Sustained-delivery platform opens new frontier in ocular therapeutic delivery

Take home

The development of sustained, ocular drug delivery aims to remove patient compliance in order to achieve the therapeutic effect.

By Steven T. Simmons, MD, Special to Ophthalmology Times

Albany, NY-For decades physicians have been searching for a solution to the traditional method of delivering medication to the eye in order to treat ocular disorders, such as inflammation, allergy, dry eye, and probably the most important, glaucoma. Many therapeutic agents are available that-when prescribed and used appropriately-handle the majority of patient issues without incident.

However, the problem lies in the phrase “used appropriately.”

We, as physicians, know how difficult it is to take medications appropriately over time. Compliance is critical to any successful medical treatment-especially in chronic, asymptomatic diseases like glaucoma.

Because of physician reliance on patient compliance for a successful therapeutic effect from eye drops, numerous efforts are being directed toward the development of sustained-release platforms using eye medications that have previously been approved. These medications are effective when used appropriately.

However, we all know that more than half of patients fail to comply with the dosing regimens they are prescribed. Thus, one of the goals of sustained, ocular drug delivery is to remove patient compliance in order to achieve the therapeutic effect.

Ideally if we, as physicians, can control patients’ drug administration-whether for glaucoma or other diseases-there is a much higher likelihood of improved outcomes in response to treatments.

There are essentially two approaches to administration of these sustained-release systems: 1) Invasive-such as the injection of an insert through the cornea into the anterior chamber or surgical placement of a delivery device under the conjunctiva.

2) Non-invasive-such as the placement of a device in the tear duct or on the ocular surface.

Invasive systems have the advantage of being placed closer to the targeted site of action, but have the disadvantage of causing repeated tissue trauma and exposure to infection and rejection which could be concerning with chronic diseases like glaucoma. Another concern using invasive approaches is in the situation where the insert or implant must be removed. This will pose additional surgical risk to the patient and add significant cost to the health-care system.

Non-invasive delivery systems overcome these significant disadvantages because they are easily placed without tissue damage, easily removed when needed and because they are non-invasive, will likely result in lower infection and complication rates.

There are two main locations for the placement of a non-invasive sustained release system on the ocular surface or in the tear duct. One of the most promising sustained-release programs-known as the punctal plug delivery system (PPDS)-is being developed by Mati Therapeutics Inc. The company was founded by Bob Butchofsky and Chris Muller, who have been in the ophthalmic and medical device industry for more than 25 years and understand for the need for increased compliance and convenience in administering ophthalmic medications.

Punctal plugs have been available for decades in ophthalmology and even though they have improved over the years they still come with considerable drawbacks. The three areas of most concern are retention rate, patient comfort, and ease of insertion. For use in dry eye conditions the newest plugs have addressed the issues of patient comfort and ease of insertion fairly well. Retention rates still tend to be low which is manageable with dry eye patients since their symptoms tend to return if the plug is dislodged and there is a low risk of disease progression in the short term until the patient has their next visit. When considering a therapeutic delivery plug, retention rates are critical and had to be improved in order to treat glaucoma patients successfully.

The sustained-delivery platform developed by Mati Therapeutics Inc. has had well over $100 million invested in its development and this investment has helped the PPDS platform (Evolute) to overcome many of the historical hurdles limiting ocular sustained delivery devices in the past. Some of the main obstacles historically have been “long-term efficacy,”, “controlled delivery of medication”, and “retention rates of a long term non-surgical device.” In order to meet these needs Mati has developed more than 100 iterations of the sustained release platform and treated more than 1,000 patients to ensure the correct development path. All of this research ended up in the creation of the sustained-delivery platform which overcomes each of these barriers by combining a silicone punctal plug with a sustained-release, drug-eluting core.

The advantages of using a silicone plug, which is non-bioerodable, non-biodegradable or non-bioabsorbable, to anchor the drug core is that the retention features do not change over time. This has resulted in a consistent, predicable retention rate of 92% for the system over 90 days according to the latest, multicenter phase II trial. The other advantage of a system that does not change over time is that removal of the system is not complicated because it is readily identifiable and easily removed.

The sustained-release drug core is also composed of non-bioerodable, non-biodegradable or non-bioabsorbable components. This results in a robust and predictable long term elution profile because the system is primarily governed by the rate of diffusion of the active drug into the tear film from the core. Other sustained release systems which use biodegradation of the matrix to release active drug, and this can be variable based on the subject’s tear composition and production rate. These variables do not affect the Mati system and will not cause an alteration to the elution rate. Biodegradable systems or other systems that change shape over time also suffer from the disadvantage that these changes may result in the loss of the core from the device adversely effecting efficacy.

The first product being developed incorporates latanoprost into the sustained-delivery platform for the treatment of glaucoma. Through extensive formulation development, the Evolute latanoprost drug core was developed to minimize any large burst of medication, reducing local and systemic side effects. The elution rate has delivered a consistent 5 to 6 mm Hg IOP reduction from untreated baseline over 12 weeks.

An additional benefit, the platform is preservative-free. We are all familiar with the toxicity and other issues associated with long-term use of preserved eye drops. Preservatives such as benzalkonium chloride (BAK) and others are suspected of causing ocular surface issues, such as conjunctival inflammation, tear film instability, corneal toxicity, anterior chamber inflammation, and allergic reactions.

In clinical studies, the vast majority of patients preferred the sustained-delivery platform to eye drops. This isn’t surprising because of the passive nature of the system from the patient’s perspective. The patient no longer has to adhere to time-sensitive daily regimens once the device has been inserted. This may prove to be a huge benefit for ophthalmologists and their patients ensuring better adherence and more consistent administration of the therapeutic agent-potentially leading to improved outcomes.

Steven T. Simmons, MD, is co-director of Glaucoma Consultants, Albany, NY, and associate clinical professor of ophthalmology, Albany Medical Center. Dr. Simmon’s research interests in the field of glaucoma include new pharmaceutical development, adjunctive use of glaucoma medications, and primary surgery for the treatment of glaucoma.