The eye is well-fortified to repel the delivery of drugs, having many systems designed to dilute and remove them. To get the best effect from an ophthalmic drug, therefore, researchers need to know how to get around these obstacles and deliver the drug where it needs to go. This month we'll extend the discussion of clinical pharmacokinetics we began last month to include the successes and failures of current drug-delivery systems. We'll also review the barriers to entry in marketing a successful drug-delivery product and review the devices you may soon see on the market.

Delivery Strategies
As we discussed last month, the anatomy of the eye presents a number of challenges to topical treatment. Before making it past the tear film, more than 90 percent of the drug from an eye drop will be lost.1 (A review of the bioavailability obstacles for a topical drop at each layer of the eye appears in Table 1.)

Table 1. Obstacles to Bioavailability
• Tear Film
 • Tear turnover (16 percent per minute)
• Tear drainage
      -Lid spillover     
     - Drainage through nasolacrimal duct
 • Absorbed by vascularized tissues
    - Limited absorption. Approximately 1 percent or less of the drug permeates the cornea. Drugs that penetrate the sclera or conjunctiva are removed by local circulation and undergo systemic absorption.
• Tear film protein binding and degradation
• Dilution with tears
• Evaporation
• Increased tearing due to drop discomfort/irritation
      - Drop discomfort also causes decreased patient compliance
The Cornea
• Epithelial layer is lipophilic and sublayers are hydrophilic
     - Effective penetration requires that the drug have some hydrophilic and lipophilic character
The Aqueous Humor
• Dilution in the aqueous humor
• Binding with aqueous humor proteins
• Metabolism from active to inactive forms
• Aqueous humor turnover
The Iris
• Melanin in the iris may bind lipophilic drugs
The Retina
• Hydrophilic drugs are prevented from crossing the blood-retina barrier by tight junction complexes
• Lipophilic drugs easily pass in and out of the retina

The frequent dosing required to overcome the barriers in Table 1, combined with the possible difficulty for the patient to instill a drop, lead to increased side effects, increased ocular surface toxicity and poor dosing compliance.
Seemingly, a device without the need for frequent dosing would enjoy wide acceptance. To date, however, no ocular surface and/or anterior chamber/ciliary body inserts or delivery devices on the market have been liberally prescribed. For example, Ocusert Pilo, originally developed by Alza Corporation (Mountain View, Calif.), is a pilocarpine-loaded, insoluble device placed in either the upper or lower cul-de-sac. It's approved to deliver pilocarpine for seven days—equivalent to q.i.d. dosing of a topical drop. The device failed to achieve widespread use, however, due to difficulties in compliance. The users of the device, an older patient population, found it difficult to insert and it frequently ejected from their eyes. Today, a successful delivery device for ocular surface and anterior chamber/ciliary body disease must overcome a number of barriers to entry due to the success of eye drops (See Table 2).

Table 2. Characteristics of a Successful Device
• Delivery of drug must be stable, consistent and reproducible
      - Zero-order kinetics
• Design and physical characteristics must match the drug to prevent cross-reaction with the medication and a desired release rate that's not dependent on tear turnover
• Must be able to withstand terminal sterilization (heat or gas)
• Cost to patient must be justified compared with conventional eye drop
      - Increased cost must provide increased benefit
• Must be comfortable to use
      - Should not cause irritation or foreign-body sensation
• Resist expulsion by rubbing or on its own
• Easy for the patient to insert and replace
• Consideration for patient population; older patients will have difficulty manipulating the device
• Should not damage or obstruct normal ocular functions
      - Non-blurring     
     - No lid caking
      - No restriction of oxygen to cornea
      - No membrane rupture
      - Non-toxic

Working with an awareness of the barriers in Table 2, some technologies in development are focused on improving drug delivery.

Liposomes and nanoparticles are lipid shells, about 20-1000 nm in size, that resemble the membrane of cells. As we mentioned earlier, more than 90 percent of the drug is lost at the tear film before entering the eye, and these devices are aimed at reducing that loss. Liposomes' and nanoparticles' likeness to cell membranes may enhance their ability to fuse quickly with corneal cells for drug delivery before being lost in the tears. Also, they're favorable for the delivery of drugs that are hydrophobic and poorly permeable, such as steroids, non-steroidal anti-inflammatories and immunosuppressants.

Liposomes. Liposomes are currently used to assist with the delivery of two marketed drugs, doxorubicin, an anticancer therapy; and amphotericin B, an antifungal drug, and are currently in development for the delivery of agents to the eye. Optime Therapeutics (Petaluma, Calif.) is developing a liposome delivery called Optisome. Using this technology, the company plans to develop drugs for dry-eye syndrome, glaucoma, conjunctivitis, postoperative pain and uveitis.

Nanoparticles. The University of Florida has taken a different approach, using nanoparticles for drug delivery. They're developing a technology that incorporates drug-encapsulated nanoparticles inside the lens matrix of poly-2-hydroxyethyl methacrylate soft contact lenses. At 30-50 nm, the nanoparticles are smaller than the wavelength of visible light, so they don't compromise vision. Researchers believe that the medication diffuses out of the nanoparticles and through the contact lens to the post-lens tear film where it can be absorbed by the cornea. 

