Originally Published MDDI July 2005
A polymer coating applied to a coil surface enables the sustained release of drugs to the back of the eye.
Signe Varner, Nancy Hupfer, and John Buan
Unlike diseases of the front of the eye, where drugs can be delivered topically, retinal diseases require a more site-specific approach. Eye drops and ointments rarely penetrate the back of the eye, and the blood-ocular barrier hinders penetration of systemically administered drugs into ocular tissue. Improving the treatment of chronic ocular disease requires technologies that can provide sustained intraocular delivery of drugs for months or even years.
This article discusses the development of a new coating technology that provides a more patient-friendly and efficacious method of ocular drug delivery. Continuous intravitreal drug delivery enables the sustained release of drugs to the back of the eye, which offers versatility and flexibility for drug formulation and pharmacokinetics control. In addition to minimizing systemic drug levels and overcoming physiological barriers to drug penetration, sustained delivery also minimizes the dependence on patient compliance.
Retinal Diseases and Treatments
Retinal diseases, such as diabetic macular edema (DME) and age-related macular degeneration (AMD), represent the leading causes of vision loss in the Western world.
Diabetic Macular Edema. DME is the result of retinal microvascular changes that occur in patients with diabetes. Thickening of the basement membrane and reduction in the number of pericytes is believed to cause increased permeability and incompetence of retinal vasculature. This compromise of the blood-retinal barrier leads to fluid accumulation (edema) in the macula.1
Several factors give rise to the occurrence of DME in any one patient, including how long a patient has had diabetes, the type of diabetes the patient has, the presence of severe hypertension, fluid retention, low protein in body fluids (hypoalbuminemia), and high levels of fats in the blood (hyperlipidemia).1
DME is the leading cause of legal blindness among Americans between the ages of 20 and 74. There are an estimated 500,000 cases of macular edema in the United States, and 325,000 of these cases represent clinically significant macular edema, i.e., cases with a high risk of vision loss. An estimated 80,000 cases of macular edema, 56,000 cases of clinically significant macular edema, and 5000 new cases of legal blindness are reported each year as a result of diabetic retinopathy.
One currently accepted treatment for advanced DME is laser photocoagulation to close the leaking micro-aneurysms. Laser treatments can reduce the rate of moderate vision loss by 50%. However, while laser treatments reduce the rate of progression, once visual acuity is already reduced, laser-treated eyes are unlikely to improve to 20/40 or better. Also, the degree of visual gain following laser treatment is moderate and may take months to occur. These observations have led to the search for other approaches to the treatment of DME.2
A second option is to surgically remove the vitreous (pars plana vitrectomy). This treatment requires a complex surgery with inherent risks and recovery time. It may also be applicable only to a specific subset of eyes with DME. Additionally, numerous pharmacological agents, including antiangiogenesis compounds, statins, and corticosteroids are being investigated for the treatment of DME. In these studies, the drugs are delivered either systemically or intravitreally. No drug has been approved by FDA for treatment of DME.
Age-Related Macular Degeneration. The etiology of AMD is quite different from that of DME. AMD is a disease that blurs the sharp, central vision needed for straight-ahead activities such as reading, sewing, and driving. Although it causes no pain, AMD affects the macula, the part of the eye that allows people to see fine detail. Exudative, or wet, AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye, leading to rapid damage to the macula.3
AMD is estimated to affect 28% of people between the ages of 65 and 75. It afflicts more than 46% of people aged 75 and older and is considered the leading cause of vision loss in Americans age 60 and older. There are approximately 200,000 new cases of AMD each year in the United States, and the annual incidence is expected to grow as the population ages. Currently, wet AMD is the only form of the disease with FDA-approved treatment options.
The three treatment pathways for wet AMD include laser surgery, photodynamic therapy, and pharmacotherapy. Laser surgery destroys the fragile blood vessels that are leaking into the space behind the retina. However, laser treatment may also destroy some surrounding healthy tissue and some vision, and the risk of new blood vessels developing after laser treatment is high. Repeated treatments may be necessary, and in some cases, vision loss may progress despite repeated treatments.3
In photodynamic therapy, Visudyne (QLT Inc.; Vancouver, BC, Canada), a photoactivated cytotoxic agent, is administered intravenously. A specially tuned laser is focused into the eye to activate the drug circulating in the retinal vasculature. The cytotoxic agent is released in the vessels targeted by the laser and the vessels are destroyed, stopping the flow and leaking. While this therapy brings positive results to some patients, the disease continues to progress in others.
