Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

3.1Topical Delivery

As discussed in section 2, drug penetration must be sufficient to produce adequate posterior levels from topical administration. This is best achieved by superior drug design or by using excipients that enhance the penetration of drugs. Reservoir or matrix drug delivery devices placed at the ocular surface may be able to extend the residence time of a drug. With continuous levels bathing the corneal surface, the possibility for greater transport to the posterior is enhanced. However, although topical inserts (e.g. Ocusert®) have been around for some time, they have limited delivery success, primarily because of difficulties with insertion and ocular retention by the patient. For chronic diseases such as those encountered in the posterior segment, it is unlikely that such devices will be a primary tactic to achieve therapy. To date, there is no significant effort in this area for enhancement of posterior drug levels.

Iontophoresis has been touted as an alternate topical drug delivery method—and someday, it may be. Two key designs have been reported. In one, a small flexible topical device (shaped to the outer eye like a contact lens) is inserted in the cul-de-sac and emits a low electrical current, which drives ionic drugs from the front of the eye to the back. A second design utilizes an eyepiece that is placed on the eye while drug is infused from a syringe reservoir to the eyepiece. Reports have examined the ability of iontophoresis to facilitate ocular delivery of acetylsalicylic acid,69 gentamicin,70 dexamethasone,71 combretastatin A4,72 diclofenac,73 amikacin,74 methylprednisolone,75 DNA and dyes,76 carboplatin,77 and ganciclovir.78 The effects have been variable, and measurements of success are based on achieving an appropriate current intensity and duration of exposure to the current. As such, improvements in penetration range anywhere from 10-50%. Unfortunately, consistently reproducible drug delivery at a safe current level has not been unequivocally demonstrated. Additionally, many drugs that are nonionic or have a high molecular weight (≤ 8000 Daltons) will have great difficulty moving with the applied current. Finally, and probably most importantly, the vitreal turnover of small solubilized molecules is short (i.e., a day or two), and consequently, iontophoresis for drug molecules ≤ 1000 Daltons would likely need to be performed frequently in order to maintain an effective anti-angiogenic concentration at the target tissue; home iontophoretic kits are not available, and frequent visits to the doctor for iontophoresis therapy may lead to poor patient compliance due to cost and inconvenience.

3.2Subconjunctival Implants

Bioerodible implants have been placed in the subconjunctival compartment predominantly for anterior applications such as glaucoma filtration surgery. Antimetabolites like 5-fluorouracil79-81 or daunorubicin82 have been incorporated into polylactide-co-glycolide or polyorthoester implants to maintain bleb integrity by inhibiting fibroblast proliferation. Similarly, cyclosporin A has been incorporated into these same polymers and implanted in the subconjunctival space to effect prolongation of corneal allografts.83,84 There has been evidence that subconjunctival placement of fluorescent labeled dextran has the ability to reach retinal and uveal tissues possibly via movement through the uveoscleral outflow pathway.85 To date, reports have indicated that the subconjunctival route may only provide a limited capacity to deliver sufficient level of drugs from implanted devices. Kim et al.86 measured ocular tissue levels of a lipophilic fluorescent tracer that had been incorporated into implants constructed of either hydroxypropylcellulose, polyvinyl alcohol, or silicone and implanted into the subconjunctival space of rats. Only the most rapidly releasing implant design resulted in measurable levels in the choroid and subretinal space. In a similar experiment, this same group utilized dynamic three-dimensional magnetic resonance imaging to follow gadolinium-diethylenetriaminopentaacetic acid (DTPA) distribution from subconjunctival polymer implants.87 Only a small fraction (0.12%) of the total dose was detectable in the vitreous, with no levels detected in other posterior segment tissues. In spite of these findings, this group has demonstrated in animal efficacy models that subconjunctival implants might provide sufficient levels of drugs to be of value. In a vascular endothelial growth factor (VEGF)-induced neovascularization model in rats, cytochalasin incorporated into subconjunctival implants inhibited choroidal neovascularization (CNV) better than sham implants.88 This same model was used to show that 2-methoxyestradiol implants also were capable of reducing CNV by 50% at one week.89 In certain cases, a solid implant may not be necessary. This may be the case for low-solubility suspensions, which can offer significantly longer durations following subconjunctival injection. For example, retinal levels of Celecoxib have been detected following a subconjunctival suspension depot,90 suggesting potential for anterior delivery of this agent to inhibit diabetes-induced retinal VEGF expression and vascular leakage.

