Chapter 17

Protein Drug Delivery and Formulation

Development

Rinku Baid, Puneet Tyagi, Shelley A. Durazo, and Uday B. Kompella

Abstract  Several therapeutic agents including low and high molecular weight drugs intended for treating back of the eye disorders are routinely administered as intravitreal injections. Intravitreal injection of Lucentis®, a therapeutic protein, was approved in 2006 for treating the wet form of age-related macular degeneration. This chapter summarizes the challenges and opportunities in delivering therapeutic proteins to the eye. Specifically, barriers to delivery including permeability barriers, examples of marketed therapeutic agents as well as those under development, formulation approaches for proteins, and novel delivery systems are discussed. Wherever appropriate, other macromolecules such as aptamers that bind specific protein targets are also discussed.

17.1  Introduction

For people between the ages of 25 and 74 in the United States, the most common cause of blindness is diabetic retinopathy (progressive damage of retina due to diabetes)­ (Congdon et al. 2004). For people aged 60 and older, cataract (impaired vision due to the development of cloudiness or opacity in the lens), retinitis pigmentosa (RP, a retinal disease that causes progressive peripheral loss of vision leading to central vision loss in the retina), and age-related macular degeneration (AMD, degeneration of macula due to age, stress, poor nutrition, and other factors, leading to loss of vision) are the major causes of blindness. Of the above disorders, diabetic

U.B. Kompella (*)

Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado, 12850 East Montview Blvd., C238-V20, Aurora, CO 80045, USA

Department of Ophthalmology, University of Colorado, Aurora, CO, USA e-mail: uday.kompella@ucdenver.edu

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 409 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_17,

© American Association of Pharmaceutical Scientists, 2011

retinopathy and AMD have neovascular forms of the disease. In proliferative ­diabetic retinopathy (PDR) and neovascular AMD (NVAMD) or wet AMD, retinal neovascularization and choroidal neovascularization (CNV) are evident, respectively. As discussed in this chapter, macromolecule drugs have revolutionized the treatment of wet AMD. Currently, several other macromolecules are under development for the back of the eye. Below, prior approaches to treat wet AMD along with examples of macromolecule therapeutics for this and other back of the eye disorders are discussed.

At least as early as 1971, laser photocoagulation was introduced as the primary treatment for neovascularization (new vessel growth). For laser photocoagulation, an argon, xenon, or krypton laser is aimed at the new blood vessels in order to destroy them using laser generated thermal energy (May et al. 1976; Group 1991). Since thermal laser photocoagulation may lead to reduced vision due to the destruction of photoreceptors in the targeted area of the retina, especially the fovea (a region of the macula responsible for fine vision), it is applicable when abnormal vessels do not occupy the foveal region. Clinical evidence shows a decrease in the rate of severe visual loss and prevention of further contrast sensitivity loss with laser photocoagulation. However, following laser photocoagulation, recurrence of neovascularization occurs within 2 years of treatment (Group 1991; Yamaoka et al. 1994). Regardless of potential adverse events and poor clinical outcome after 2 years, laser photocoagulation remains the main treatment option for PDR and investigations are underway to improve the clinical outcomes with this technique (Nagpal et al. 2010).

Another treatment for neovascularization is photodynamic therapy (PDT) (Kaiser 2005), which entails intravenous infusion of verteporfin, a photosensitizing agent, which binds to low density lipoprotein (LDL) receptors that are elevated in abnormal endothelial vessels. Subsequent application of laser energy activates verteporfin, which then produces free radicals, ultimately causing damage to endothelial cells and thrombus formation. Photofrin® was approved in 1995 for the treatment of malignant dysphagia caused by esophageal cancer and Visudyne® was approved in 2000 as the first pharmacotherapy for treating neovascular or wet AMD. Compared to thermal laser photocoagulation, treatment with PDT is safer (Schmidt-Erfurth et al. 1998). Photocoagulation and PDT are effective only during the proliferative stage of disease. A clinical trial in 1998 found that leakage from CNV in a majority of the patients was stabilized up to 3 months after PDT treatment, yet recurrence of CNV was observed in 50% of the eyes after 2 years of PDT treatment (Schmidt-Erfurth et al. 1998; Wormald et al. 2007). However, with the arrival of anti-vascular endothelial growth factor (anti-VEGF) therapy, laser photocoagulation and PDT are finding less widespread use.

Advances in anti-VEGF drug discovery introduced promising and revolutionary macromolecule therapeutic agents for ocular diseases. Pegaptanib (Macugen®, EyeTech), a PEGylated aptamer (oligonucleotide ligands having selective high binding affinity for molecular targets) is effective in preventing vision loss in patients with CNV by binding to VEGF. Ranibizumab (Lucentis®, Genentech), a monoclonal antibody fragment, has been shown to improve visual acuity in patients with wet AMD.