Topical drug delivery to the retina: obstacles and routes to success

ABSTRACT

Introduction

Retinal diseases are one of the main reasons for vision loss where all available drug treatments are based on invasive drug administration such as intravitreal injections. Despite huge efforts and some promising results in animal models, almost all delivery technologies tested have failed in human trials. There are however examples of clinically effective topical delivery systems such as fast dissolving aqueous eye drop suspensions.

Areas covered

Six obstacles to topical drug delivery to the eye have been identified and discussed in some details. These obstacles consist of static membrane barriers to drug permeation into the eye, dynamic barriers such as the lacrimal drainage and physiochemical barriers such as low thermodynamic activity. It is explained how and why these obstacles hamper drug permeation and how different technologies, both those that are applied in marketed drug products and those that are under investigation, have addressed these obstacles.

Expert opinion

The reason that most topical drug delivery systems have failed to deliver therapeutic drug concentrations to the retina is that they do not address physiochemical barriers such as the thermodynamic activity of the permeating drug molecules. Topical drug delivery to the retina has only been successful when the static, dynamic, and physiochemical barriers are addressed simultaneously.

KEYWORDS:

• Topical drug delivery
• static barrier
• dynamic barrier
• thermodynamic barrier
• drug delivery system
• eye anatomy
• passive diffusion
• retina

Article highlights

• Retinal diseases are common causes of vision loss and blindness.

• Although the eye is readily accessible, its anatomy creates significant challenges in ophthalmic drug delivery, especially to the posterior tissues such as retina.

• Topical and systemic drug delivery have only resulted in subtherapeutic drug levels in the posterior eye tissues.

• Current drug treatments of posterior eye diseases are all based on invasive drug delivery such as intravitreal injections and implants.

• Invasive systems have many drawbacks such as increased risk of ocular infections and hemorrhage, and the inconvenience of frequent ocular injections. Thus, there is a growing need for topical drug delivery systems to treat chronic diseases in the posterior segment.

• Drug permeation from the eye surface to the posterior tissues of the eye is hampered by several obstacles such as drug solubility in the tear fluid, lacrimal drainage, mucus on the eye surface, low thermodynamic activity, permeation through the lipophilic epithelium, and extraction by vascular tissues.

• Most topical drug delivery systems under development have failed to deliver therapeutic drug concentrations to the retina. The main reason is that they fail to address physiochemical barriers such as the thermodynamic activity of the permeating drug molecules.

• Studies show that by thorough physical and thermodynamic optimization of the delivery system it is possible to obtain therapeutic drug levels in the retina after topical drug administration.

• In clinical studies, fast-dissolving aqueous eye drop suspensions, which give high concentration of dissolved drug in the tear fluid of high thermodynamic activity for extended time, have been able to create therapeutic drug levels in the retina.

Acknowledgments

The author would like to thank Dr Marcia de Souza Lima for her critical review of the manuscript.

Declaration of interest

T Loftsson holds a part-time position at Oculis and owns stocks in the company. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.