3.3Intravitreal Devices

Introduction of a delivery system to the vitreous is best achieved using the least invasive approach possible to reduce trauma and risk of endophthalmitis. A self-sealing injection through a small-bore (e.g. 25 gauge) needle is desired if possible. Drug delivery systems that meet this criterion include bioabsorbable polymer threads, liposomes, microspheres, microcapsules, and nanoor micro-particles. These may be injected into the vitreous through the pars plana and deliver drug pan-retinally for a modest period of time after which the excipients are bioabsorbed. The primary advantage of such formulations over the typical intravitreal solutions or suspensions is that biodegradable drug delivery devices will last longer, which means that fewer injections will be necessary. The downside of injecting drug delivery formulations into the vitreous is essentially the same as injecting a solution or suspension, except that the latter requires fewer intrusions and therefore should reduce the net number of adverse effects. Patient compliance may be improved by the reduced injection schedule.

It remains to be seen whether tethering is an absolute requirement for small bioeroding implants to prevent drift from the site of implantation. This is particularly germane in patients where vitreous has liquefied or where full or partial vitrectomies have been performed. Delivery rates may also be affected, depending on the state of the vitreous compartment. For example, the presence of a silicone oil tamponade would likely have a fairly dramatic impact on release kinetics compared to normal vitreous.

Significant experience with intravitreal devices was gained via Vitrasert implantation.91,92 Many intravitreal devices have been since patented, but only a few have advanced commercially or into clinical studies (e.g. Posurdex® 93-95 and RetisertTM 96,97). Typically, intravitreal devices are implanted in the pars plana region of the eye, for surgical accessibility, to avoid disruption of the retina, and to limit interference with vision (Figure 6A).

Non-eroding or eroding matrix and reservoir devices are capable of providing pan-retinal drug delivery, but bioabsorbable devices will generally deliver drug for only a few weeks or months, whereas the non-degradable devices deliver for a year or more. However, one caution here: because a device can deliver drug for long durations does not necessarily mean that it is more desirable than a short-acting device. In the two examples given above, the Posurdex® has been demonstrated in clinical studies to have lower rates of cataract progression and serious elevations of intraocular pressure (IOP) than the Retisert™ device in the treatment of uveitis. At this point in time, it remains to be determined whether repeated injections (if needed) of a Posurdex® biodegradable dexamethasone pellet would offset its apparent

advantages. Both types of devices have the potential to cause the same serious adverse effects seen with intravitreal injections (i.e., retinal detachment, endophthalmitis, and hemorrhage) in addition to any physical adverse events from the surgery or injector/cannula introduction, as well as the drug-induced side effects.

Intravitreal devices can also be designed to traverse the sclera, which then serves as an anchor for the device (Figure 6B). With this approach, somewhat less invasive procedures can be utilized compared to that for Retisert™.

Figure 22-6. (A) Intravitreal device placement. (B) Pars plana device for intravitreal delivery.

For this type of device, several styles of drug delivery can be fashioned. In Figure 7, three such designs are shown. Device A, constructed from noneroding silicone, can be prepared either as a matrix implant or a reservoir type with a refillable chamber.98 Device B is totally bioeroding and has shown utility for delivery of ganciclovir and fluconazole.99-102 Device C is a

metal coil that is coated with drug (e.g. triamcinolone) in a polymer base and is inserted and removed by a screw type technique.103,104

Regardless of the specific style of implant at the pars plana position, drug distribution to the retina and underlying uveal tissues would be expected to follow a gradient pattern over time.105 Examples of other drugs studied from various types of intravitreal implants are triamcinolone,106 2- methoxyestradiol,107,108 doxycycline,109 dexamethasone,110 daunomycin,111 5- fluorouracil,112 FK506,113 and ciprofloxacin.114