Lastly, Macugen (Pfizer Inc.; New York City) was recently approved by FDA for the treatment of wet AMD. This drug is an antiangiogenesis agent that suppresses the formation of new blood vessels in the back of the eye. The drug is administered by intravitreal injection, using a syringe, once every 6 weeks for a duration determined by the patient's physician. As with Visudyne, Macugen does provide benefit to some, but not all, patients.
Intraocular Drug Delivery
Many other drugs intended for the treatment of retinal disease are in the trial phase of development. These drugs are administered by direct intravitreal injection rather than orally or by intravenous injection. The short intraocular half-life of these drugs necessitates repeat injections every 4–6 weeks for up to 2 years.
This schedule is difficult for patients to endure and maintain, and the regimen carries an increased risk of tissue damage and infection. With approximately 12 pharmaceutical compounds currently in randomized clinical trials for the treatment of retinal disease, the need for an improved method of ocular drug delivery has never been more acute.
Continuous Intravitreal Drug Delivery
|Figure 1. An intravitreal implant is shown here next to a dime, which indicates relative size.|
A new drug-delivery option for the sustained release of drugs to the back of the eye is expected to enter clinical trials sometime in 2005. Unlike intra-vitreal or intravenous injections, this technology platform offers versatility and flexibility for drug formulation and pharmacokinetics control. The coil seen in Figure 1 is an implantable platform that leverages a proven polymer drug-delivery technology with a unique mechanical scaffold (a wire coil). The small size of the coil enables implantation through a pars plana needlestick less than 0.5 mm in diameter.
The unique helical design maximizes the surface area available for drug delivery and ensures secure anchoring of the implant against the sclera, keeping it out of the visual field and facilitating retrieval. The thin cap is designed to reside under the conjunctival membrane of the eye (see Figure 2). The drug resides within the patented polymer coating applied to the coil surface. The drug-release characteristics are controlled by the combination of the polymers in the coating and the process by which they are applied.
|Figure 2. The cap of an intravitreal implant is shown 3 months after implantation.|
In addition to the intravitreal uses for retinal diseases such as DME and AMD, sustained intraocular drug delivery may also prove to be an attractive alternative to topical eye drops for anterior diseases such as glaucoma. Glaucoma medications, the majority of which are delivered topically, represented a $1.4 billion market in 2002. Patient compliance is a significant problem with topical administration, particularly in the elderly population. It is recognized that less than 30% of patients administer drops as indicated. Lack of patient compliance can lead to costly and invasive surgical procedures. A sustained intraocular delivery system capable of providing medications for months at a time would represent a significant improvement in the treatment of this patient population.
Case Study: An Intravitreal Drug, a Polymer Coating, and an Implant Design
The technical feasibility of such a combination system for long-term intraocular drug delivery has been demonstrated in a study of a polymer-coated implant developed to incorporate the sustained intravitreal release of the corticosteroid triamcinolone acetonide (TA).
Drug-Delivery Polymer Matrix Coating. Medical device and pharmaceutical companies now have the technology and ability to combine, or marry, controlled drug delivery with an implantable platform. This enabling methodology offers several advantages over systemic delivery of a drug: the drug is targeted to the intended site of action, ensuring that the tissue needing the drug receives it; there is no need to use high or toxic systemic doses to achieve sufficient local concentrations; and a sustained, controlled dosing level can be maintained over a predetermined period of time.
The intravitreal implant uses the same drug-delivery polymer coating to control release of the active drug as that used in the first-to-market coronary stent. Since its approval, that stent has been implanted in more than 1 million patients. The coating is a durable polymer matrix especially suited to the controlled release of entrapped hydrophobic molecules. This application, treatment of a chronic disease condition over many years, requires a longer drug-elution duration and higher drug loading than that used in drug-eluting stents. Additionally, the minimally invasive nature of the implant design allows repeated procedures until the therapy is complete. In the case of this intravitreal implant, triamcinolone drug release can be tuned for durations ranging from 6 months up to 2 years.
Triamcinolone Acetonide. While not specifically approved for ophthalmic use, TA has a relatively long history of use in the treatment of ocular inflammation, with administration through a variety of methods, including intra-vitreal injection. Published reports describe the use of intravitreal TA in a wide range of ophthalmic disorders, including AMD and DME.
The toxicity and pharmacokinetics of intravitreal TA injection have been investigated in animal models, and the duration of visible intravitreal crystalline triamcinolone has been shown to be approximately 2 months, thus providing an extended period of activity in ocular tissues adjacent to the vitreous cavity.
