Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

of a randomized trial--Diabetic Retinopathy Vitrectomy Study Report 4. Ophthalmology 95, 1321-1334, (1988).

53.F. L. Ferris, How effective are treatments for diabetic retinopathy? JAMA 269, 1290-1291, (1993).

54.DCCT Research Group. The effect of intensive treatment of diabetes in the development and progression of long-term complications in insulin-dependent diabetes. N. Engl. J. Med. 329, 977-986, (1993).

55.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837-853, (1998).

56.C. Tikellis, M. E. Cooper, S. M. Twigg, W. C. Burns, and M. Tolcos, Connective tissue growth factor is up-regulated in the diabetic retina: amelioration by angiotensinconverting enzyme inhibition. Endocrinology 145, 860-866, (2004).

57.M. Hollborn, C. Krausse, I. Iandiev, et al. Glial cell expression of hepatocyte growth factor in vitreoretinal proliferative disease. Lab. Invest. 84, 963-972, (2004).

58.DCCT Research Group. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 46, 1829-1839, (1997).

Chapter 22

SYSTEMS FOR DRUG DELIVERY TO THE POSTERIOR SEGMENT OF THE EYE

Alan L. Weiner, PhD, and David A. Marsh, PhD

Alcon Research Ltd., Fort Worth, Texas

1.INTRODUCTION

There are numerous considerations when developing drug delivery therapies for posterior ocular diseases. First, there needs to be an understanding of the absorption, distribution, metabolism, and excretion patterns of the specific drug. Second, the toxicological and pharmacological profiles of the drug and its metabolites should be established. Most important, however, is the consideration of the ultimate target of ocular drug therapy (Table 1). To this end, a series of critical questions should be addressed:

1.Where is the lesion (i.e., macula, equator, etc.)?

2.Within that lesion, which tissue contains the target drug receptor (retina, choroid, sclera, etc.)?

3.What area of drug coverage is needed for treatment of the lesion (e.g., macula only, localized lesion at the equator, pan-retinal distribution, etc.)?

4.What concentration of drug is needed at the target tissue to ensure efficacy?

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© Springer Science+Business Media B.V. 2008

5.What is the required duration of the drug delivery needed at the receptors to treat this disease?

Table 22-1. Posterior Ocular Lesions Associated with Angiogenesis

For certain disease states, the drug distribution target may vary, depending on the severity of the condition. For example, a quadranic branch retinal vein occlusion may require only localized treatment, whereas a more severe hemispheric or central vein occlusion would mandate a system that delivers more general pan-retinal concentrations.

Once the above questions have been addressed, one can then determine the best route of administration—i.e., systemic or intraocular—and, if intraocular administration is chosen, the best type of drug delivery device (bioabsorbable or non-absorbable; pan-retinal or local ocular). The strategy behind these choices will be discussed below.

2.ADMINISTRATION SITES FOR DELIVERING ANTI-ANGIOGENIC DRUGS TO THE POSTERIOR SEGMENT

Drugs for treatment of posterior ocular angiogenic diseases may be administered orally (e.g. vitamins), or by the parenteral route (e.g. photodynamic agents). Oral administration is generally the patient’s most preferred route, given the simplicity. However, oral delivery of potent drugs exposes the entire body to potential serious adverse effects. And, while antiangiogenic drugs are given orally for treatment of cancer, the risk-versus- benefit ratio may change dramatically if the same dose is given orally for a non-life threatening ocular disease. Additionally, in order to cross the bloodretina barrier in effective amounts, it may be necessary to increase the oral dose substantially over the anti-cancer dose in order to achieve efficacy. Also, some drugs will have a substantial “first pass effect,” requiring higher doses than those required for parenteral delivery, and, as a consequence, oral dosing may produce more toxicity than parenteral delivery due to high levels of toxic metabolites.