A B C

Figure 22-7. Pars Plana Device Designs: (A) Weiner, et. al., 1995, US Patent 5,466,233; (B) Ogura, et. al. 1998, US Patent 5,707,643, (C) Varner et al, 2004, US Patent 6,719,750

3.4Juxtascleral Devices

Delivery systems may be injected or implanted either below the Tenon’s capsule or suprachoroidally proximal to a lesion. Via transcleral penetration, drug levels can be established in the choroid and retina. However, panretinal delivery from this site of administration has not been demonstrated. Thus, drug distribution may be dependent on a number of factors, including solubility and scleral thickness. It has been shown in an isolated tissue model that elevated pressures can affect scleral permeability, although this is not related to significant changes in scleral thickness or hydration.115 In this same study, extended delivery across the sclera was shown for dexamethasone using pluronic gel or fibrin sealant.

There are only a few reports on long-term sustained delivery of molecules via the juxtascleral route using specific implanted devices. One of those is a novel unidirectional juxtascleral device116-118 loaded with a solid dose of RETAANE® (Figure 8), which has been shown, in rabbits, to deliver drug to the macula for two years or longer.119 The surgical implantation is relatively simple, and the procedure does not penetrate the vitreous; consequently, the potential for serious adverse effects is markedly reduced.120

Anecortave Acetate

Drug Core

Figure 22-8. Placement of the Anecortave Acetate Transcleral Delivery Implant.

The active metabolite, anecortave acetate, was observed in both choroid and retina at concentrations of 1.3 µM at 1 week. Its concentration declined to about 0.2 µM and 0.1 µM, respectively, by 6 weeks, remaining consistently at these levels over the 2-year period. In these studies, the sclera appeared to act as a sink for the drug, with increasing levels over the 2 years observed.

A series of similar devices has been described in which cyclosporin A and 2-methoxyestradiol drug cores are enclosed in various laminate-type holder devices enclosed in semi-permeable membranes.121 In vitro drug release over months has been demonstrated.

Erodible matrices are also under investigation when administered by the juxtascleral route. One example is microspheres of polylactic-glycolic acid (PLGA) (50/50) that have been used to deliver anti-VEGF aptamer via the transcleral route. Inhibition of VEGF-induced blood-retina barrier breakdown was observed after two weeks.122

Because most investigators are interested in continuous drug delivery systems, there are few systems that have been designed specifically for pulsatile release. However, in some instances, efficacy may be optimized by this type of intermittent dosing. Transcleral pulsatile delivery of fluorescein isothiocyanate (FITC)-conjugated IgG was examined using a polypropylene device attached to the bare scleral surface of rabbits.123 Choroidal and retinal levels were quantitated out to 120 hours. The peak concentrations appeared

at 24 hours, with maximum lateral diffusion at 48 hours and residual concentrations out to 5 days.

Material biocompatibility in the region under the Tenon’s capsule will differ significantly from the intravitreous compartment, which is devoid of cellular components. Silicone, for example is a well studied material in this region, particularly as it applies to scleral buckles. Fibrous encapsulation is known to occur around silicone surfaces exposed to the Tenon’s capsule. However, it has been demonstrated that if the drug-exposed surface is molded flat against the sclera, it will not become encapsulated.116 Some of the best understanding of reactivity in this anatomic region comes from glaucoma studies in which filtration devices are attached to the sclera124-127 and/or from strabismus and muscle surgery practice. Fernandez et al.128 have examined a series of biomaterials implanted in the space under the Tenon’s capsule between the extraocular muscles. Materials tested included hydrophobic polydimethylsilane (PDMS) (Baerveldt, AMO), expanded polytetrafluoroethylene (ePTFE) (Mitex and NTF), hydrophilic polyhydroxyethylmethacrylate-methylmethacrylate (pHEMA-MMA) (26 and 34) (Corneal SA), pHEMA-VP75 (Corneal SA), and hydrophobic polyethylacrylate-polyethyl methacrylate (PEA-PEMA) (Acrysoft, Alcon). The study showed that the hydrophilic materials had the least tendency toward inflammation and fibrosis.

