Treatments Pharmacologic in Knowledge Evolving• 1 chapter

The formerly mentioned new therapeutic molecules still require a direct intravitreal injection for usual clinical treatment. Thus, unfortunately, the problem of these potential treatments remains in achieving adequate bioavailibility and prolonged therapeutic tissue concentration.12

“PLAYERS” IN OCULAR TREATMENT

The eye is an extraordinary organ. Due to its accessibility and transparency, it offers a unique advantage for pharmacologic and surgical treatments and is therefore very attractive from the perspective of drug delivery. However, its unique structure requires many different therapies, especially in regard to its complex anatomical composition. The eye represents a small multicompartmental system with various tissues, boundaries, and fluid flow factors.13

Vitreous, retina, RPE, choroid, and barriers in the anterior segment, such as the stromal tissues of the cornea and the sclera, the corneal epithelium, and endothelium, might affect ocular drug pharmacokinetics. In addition the outer and inner blood–retinal barriers which are formed by RPE and retinal vascular endothelium, respectively, and the internal limiting membrane on the vitreoretinal interface represent further barriers in the posterior segment.

As a result of advances in the understanding of the pathophysiological processes in the retina and choroid, a rapidly growing interest and demand in posterior-segment drug delivery systems can be noticed.14 Unfortunately, effective treatment methods are not currently available for many of these diseases.

Posterior eye diseases present a major challenge, as they cause impaired vision and blindness for millions of patients all around the world. In industrialized countries, AMD is the major cause of blindness. Almost 2 million people are affected by this disease in the USA alone. Other major diseases of the posterior eye segment include retinal degeneration, diabetic retinopathy, and glaucoma, where loss of vision is caused by death of the retinal ganglion cells. The growing number of patients worldwide and the socioeconomic impact necessitate an earlier and more targeted treatment of these diseases.

Despite extensive research in the field of ocular pharmacotherapy and new promising treatments, the quest for a specific tissueand disease-targeted therapy is still going on.15,16

THE DRUG

The drug itself is of major importance in regard to its pharmaceutical and pharmacokinetical characteristics, including its specific molecular and chemical structure, its hydrophilic or lipophilic behavior, and finally its therapeutic mode of action.14

Based on the above characteristics a high ocular penetration should ideally be obtained, resulting in therapeutic targeted tissue concentrations. In addition, the drugs should ensure a prolonged time of action and be safe, with minimal systemic and local toxicity. The transporter vehicle or drug delivery system is designed to enhance ocular tissue penetration and establish controlled drug release. Administration methods should preferably be local, thereby reducing systemic sideeffects, and ideally be noninvasive.

ROUTE OF ADMINISTRATION

Although the conventional drug administration forms (eye drops or systemic administration) dominate the field of ocular drug delivery, history has shown that many new pharmaceutical concepts were introduced to clinical practice for the first time in ophthalmology. It was in the 1970s that the term “drug delivery system” appeared. Extensive research was performed during the last decades to improve the drug delivery or transporter vehicle part of the ocular pharmacotherapy system.3,15–17

Eye drops

Eye drops have been in use since the times of ancient Egypt for the treatment of ocular conditions. Eye drop administration is still the most used ocular drug delivery method. The inconvenience of this administration method is the need for relatively frequent instillation as ocular drug bioavailability is very low (< 5% of the dose is absorbed). Different types of ocular drops, like suspensions or solution, and ointments were developed to facilitate ocular drug molecules. Nevertheless this administration method could not demonstrate its efficacy in the treatment of the posterior pole diseases and it remains a treatment modality for the anterior segment.

Soluble ophthalmic drug inserts

For these reasons, the application of soluble ophthalmic drug inserts with a prolonged drug delivery was developed. The first inserts were introduced in the 1960s. The matrix of an acrylate-based co-polymer dissolved during a couple of hours after its application to the conjunctival sac. In the early 1970s pilocarpine-releasing Ocusert (Alza) and, later, another insert, Lacrisert (Merck) were developed. The former represents a sophisticated system that releases the drug for a week at constant rate through ethylene vinyl acetate membranes.

Ion drug exchange

Another development was the creation of liquid state delivery systems that forms a drug-releasing gel after its instillation as an eye drop. The concept of ion drug exchange from the surface of microspheres to the tear fluid was put into practice by a product that released betaxolol. Drug-immersed hydrophilic contact lenses and topical ocular liposomes were tested for drug delivery in the 1970s and 1980s, but these approaches resulted in limited improvements, especially in regard to posterior pole drug delivery. Finally, these topical ocular delivery methods failed as possible vehicle devices for treatment of the posterior ocular segment.

