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Fig. 15.8 Clinical tolerance of CCI on patients with severe intraocular inflammation. (a) Picture of the eye of a patient, before CCI, during CCI and immediately after CCI. (b) Subjective tolerance of CCI on 93 patients receiving 263 treatments
with the tissue resistance varying during the procedure, the delivered current must be adapted to these tissue changes.
In 2004, we published a portion of our results of a large clinical study evaluating the tolerance and efficacy of iontophoresis of methylprednisolone sodium succinate (Solumedrol) on patients with severe intraocular inflammation. Between April 1999 and October 2001, 93 patients were included in a study designed to evaluate the tolerance of transscleral iontophoresis. Patients with severe intraocular inflamma­tion requiring systemic corticosteroids were included in the study and received instead of the systemic therapy, transscleral iontophoresis of sodium succinate methylprednisolone 62.5 3 min and the patients received 1–5 treatments, mean 2.7 ± 0.9.
As shown in Fig. 15.8, the treatment was well tolerated with 86% of the patients experiencing none to slight pain during the procedure. Seventeen patients were treated for acute graft rejection with iontophoresis of methylprednisolone in place of systemic pulsetherapy. As published in 2004, we showed that this local treatment allowed to reverse the rejection with an efficacy comparable to the known effects of pulse therapy in this indication (Halhal et al. 2004) (Fig. 15.9). Already at day 10, and after three iontophoresis, 88% demonstrated a complete reversal of the rejection processes. In two eyes, only a partial and temporary improvement was observed.
mg/mL. Intensity of the current was 1.7 ± 0.18 mA for
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Fig. 15.9 CCI of MPSS on 17 patients with acute graft rejection. (a) Example of a patient with acute graft rejection before treatment and at day 10 after three CCI of MPSS. (b) Visual acuity of 17 patients with acute graft rejection before treatment
The mean best corrected visual acuity of all 17 patients during the last follow-up visit was 0.37 ± 0.2 compared to 0.06 ± 0.05 before initiation of the iontophoresis treatment. The mean follow-up time was 13.7 months with a range of 5–29 months for the 17 patients. No significant side effects associated with the iontophoresis treatment were observed.
In 2005, Horwath-Winter et al. treated 16 patients with iodide iontophoresis for the treatment of dry eye. The patients were treated for 10 days and compared with the patients receiving iodide application without current. Significant and increased duration of symptom improvement and conditions were observed in the group of patients treated with iontophoresis (Horwath-Winter et al. 2005).
Since then, several studies have been undertaken with the Eyegate transscleral iontophoresis system. Results should be published soon and possibly lead to FDA approval.
15.5 Applications of Iontophoresis to Ocular Gene Therapy
Iontophoresis has been mostly used to promote the ocular delivery and intracellular entry single strand oligonucleotides. Asahara et al. reported on the use of iontopho­resis for promoting intraocular penetration of topically applied nucleic acid. After transcorneal iontophoresis, a topically applied 6-FAM labeled 23 base antisense ODN of human aldose reductase was detected in the aqueous humor, the vitreous
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and retina after 5, 10 and 20 min, respectively. Optimal parameters in this study were 1.5 mA (gradually reached in 2 min) and 100 V of alternating current, applied for 5 min. No sign of ocular toxicity was reported. In this single report, transcorneal iontophoresis after delivery of a plasmid encoding GFP yielded green fluorescence in the rabbit cornea, anterior chamber angle and the ciliary subepithelial tissues (Asahara et al. 2001). In our hands, direct transcorneal and transscleral iontophoresis in rabbit and rat eyes did not enhance the transfection of reporter gene plasmids to corneal or intraocular tissues (unpublished data). However, iontophoresis of ODNs applied at a current of 500 Significant intraocular concentration of ODNs within the iris/ciliary body complex was initially observed at 1 h, and a significant accumulation within the retina/choroid complex was observed at 6 h (Berdugo et al. 2003). In this study, we used a custom- made polyethylene-coated transcorneoscleral eye probe with annular surface of
0.5 cm2 covering the cornea, the limbus and the scleral area adjacent to the limbus. A 27-gauge needle placed in the rat leg served as the anodal return electrode.
Furthermore, using antisense-NOSII ODN we successfully achieved significant down-regulation of NOSII expression in the iris/ciliary body tissues of rat eyes with endotoxin-induced uveitis (Voigt et al. 2002a–c).
After transcorneoscleral iontophoresis (1.5 mA/cm2 for 5 min) of fluorescent phosphorothioate anti-VEGF-R-2 ODN in rat eyes, we observed ODN in all corneal layers (with higher concentrations within Descemet membrane) and in the iris. When corneal neovessels were present, ODN was detected in vascular endothelial cells and in infiltrating leucocytes. ODN extracted from the tissues 90 min after iontophoresis were found intact.
Using a specifically designed transpalpebral iontophoresis device, we studied the internalization of ODN in the retinal layers of new born rd1/rd1 mice. In this mouse model, rapid retinal degeneration occurs as a result (in part) of a point mutation in the gene encoding the b-subunit of rod photoreceptor cGMP-phosphodiesterase (b­PDE). Transpalpebral cathodal saline iontophoresis was more efficient than anodal iontophoresis in enhancing the penetration of intravitreally injected ODN (encoding for the sense wild type b-PDE) in the nuclei of all retinal layers. Moreover, photo­receptor delivery of ODN was significantly higher when cathodal saline transpalpe­bral iontophoresis was applied prior to the ODN injection. This study thus illustrates that a tissue postiontophoretic penetration enhancement takes place (Andrieu-Soler et
al. 2006, 2007).
mA (1 mA/cm2) enhanced their intraocular penetration.