Systemic parenteral administration of angiogenic drugs will overcome the problem of a drug causing toxicity due to its “first pass effect.” However, the distribution of the drug still exposes the entire body to potentially serious adverse effects and, like oral drug delivery, may require high doses to penetrate the blood-retina barrier. Moreover, routine parenteral administration is both inconvenient and expensive for patients and may lead to patient non-compliance. Finally, parenteral administration has the potential for some unfavorable kinetics, where each injection may expose the tissue to potentially toxic levels of drug and later, before the next injection, to ineffective concentrations (Figure 1). This latter problem may be mitigated with drug delivery devices such as dermal patches and sub-dermal devices or by use of bioabsorbable pellets, liposomes, microspheres, microcapsules, or microparticles, which will deliver drug in a sustained or zero order manner, although certain bioabsorbable materials may have unique systemic side effects if given intravenously. For the ophthalmic route, the application of topical drops or repetitive injections of solutions will follow a kinetic pattern in the ocular tissue similar to that illustrated in Figure 1.

Figure 22-1. Kinetics of Parenteral Administration.

However, drug delivery devices offer the opportunity to provide sustained (Figure 2) or, ideally, controlled-release (Figure 3) [zero-order] drug delivery at effective, safe doses for days, months or years. Generally, for ocular delivery, these devices may be designed to provide short-term, intermediate, or long-term drug duration, the selection of which depends upon the length of time it is anticipated that the lesion needs to be treated. If the duration of treatment is days or months, it is probably best to use a bioabsorbable device (i.e., bioerodible or biodegradable). On the other hand, if the duration of lesion treatment is anticipated to be a year or longer, a nondegradable device may be the only way to deliver the high drug-loading dose needed to provide continuous drug delivery for multi-year delivery; generally, non-degradable devices control drug delivery rates better than bioabsorbable devices.

Topical ocular applications of a drug solution or suspension generally fail to deliver effective doses of drug to the posterior segment; typically, after instillation of an eye drop, less than 5% of the applied drug penetrates the cornea and reaches intraocular tissues. The major fraction of the instilled dose is usually absorbed systemically via the naso-lacrimal duct or through the conjunctiva.

Studies have demonstrated that there is potential for many drugs to reach the posterior tissues from topical application, but establishment of levels may be influenced by the disease state.1,2 For many years, glaucoma agents have been designed to penetrate sufficiently to effect therapy in the anterior chamber tissues, and in certain cases, a “neuroprotective” effect of these agents has also been proposed based on measured vitreous or retinal levels.3- 5 The design of drugs specifically for therapy of posterior segment disease is on the horizon. For example, promising drugs like Nepafenac have shown potential for effecting therapy of posterior neovascularization from topical administration.6

In situations when the drug alone is insufficient to reach the posterior chamber, unique pro-drugs may be developed to improve the potential permeation.7,8

A contemporary approach for improving anterior to posterior movement of a drug is by a physical augmentation using iontophoresis, which will be discussed at greater length in a subsequent section of this chapter.

Subconjunctival injection may someday provide an alternate route of drug administration to posterior ocular tissues, but consistent and effective delivery of a drug to angiogenic lesions has yet to be demonstrated. It has been observed that both anterior and vitreous levels can be established from subconjunctival injection,9 and thus, to date, it has been a common route of administration for anti-infectives.10,11 However, such injections will likely be subject to the kinetic problems shown in Figure 1, unless slower release formulations such as microspheres are used.

Administration of a drug behind the eyeball into the middle of the muscle cone (retrobulbar) is a common approach for induction of anesthesia or akinesia of the eye. Only limited experimentation has been done with other types of drugs, including steroids,12-14 glaucoma agents15,16 and cytokines.17 However, a few of these studies have reported that such periocular administration can result in posterior drug levels sufficient for treating cystoid macular edema, optic neuritis, and choroidal neovascularization.