Corneal shields. Similar in shape to a contact lens, corneal shields are frequently used as postoperative bandages for wound healing and surface protection. Bausch & Lomb and the University of Illinois at Chicago Eye Center are currently researching collagen corneal shields for drug delivery. These shields have been investigated for 20 years for drug delivery, but haven't had much acceptance.

Collagen is highly biocompatible. After being placed in the eye, it dissolves. Shields are currently being made to dissolve in six, 12, 24, 48, 72 hours and a week. Medication is absorbed by the collagen shield and then slowly released as the shield dissolves.

Vitreoretinal Drug Delivery
Currently, the industry's focus for developing drug delivery devices and injections has moved toward drug delivery for vitreoretinal diseases.

This move is primarily financial. According to analysts at the investment bank UBS Warburg, 55 percent of debilitating eye diseases occur in the posterior segment, yet account for less than 5 percent of drug revenue.2 As such, the drug maker Oculex (Sunnyvale, Calif.) estimates that the market for age-related macular degeneration may be $2 billion.3 Much research is focused on treatments for AMD, macular edema, diabetic retinopathy and diabetic macular edema. To date, no highly effective pharmaceutical treatments are available for these diseases, partly due to the difficulty in delivering drugs to the vitreous or retina. 

Injection. Most injection treatments under investigation are anti-angiogenic agents aimed at preventing the growth of new vessels in wet AMD. Three drugs in development are intended to inhibit vascular endothelial growth factor (VEGF). Macugen (pegaptanib sodium, Eyetech, New York City and Pfizer), ranibizumab (rhuFab V2, Genentech) and combretastatin (CA4P, Oxigene, Watertown, Mass.) are delivered via intravitreal injection.

Other treatments under investigation include anecortave acetate (Alcon), an angiostatic steroid, delivered by juxtascleral injection. Research on a slow-release juxtascleral anecortave acetate implant is also under way.

Many think that angiogenesis is naturally regulated in the eye by the balance of two proteins, VEGF and pigment endothelium derived factor. PEDF is believed to inhibit new blood vessel growth. AdPEDF.11 (GenVec, Gaithersburg, Md.), an adenovector carrying a progene for human PEDF, is being investigated as genetic therapy for wet AMD.

Drug delivery implants. One of the initial drug delivery devices for vitreoretinal disease is the Vitrasert implant for AIDS-related cytomegalovirus retinitis currently marketed by Bausch & Lomb. The product was developed by Control Delivery Systems (Watertown, Mass.) using its Aeon technology, a controlled rate and duration of release delivery system. The device is surgically implanted into the vitreous where it releases the antiviral drug ganciclovir. The device is replaced when the drug is depleted, usually after six to eight months.
Using a technology similar to Vitrasert called Envision TD, Bausch & Lomb and Control Delivery Systems are developing Retisert, an intravitreal device containing the steroid fluocinolone acetonide, which is currently in clinical studies for posterior uveitis, diabetic macular edema and AMD.

Another steroid-releasing device being developed by Oculex is Posurdex, a slow-release dexamethasone intravitreal implant currently in human trials for persistent macular edema associated with diabetic retinopathy, uveitis, vein occlusion and Irvine-Gass syndrome. Posurdex uses a completely biodegradable polymer that dissolves over time.

An interesting technology being developed by Paris' Neurotech S.A. is Encapsulated Cell Therapy. Their lead product, NT-501, consists of encapsulated retinal pigment epithelial cells, which are genetically modified to secrete ciliary neurotrophic factor for the treatment of retinitis pigmentosa. CNTF is a protein that may prevent degeneration of photoreceptors in RP. The cells are inside a membrane designed to permit the intake of oxygen and nutrients and the release of CNTF. The cells are maintained in a biological matrix that supports long-term survival in vivo. The current prototype is about 10 mm long and may be able to be implanted into the vitreous and anchored to the sclera in 15 minutes.

Iontophoresis. As an alternative to parenteral or systemic delivery, iontophoresis is being investigated for ocular uses. By applying an electrical current to a topically applied drug, iontophoresis is capable of pushing it through specific tissues to a target treatment area. Depending on the charge of the drug, a positive or negative charge can propel it. Iontophoresis has been used for transdermal delivery of anti-inflammatory drugs.

Eyegate (Optis Group, Paris) and OcuPhor (IOMED, Salt Lake City) are two ophthalmic iontophoresis systems being investigated. Similar to transdermal delivery, iontophoresis may offer a less invasive alternative to injections or delivery implants.

While many technologies have been and will be investigated for ocular drug delivery, few have been successful. Though it's hard to beat the ease of q.d. dosing with a drop, manufacturers will continue to try. The outlook may be brighter for vitreoretinal disease, where the possible complications of surgery or intravitreal injection make inserts an attractive option.  

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Mr. Shapiro is a research associate at Ophthalmic Research Associates in North Andover.

1. Worakul, Nimit et al. Ocular Pharmacokinetics. In: Albert D, ed. Principles and Practice of Ophthalmology, 2nd ed. Philadelphia: W.B. Saunders Company, 2000: 202-211.
2. Croes K, with commentary from Banc of America Securities, Millenium Research Group, Raymond James LTD., SG Cowen, Standard & Poor's, Thomas Weisel Partners, and UBS Warburg.  Eye Pharmaceuticals & Disease Treatments: Back-of-the-Eye Therapies Driving Double-Digit Category Growth. Optistock website.
3. Dain Rauscher Wessels estimates. Oculex website.