Ocular Drug Delivery: In Search of the Holy Grail

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by Dr. Sunni Patel, medeuronet clinical scientist

It is undeniable that the ophthalmic pharmaceutical industry commands a majority of the revenue, investment and spotlight in the medical world – and rightfully so. Recent figures suggest that the cost implications of visual loss is around $3 trillion. As this cost is expected to rise further as a result of increasing prevalence of AMD, DR and glaucoma, it is no surprise that many companies are working on ocular drug delivery for the appropriate management of the ‘big three’ diseases.

medeuronet sat down with several of the key players in the ocular drug delivery scene to get a better understanding of this area as well as why we should all be considering its importance in the field of ophthalmic innovation.

michaelMichael O’Rourke (picture left), of Scotia Vision Consultants, has worked within the global drug delivery industry for more than 25 years. His experience includes launching the world’s first intra-ocular drug delivery technology in Europe, Vitrasert®, and the world’s second, Retisert®, in the USA. medeuronet spent some time with this great market innovator to understand why there is an increasing focus on development of ocular drug delivery products.

Why is ocular drug delivery so important and gathering a lot of attention?

65% of people visually impaired and 82% of all blind are 50 years and older. The numbers speak for themselves, and therefore drive the need for advancements in drug delivery and therapeutic management.

Four major blinding diseases, age-related macular degeneration, diabetic retinopathy, diabetic macular edema and glaucoma, due to their whole or partial impact on the posterior segment of the eye, and their growing market sizes, may offer the most promising opportunities for future ocular drug delivery technologies. They affect large numbers of people and pose significant risk of vision loss and blindness for those affected. Current therapeutic options for these diseases may, at best, manage the condition, slowing or halting further deterioration or disease progression.

Can you describe how the market and products have changed during your time working in this area?

There have been major advances in recent years in developing and launching new sustained release ocular drug delivery systems; however only a small number have achieved both global regulatory approval and commercial success. Despite the challenges, there remains a significant market opportunity to enhance current products or develop new technologies offering improved treatment options for patients suffering from the major blinding eye diseases.

It’s interesting to note that since 1974, only five sustained release products have been launched. This obviously highlights the risk in this market, as well as, how difficult it actually is to develop drug delivery systems with minimal side effects.

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Figure 1 caption: The history of drug delivery systems on the ophthalmic market to date.

What do you foresee with the ocular drug delivery market, and are there any advances we should look out for?

The future for sustained-release ocular drug delivery lies in reducing the treatment burden by innovations in delivery technology, biologics delivery, targeting gene therapy to the appropriate cell types, and combining effective, small-molecule therapeutics with the appropriate drug delivery system, potentially in reservoir and micro particle technologies or delivery through the supra choroidal pathway.

Patient convenience and compliance will be a key driver for drug delivery success, however a demonstration of improved efficacy for a new product is going to be essential if delivering a truely competitive, sustained- release drug delivery advantage is going to be achieved.

 

ilvaDr Ilva Rupenthal (picture left) is a Senior Lecturer in the Department of Ophthalmology at the University of Auckland, as well as the inaugural Director of the Buchanan Ocular Therapeutics Unit. She has more than 10 years of experience in the area of drug delivery. We asked her to outline some of the key things to understand with this fascinating area.

Can you briefly explain the mechanisms of ocular drug delivery?

Drugs can be delivered to the eye using various routes including topical, intracameral, intravitreal, periocular and suprachoroidal (Figure 2). To treat anterior segment diseases the majority of treatments are applied topically, while for retinal conditions intravitreal injection is the most common application route. Besides solutions for injection, there are currently also four implants on the market that are either sutured into the sclera (Vitrasert® and Retisert®) or injected into the vitreous (Iluvien® and Ozurdex®) to treat back-of-the-eye conditions.

figure 2

Figure 2 caption: Schematic cross section of the eye and possible drug delivery routes
(Modified from Rupenthal ID, Alany RG. 2008. Ocular Drug Delivery. In Gad SC (Ed.) Pharmaceutical Manufacturing Handbook: Production and Processes, New York: John Wiley & Sons, Inc. p 729-767.)

What is interesting at the moment, and what should we be keeping our eyes on?

A number of companies are now investigating sustained release systems for the treatment of ocular conditions to reduce the need for frequent topical drops or intravitreal injections. To treat conditions at the front of the eye, Ocular Therapeutix is developing punctum plugs to deliver drugs for up to three months. Meanwhile, non-aqueous eye drops are under evaluation by Novaliq, while Kala Pharmaceuticals is testing mucous-penetrating particles for improved bioavailability after topical administration.

For sustained release to the back of the eye, a number of interesting technologies are currently under investigation including polymeric particles and inserts by GrayBug and Envisia respectively, as well as, devices such as the Port Delivery System by ForSight and the MicroPumpTM by Replenish. Finally, there are many new drug molecules in the pipeline that could be game changers to the way we currently treat ocular diseases.