Intravitreal injections

In parallel with the discovery and better clinical pathophysiological understanding of posterior-segment diseases, the demand for appro­ priate treatment increased. New drugs for medication of the posterior ocular segment have emerged, but most drugs are currently delivered by repeated intravitreal injections, such as the anti-VEGF treatments currently used in the treatment of exudative AMD. Unfortunately this invasive drug delivery method can induce vitreal hemorrhages, retinal detachment, or even endophthalmitis. The risk is smaller with periocular drug administration, frequently used in the clinical ophthalmological routine as subconjunctival or peribulbar injections, such as corticoid administration (dexamethasone, triamcinolone), in the treatment of uveitis and chronic inflammatory macular edema. This route, via the conjunctiva and sclera, avoids the counterflow of aqueous humor and the lens barrier, as for drug administration with eye drops. Therefore, this route may be a possible future alternative for drug administration (including proteins and gene-based drugs) to the retina and vitreous if appropriate delivery systems are developed. The sclera is permeable to macromolecules, but choroidal blood flow and the RPE are the major barriers in drug penetration. Delivery of macromolecules is important therapeutically, since antiangiogenic antibodies, oligonucleotides, growth factors, and transgene expression products are all large molecules. Several studies have demonstrated the efficacy of different drug delivery methods via the transscleral route, such as non­ invasive application iontophoresis or subconjunctivally placed drug release implants.18

Systemic administration

Another major route of drug delivery is via systemic administration. Systemically administered drugs reach the chorioretinal tissue through

the blood circulation. However, the outer and inner blood–retinal barriers limit the influx of drugs into the retinal tissue and the vitreous cavity. Therefore, a high rate of drug concentration and frequent administration are required to maintain therapeutic concentrations, which may result in serious side-effects on nontargeted tissues and organs. Therefore, effective, safe, and comfortable methods of drug delivery are needed.

Sustained drug delivery system

This demand revived the interest in ocular-controlled release systems. Currently most research efforts are directed towards a sustained drug delivery system to treat chronic disease. The challenge is to provide a system with an improved ocular drug bioavailability and prolonged duration of activity, yet which presents a minimal risk of ocular complications. Furthermore the final aim is to develop effective drug delivery methods for posterior-segment therapies that would also be applicable for the outpatient use.

Based on experience with drug delivery inserts, used for the anterior segment, and new biophysical and biochemical implant models, the idea of drug transporter vehicles was the increasing focus of clinical ophthalmologic research.16–18

Intraocular implants

Emerging methods include polymeric-controlled release injections and implants, nanoparticulates, microencapsulated cells, and iontophoresis. The goal of the implant design is to provide prolonged activity with controlled drug release from the polymeric implant material. Different types of implants such as intraocular or periocular implants are under investigation. Intraocular administration of implants always requires minor surgery. In general, they are placed or injected intravitreally in the area of the pars plana. Although this is an invasive technique, the implants have the benefit of bypassing the blood–ocular barrier to deliver constant therapeutic levels of drug directly to the site of action. Furthermore, it reduces the side-effects associated with frequent systemic and intravitreal injections as their drug release is programmed over a certain period of time. Finally, a significantly reduced drug quantity is required with this route of administration during the treatment period. The ocular implants are classified as nonbiodegradable and biodegradable devices. Nonbiodegradable implants can provide more accurate control of drug release and longer release periods than biodegradable polymers, but nonbiodegradable systems require surgical implant removal with associated risks. Vitrasert and Retisert (Bausch & Lomb) are clinically used nonbiodegradable implants. Vitrasert is the first implantable ganciclovir delivery device which was approved by the Food and Drug Administration (FDA) in 1996. Ethylene vinyl acetate and polyvinyl alcohol (PVA) polymers control the release of ganciclovir. It is effective in controlling the progression of cytomegalovirus retinitis associated with AIDS for a period of 8 months. Retisert is the first marketed fluocinolone acetonide implant for the treatment of chronic noninfectious uveitis of the posterior segment. PVA and silicone laminate control the release of corticosteroid over a 3-year period. Both implant types occasionally showed side-effects like endophthalmitis, increased rate of retinal detachments, cataract formation, and ocular hypertension. The biodegradable implants Surodex and Ozurdex (Allergan) are currently undergoing clinical phase III studies. They are nearly identical polylactic co-glycolic acid (PLGA) implants with different doses of dexamethasone (60 µg for Surodex and 700 µg for Ozurdex). Ozurdex is designed for sustained release of dexamethasone over a period of several months after intravitreal placement.