Intravitreal administration is the most common approach used to deliver posterior levels of drugs, particularly anti-infectives used to treat endophthalmitis.18 A full review of literature studies on intravitreally injected compounds is beyond the scope of this chapter, but most recent examples of human intravitreal drug studies involve triamcinolone,19-24 tissue plasminogen activator,25,26 pegaptanib,27-30 ranibizumab,31,32 P2Y2 receptor agonist,33 and adenoviral vector for pigment epithelium-derived factor.34

Intravitreal injections deliver drug pan-retinally for a period of roughly 1 to 45 days, depending on whether the dosage form is a solution or suspension and whether the drug is a small molecule or has a relatively high molecular weight (e.g. pegaptanib). Most of the conditions described in

Table 1 will likely need long-term therapy and, therefore, require multiple injections. The obvious shortcoming of repeated intravitreal injections, aside from high cost and patient apprehension or non-compliance, is the greater potential for side effects such as retinal detachment, endophthalmitis, and hemorrhage. These adverse events may be above and beyond the inherent side effects caused by the drug. Moreover, suspended drug particles or floating depots might cause refractive scotomas. Finally, like any parenteral injection, an intravitreal injection has a kinetic disadvantage in that, shortly after dosing, drug concentration in the ocular tissue may exceed the toxic level and, toward the end of its duration—before the next injection—the drug concentration may drop below the effective level (Figure 1).

In addition to subconjunctival administration of antibiotics,

administration of these agents by the related juxtascleral route (i.e. beneath the Tenon’s capsule) has also been known for some time.36,37 However, the

real potential for transcleral posterior drug delivery has only been realized more recently. The juxtascleral route has shown possible utility for delivery of anesthetics,38-40 corticosteroids,41-43 anti-angiogenics,44-46 anti-cancer agents,47-49 and botulinum toxin.50 Injection of drug suspensions (e.g. anecortave acetate44) by this route has been demonstrated to have a duration of up to 6 months in monkeys and man. A further advantage is that the vitreous is not penetrated, so adverse effects such as retinal detachment and endophthalmitis are far less likely to occur than with an intravitreal injection. Nonetheless, therapy for a year or longer may be required for many conditions (Table 1), and therefore, multiple doses under the Tenon’s capsule may be prescribed. Although sustained drug kinetics by this administration route is an improvement over intravitreal injection, it is still not ideal. Furthermore, it should be noted that it has not yet been demonstrated that juxtascleral injections can deliver an effective dose of a drug pan-retinally. Therefore, such injections might be restricted to local treatment of lesions (i.e., lesions below or adjacent to the injection site).

There is very limited information on intrascleral depot. Among the compounds reportedly administered by this route are oligonucleotide51,52 and integrin antagonist.53 Little is known about pharmacokinetics from this site, although initial studies suggest that angiogenic diseases may be treated by this approach. One significant issue is that only a very small volume can be administered into the sclera. An intrascleral injection device has been developed to facilitate accurate injection into this tissue with minimization of possible trauma to or penetration of underlying layers.54

While it is considered a complex method of administration, subretinal administration has held particular interest in the field of cell transplantation to facilitate repair of the pigment epithelium. As well, injection of drugs has been reported in this site, specifically, tissue plasminogen activator,55 P2Y2

used alone or as copolymer combinations. These compounds have been used for many years as bioabsorbable sutures and offer a wide range of delivery durations, depending on the ratio of the ingredients. Weeks to months of delivery time can be programmed. The disadvantages of these materials include inflammatory responses, which can occur in specific tissues, and the bulk erosion mechanism (Figure 5), which can result in undesired drug bursts. Other known bioeroding materials that either have been commercialized or are in human testing include the polyanhydrides and polyorthoesters, which degrade by a surface erosion mechanism (Figure 5). Surface eroding implants also can be constructed using collagen, alginate, hydroxypropylcellulose, hyaluronan, and various lipids.

For non-degradable systems, there are a number of useful compatible biomaterials including polyvinylalcohol, ethylene vinyl acetate, siloxane polymers, various methacrylate and ethylacrylate polymers, polyvinylidine fluoride, polysulfone, and polyimides.

For reference, there are many excellent and extensive reviews on the use of these polymers in general or ophthalmic indications.65-68

Bulk erosion Surface erosion

Figure 22-5. Mechanisms of erosion for biopolymers.