of these issues. Several kinds of viruses, including retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications. The transfer of genetic material into lacrimal epithelial cells and tissues, both in vitro and in vivo, has been critical for the study of tear secretory mechanisms and autoimmunity of the lacrimal gland. These studies will help in the development of therapeutic interventions for autoimmune disorders such as Sjögren's syndrome and dry eye syndromes which are associated with lacrimal dysfunction. These studies are also critical for future endeavors which utilize the lacrimal gland as a reservoir for the production of therapeutic factors which can be released in tears, providing treatment for diseases of the cornea and posterior segment. This review will discuss the developments related to gene delivery and gene therapy in the lacrimal gland using several viral vector systems.
Keywords: Abbreviations; Ad; adenovirus; IL; interleukin; IFN; interferon; TNF; tumor necrosis factor; β-gal; β-galactosidaseViral vectors; Lacrimal gland; Gene therapy; Gene delivery; Sjögren's syndrome; Exocytosis
Industrial perspective in ocular drug delivery by Yusuf Ali; Kari Lehmussaari (pp. 1258-1268).
In the development of a commercial drug product, the formulator must consider various perspectives. The bioavailability of the active drug substance is often the major hurdle to overcome. In the past it has been common to add viscosity-enhancing agents or mucoadhesive polymers into formulations to improve ocular bioavailability. In addition to these conventional approaches, non-conventional technologies such as nanotechnology, microspheres and prodrugs could be considered to optimize the product.Along with bioavailability, the formulator must also consider the tolerability and stability of the final drug product. Quite often, the final formulation is the ideal compromise between the three.Authorities in different parts of the world have set strict requirements and guidelines for development and approval of drug products. In order to secure an expeditious development process and the shortest possible review and approval time, the formulator should be familiar with the current requirements and regulations.
Keywords: Ocular drug delivery; Eye drops; Suspensions; Ointments; Gels; Dosage forms; Mucoadhesives; Regulatory requirements; New drug application; Marketing authorization application; Clinical trial application; Investigational new drugs