So far scleral implants have only been studied on an animal model. The device released betamethasone in a constant manner for at least 3 months without detectable drug concentration in the aqueous humor. Surprisingly, this route resulted in a more effective delivery to the macular region than the intravitreal implants. The transscleral delivery system is thus a promising alternative for the treatment of retinal and choroidal diseases.19,20

Microparticles and nanoparticles

Another control-releasing strategy is to encapsulate the drug in micro­ particles or nanoparticles.21 Usually biodegradable and biocompatible polymers are used, such as polylactide and PLGA, which both are FDA-approved. These systems can provide sustained drug delivery for weeks or even months just by the administration of one single intra­ vitreal injection. To date, some microsphere formulations have been analyzed in preclinical studies, but have not yet undergone clinical trials. Subconjunctival or periocular injections of microspheres were administered to provide transscleral drug delivery instead of invasive intravitreal administration, which can cause vitreal clouding. Targeted microspheres with PKC412, an inhibitor of protein kinase C and of receptors for VEGF, were used to treat CNV.22 The microsphere system was moreover studied to release pegaptanib sodium (anti-VEGF aptamer). This molecule is already a standard treatment for wet AMD. The pegaptanib-loaded microspheres were either administered through the scleral route or by intravitreal injection.23,24 Both administration methods released the aptamer over several weeks after injection.

Liposomes

Nanoparticulates and liposomes are suitable for intracellular drug delivery and could thus be used to treat retinal disorders. Liposomes are biocompatible, biodegradable, and can be made of natural lipids. On the one hand, hydrophilic as well as lipophilic drugs can be encapsulated to the lipid walls or the aqueous interior of the liposomes. On the other hand, these carriers can be engineered to target certain cell types. Preclinical experiments have demonstrated the presence of nanoparticles and liposomes in RPE cells probably due to the phagocytic capacity of RPE cells. Nanoparticles are retained within the RPE cells even 4 months after a single intravitreal injection.25 Liposomes can be prepared with different sizes, stability, and pharmacokinetics. Further, the liposomal surfaces can be modified to allow preferential binding, for example, to the endothelium cells of proliferating neovascular vessels. Liposome technology has been used to develop light-induced systems for retinal disease (for example, Visudyne, Novartis Pharmaceuticals).

Light-induced systems can either be light-activated drugs (i.e., photodynamic therapy) or light-activated delivery systems. So far verteporfin (Visudyne, Novartis Pharmaceuticals) is the only ocular liposomal drug currently in clinical use. Recently another light-induced drug delivery system was combined with a viral transport. This light-induced drug delivery system is based on VP22, a structural protein of herpes simplex virus.26 The purified VP22 protein binds antisense oligonucleotide of human craf kinase. To obtain a light-induced activation of the drug after intravitreal injection, a fluorochrome is covalently linked to either the protein or to the oligonucleotide. The carriers remain in the cytoplasm of various retinal cell types. Due to transscleral illumination the delivery of free oligonucleotides can be obtained.

Encapsulated cell technology (ECT)

A different promising new drug delivery method is based on the principle of ECT. The concept is to entrap immunologically isolated cells with microcapsules or hollow fibers before their administration into the eye. The genetically engineered cells continuously produce a therapeutic protein at the site of implantation. Thus technology enables the controlled, continuous, and long-term delivery of therapeutic proteins directly to the posterior segment of the eye. The implant is inserted through a small scleral incision and placed at the pars plana. The implant is sutured in order to allow its retrieval when desired. ECT product NT501 (Neurotech) with encapsulated genetically modified human RPE cells which secreted ciliary neurotrophic factor to the vitreous were implanted in the eyes of patient with retinitis pigmentosa for a period of 6 months. An improvement of visual acuity was reported and the device was well tolerated.27 ECT may have a therapeutic potential as a delivery system for chronic ophthalmic diseases lacking effective therapies, and as a drug vehicle for anti-inflammatory factors.28 Long-term safety and efficacy have yet to be clinically studied.

Treatments Pharmacologic in Knowledge Evolving • 1 CHAPTER