3.5Subretinal implants

The practice of implanting foreign materials in the subretinal space is a relatively new concept. The overriding risk associated with potential retinal detachment has historically limited ambitions to probe this anatomical site. However, recent impetus has come from exciting attempts to restore vision

to retinitis pigmentosa patients by implanting microphotodiode array silicon chips.129,130 Additional materials such as polyimide, aluminum oxide-coated

polyimide, amorphous carbon, parylene, poly(vinyl pyrrolidone), and polyethylene glycol have also been studied in the subretinal space in Yucatan miniature pigs.131 In this study, no gross inflammation, fibrous proliferation, or retinal pigment epithelial proliferation was evident. The amorphous carbon-coated polyimide materials were free of the fibrous coating after implantation. Radiation implants (beta radiation using either strontium-90 or palladium-103) have also been placed in the subretinal

region for therapy of exudative age-related macular degeneration (AMD).132,133 As for drugs, triamcinolone has been used subretinally either

when injected as a suspension134 or in a poly-ε caprolactone filament.135 A subretinal injection device has been fashioned for delivery of the latter.136 At least one month of delivery from the filament was observed in rabbits.

Further testing in an animal model of CNV is in progress. The extent of drug distribution from the site of implantation was not reported.

4.FINAL CONSIDERATIONS

Today, “high throughput” receptor testing allows investigators to rapidly evaluate chemical libraries for molecules that bind to specific human receptors or groups of receptors that are deemed to be involved in an ocular disease. In this way, thousands of compounds may be screened for potential efficacy in just a few months. However, identifying highly selective molecules for inhibition (or stimulation) of a given receptor (e.g., inhibition of VEGF receptors) does not guarantee a successful therapy in vivo. There are several reasons for this:

1.The inhibited (or stimulated) receptor may be only one of many modulators of the disease state.

2.There may be feedback mechanisms that negate the action of the drug, or tachyphylaxis may occur.

3.The candidate molecule(s) could be so toxic that an effective dose cannot be delivered safely.

4.The molecule may be metabolized or eliminated too rapidly.

Further testing of candidate molecules in vivo is necessary. The drug should be demonstrated to be effective in an appropriate animal model for the target disease, preferably by an intravitreal route of administration; intravitreal delivery minimizes the variables of absorption, distribution, metabolism, immune response, and elimination, which might accompany other routes of administration (e.g. subcutaneous, intramuscular, intraperitoneal, oral, etc.); if the drug is effective in the animal model by an intravitreal injection, there is no reason why it should not be effective in an intravitreal device. But beware—the converse is not necessarily true; an ineffective intravitreal injection may be due to a rapid turnover of drug in the vitreous, so it is still possible that an intravitreal device, which controls the rate and duration of release of that same drug, may demonstrate efficacy, even though the injection failed.

The second consideration in developing a drug delivery device is to establish in-eye potency and safety in animals. Ideally, the drug should have a wide therapeutic index. Also, the drug should be highly potent, so that a tiny device can provide a sufficient dose for a reasonable duration.

The third consideration is determining what a “sufficient dose for a reasonable duration” is for the targeted disease. “Sufficient dose” is defined as the steady-state concentration of drug needed to produce the desired effect in the animal model and, hopefully, in man. “Reasonable duration” is

defined as the duration needed to either cure the disease or to ameliorate and maintain suppression of disease symptoms. If the target disease is acute, a brief exposure (hours, days, or weeks) to an effective steady-state concentration may be all that is required. If the disease is chronic, it is likely that the patient will need a more prolonged exposure (months or years) to an effective steady-state concentration of the drug.

If a short-term (hours, days) or intermediate-term (weeks, months) duration is all that is required to treat the disease, then a biodegradable device makes the most sense. A biodegradable device may provide easier administration and fewer adverse effects while eliminating the need for device removal at the end of the treatment period. In contrast, a long-term non-degradable device (≥ 1 year) may provide superior control of drug release, superior retrievability in case of serious adverse effects, and fewer invasive procedures for chronic therapy than the biodegradable device.

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