Proven Sustained Drug Delivery. As the polymer coating was optimized for delivery of TA, in vitro elution was monitored in parallel with chemistry and manufacturing development. Elution experiments performed on the coated coils showed that a high level of drug loading and a wide range of in vitro release rates can be achieved by modification and fine-tuning of the coating formulation. The duration of drug release from the coating into phosphate-buffered saline is approximately 140 days using a fast-release formulation, while the release duration from medium- and slow-release formulations is projected to approach 1 and 3 years, respectively (Figure 3). Slower-releasing formulations approximated the zero-order-release kinetics considered desirable to maintain consistent drug levels in the eye.
|Figure 4. In vivo elution of triamcinolone acetonide from the intravitreal implant. The graph shows 6-month results.|
The long drug-elution duration may not only improve the efficacy and ease-of-use of the product, but also obviate the patient-compliance problem often associated with traditional forms of drug delivery. Elution curves generated from explanted implants confirmed a controlled, sustained drug-delivery capability in vivo (see Figure 4). In the case of the Dose A (slow-release) implant, sustained delivery is predicted to last for at least 2 years.
Preclinical Safety and Biocompatibility. Safety and biocompatibility of the triamcinolone implant have been studied extensively in preclinical
models. In two comprehensive studies, sustained-release implants containing TA were placed in rabbit eyes and followed clinically for 6 months. Following a small incision in the conjunctiva, each implant was positioned intravitreally by insertion through the sclera, 3 mm from the edge of the iris. A 30-gauge needle was introduced through the sclera before placement of the implant. The implant was rotated through the sclerotomy using a custom surgical instrument. Once the implant cap firmly abutted the sclera, the conjunctiva was closed using one or two absorbable sutures.
The entire implantation procedure consistently took 15–20 minutes. Eyes were monitored by fundus examination, electroretinography, ocular coherence tomography, and histopathology. A total of more than 100 eyes were followed for up to 9 months postimplantation. The implant was well tolerated, with no observed retinal toxicity. In addition, very little fibrous encapsulation was observed, as demonstrated by histopathology (see Figure 5).4
|Figure 5. A 3-month postoperative, resin-embedded histology section from a study using rabbits. Very little fibrous encapsulation was observed.|
Removal of the implant was similarly straightforward. Following conjunctival dissection around the cap, the implant was gently rotated out of the original sclerotomy. The remaining opening in the sclera measured approximately 0.5 mm in diameter and was either closed with a single suture or left open. The conjunctiva was closed with one or two sutures. Both techniques prevented infection and resulted in wound healing. In no case did implant removal result in retinal detachment.
Additional in vitro and in vivo biocompatibility studies for the polymer and platform were performed to address requirements from the international standard ISO 10993, Biological Evaluation of Medical Devices.
Regulatory Issues. As the product proceeds to the next stage, discussions have taken place with FDA on the suitability of the development work to support a small safety study. Based on input from FDA discussion, work began on an investigational new drug (IND) application to support the use of the implant in a Phase I clinical trial for patients with DME. A Phase I clinical study will evaluate the safety of the drug-delivery implant therapy. Future clinical studies are also being designed that will address the efficacy of this treatment in AMD and other ocular diseases.
Retinal diseases, such as DME and AMD, represent the leading causes of vision loss in the Western world. Unlike diseases of the front of the eye, where drugs can be delivered topically, retinal diseases require a site-specific approach.
A new drug-delivery option for the sustained release of drugs to the back of the eye will likely enter clinical trials sometime in 2005. Technologies such as this can provide sustained intraocular delivery of drugs for months or years, dramatically improving the treatment of chronic ocular disease. The technical feasibility of developing a system for intraocular drug delivery has been demonstrated. An implant has been developed to incorporate the sustained intravitreal release of the corticosteroid triamcinolone acetonide. In addition to minimizing systemic drug levels and overcoming physiological barriers to drug penetration, this approach also minimizes the dependence on patient compliance.
1. Treatment and Prevention of Diabetic Retinopathy [online] (Atlanta: Center for Accredited Healthcare Education [cited 31 May 2005]); available from Internet: www.caringfordiabetes.com.
2. Stanley Chang, “Recent Developments in the Treatment of Diabetic Macular Edema,” The Eleventh Health Conference [online] (Teaneck, NJ: Federation of Chinese American and Chinese Canadian Medical Societies [cited 31 May 2005]); available from Internet: www.fcmsdocs.org/Conference/11th/Diabetic%20Macular%20Edema.pdf.
3. “Age-Related Macular Degeneration: What You Should Know” [online] (Bethesda, MD: NIH National Eye Institute [cited 31 May 2005]); available from Internet: www.nei.nih.gov/health/maculardegen/armd_facts.asp.
4. R Tano et al., “Helical Intravitreal Triamcinolone Implant: Surgical Method Development and Outcomes” (paper presented at the Association for Research in Vision and Ophthalmology, Ft. Lauderdale, FL, May 1–6, 2005).
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