With such advancements, are our expectations becoming higher and higher in terms of drug delivery, and as a consequence of this, are patients now also expecting more in terms of disease management?

Our expectations are certainly becoming higher, but matching these new technologies with drug pharmacokinetics and translating pre-clinical studies into human clinical trials is not an easy task. I think patients get really excited when they hear about all these new drugs and technologies, but we need to keep in mind that not all of them are suitable for every patient.

What do you envisage the future being like for drug delivery?

Ideally, we would have some sort of ocular implant that can deliver drug(s) over prolonged periods with the possibility to regulate the dose for each individual patient. This would reduce the need for frequent intravitreal injections with regards to the treatment of retinal diseases, but would also allow increasing the dose non-invasively in case the condition worsens or reducing the dose if the disease improves or in the case of adverse events. One might think that drug delivery to such a small organ should be easy, but the eye has some really particular barriers to protect itself from the environment and these are difficult to overcome.

Recently, Ophthalmology Times reported on the possibility of drug-eluting contact lenses as the new means of management for glaucoma. With patient compliance being a major factor in driving disease progression, it would seem that contact lenses could be the answer in making topical drops a thing of the past.

 

UntitledWe were extremely lucky to get some one-to-one time with Prof Heather Sheardown (picture left) from the Dept of Chemical Engineering at McMaster University, Canada. Her interesting and pioneering work in contact lens materials in the use of drug delivery makes for quite an interesting read!

Why contact lenses for drug delivery?

There are a number of advantages of using contact lenses for treating diseases of the anterior segment including the on-eye location, the potential to alleviate the need for the instillation of multiple drops over a long period of time, and the potential to maintain drug concentrations at a higher level in the pre corneal tear film.  New materials such as silicone hydrogels have the potential to prolong the release of a drug which allows for longer periods of drug release.  These materials also have the potential to be worn for extended periods of time (days-weeks) which allows for longer treatment.

How does drug delivery in contact lenses work? What conditions can it be used to treat?

Since contact lenses are designed for extended on-eye use, they have the potential to deliver drug to the eye during the period of wear.  Various delivery mechanisms can be used but in most cases, because of the hydrogel nature of the materials, release is of a relatively short duration.  There are many factors that control the release of drug; material factors as well as tear drainage effects are significant.  Penetration through the anterior ocular tissues also plays a significant role in determining release.

Since transport through the cornea remains a problem, conditions that are best suited to lens delivery are anterior segment conditions, which can be treated by drops but often require multiple instillations over a long period of time.

Briefly describe your work in contact lenses. We see reports that drug delivery is limited in terms of hours, so do you see it for short-term drug release and management of inflammatory conditions like anterior uveitis?

Our work in contact lenses involves using silicone hydrogels and other agents to control drug release.

Extended drug delivery is a possibility with these types of materials.  However, since ocular health is affected by long term lens wear, these types of systems are better suited to shorter term conditions.  Inflammatory and infectious conditions as well as allergic conditions are excellent candidates for this type of treatment.  Note that with silicone hydrogels wear periods of up to 30 days are permitted and thus these can potentially be used to enhance treatment for longer term and more chronic conditions such as glaucoma.

With advances in materials and contact lenses, surely it would be easier to see developments in this area? What has slowed down the progress?

Drainage of the tear layer remains a problem since the drug is released into a dynamic layer that is rapidly cleared from the eye.  This essentially changes the kinetics of drug release since the convective flows of the tears carry away drug.  Some mechanism to maintain drug on the ocular surface would be of interest.

What do you see as the future in contact lens drug delivery?

Areas of future interest for contact lens based drug delivery include new drugs for treating anterior segment conditions, with allergy being of particular interest since this is a condition that is exacerbated by lens wear.  Additionally, release of wetting agents from lenses would be of interest to alleviate lens induced dry eye.

Closing Thoughts

Our three interviews highlight that ophthalmic drug delivery is definitely interesting and advancing at an incredible pace. It is necessary to address the growing epidemic of visual loss in the Westernised world but it is wrought with many a problem. The concept of the Holy Grail was coined by Ophthalmology Times in 2011 as a new beacon of hope in the field of disease management. Four years down the road, it appears that Indiana Jones had more success in acquiring the coveted artefact. Why is this the case, and will successful drug delivery remain a figment of our imaginations as a utopian fantasy? Many in the field of drug delivery would suggest otherwise, and Michel O’Rourke believes that there are at least three “Sustained Release: Holy Grails” yet to be discovered:

1) Delivery of Biologics – difficult to achieve due to the denaturing effect of proteins and need for high percentage drug loading to achieve a therapeutic effect

2) Glaucoma – has the same challenges as any other delivery system in that the drug has to match the platform technology to allow for at least 6-months delivery.

3) Dry age-related macular degeneration – a new pharmaceutical treatment for dry AMD has not been approved – so a sustained release version will follow drug approval, so would be many years away.

For the moment, all we can suggest is to watch this space and witness the developments, investments and innovations in the market as an interesting few years are expected.

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