15.6 Future Developments
Given the possibility of deliberate manipulation of the properties of the skin charge distribution by altering the formulation of the physicochemical properties of the permeant, or the formulation vehicle in which a permeant molecule is applied, clinical consideration must be given to how a drug and an iontophoretic controller device are coupled to the target tissue. For ophthalmic applications, the current drug solutions
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prepared for iontophoretic treatment often employ formulations developed for other drug delivery modalities (e.g., drops). These solutions are not ideal as they have not been adapted to target ocular surfaces using an electrical field. For iontophoretic applications to the skin, more advanced semi-solid and gel formulations, often mod­ified after those developed for passive transdermal drug delivery, are readily com­patible with the skin surface. These formulation vehicles allow for manipulation of electrical conductivity, bioadhesion and viscoelastic properties to assure compati­bility and stability over the desired application time. Moreover, deliberate formula­tions for ophthalmic drug interest are envisioned as a needed aspect of the development of ocular iontophoresis.
In the future, reverse iontophoresis may be used to dose intraocular biomarkers allowing for instant diagnostic. Delivery of the therapeutic compounds could then be modulated in response to this specific biodiagnostic.
The first step towards this future is to allow iontophoresis to enter clinical practice.
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Chapter 16
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Drug and Gene Therapy Mediated by Physical Methods
John M. Nickerson and Jeffrey H. Boatright
Abstract A strategy to deliver drugs to the posterior segment of the eye is via a
combination of physical methods to place the drug adjacent to the target cell and to open the cell membrane so that the drug can pass into the cell. Electric fields can be used to transport small and large charged molecules and to open pores in the plasma membrane. Here we review these physical methods and the progress to exploit elec­tric fields in drug delivery.
16.1 Introduction
Effective drug treatment in the posterior segment remains a challenge for ophthal­mologists and pharmaceutical scientists. Several physical approaches offer the opportunity to deliver drugs or other agents to the posterior segment and into the interior of a target cell. Some of these processes overcome drug delivery impedi­ments by use of electromagnetic fields to transiently break or disrupt barriers to cell entry, and the techniques include most frequently: iontophoresis, electroporation, electrophoresis, or photo-acoustic energies to accomplish delivery. While none of these technologies is new, improvements to these approaches now offer realistic drug delivery via these physical methods. These physical methods often may be used in conjunction with other approaches such as formulation of drugs in nano- or microparticles for sustained long-term drug release and local delivery via injection at the target site to enhance efficacy.
J.M. Nickerson (*) Department of Ophthalmology, Emory University, 1365B Clifton Road, Atlanta, GA 30322, USA e-mail: litjn@emory.edu
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_16, © American Association of Pharmaceutical Scientists, 2011
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16.2 Background
Some chapters in this book consider ways to improve drugs and to identify better candidate targets for different and more efficacious drugs in treating diseases of the posterior segment. Other chapters consider the current state of the art, current standard of care, and the problems associated with current best practices for the treatment of eye diseases in the posterior segment of the eye. Key elements in the success of a new drug include its formulation, the route of delivery, and its targeting to appropriate cells. The latter two points are the focus of this chapter.
16.2.1 Intravitreal Injections
The greatest success in treating diseases of the posterior segment have been through intravitreal injection or intravitreal implantation of slowly eroding mate­rials to release a drug. Most other methods (topical eye drops, systemic oral, subconjunctival, and parenteral) have not been as effective in drug delivery due primarily to dilution. Because of the rapid rate of increase and the already large number of intravitreal injections for treating wet AMD, there are concerns on several fronts that this approach might warrant improvement or change to reduce risks of complications, changes in protocol to reduce health care cost, and modi­fication to reduce burdens on patients and their caregivers. Drugs such as Ranibizumab (Lucentis) and Bevacizumab (Avastin) are remarkable in that they halt neovascularization and improve visual acuity in wet AMD. These two drugs appear to improve the quality of life for the patient, though these drugs handcuff the patient to the doctor and present logistical nightmares for relatives and care­givers because of the high frequency of treatment and continued need for repeat treatments. Ranibizumab is expensive. Treatment with either drug raises costs including physicians’ services and imaging services (cf., OCTs to judge the effec­tiveness of these treatments). Clearly, these drugs have become the standard of care despite these limitations, because of their apparent superiority over previous treatments such as macugen, PDT, laser photocoagulation, or forms of combina­tion therapy.
Alternatives are needed for the treatment of AMD, especially for the dry form. Similar issues are becoming more obvious with other related retinal diseases that all culminate in Macular Edema.
A major part of the success of Bevacizumab and Ranibizumab is the route of drug delivery, intravitreal injection across the pars plana. Highlighted in other chap­ters in this book were the initial reticence to undertake intravitreal injections of any agent until the success of clinical trials to treat endophthalmitis and uveitis, and suc­cessful implantation of slow release formulations of ganciclovir for CMV retinitis in AIDS patients.