Conventional drug delivery vehicles are giving way to innovative systems, but much research remains to be done on these novel technologies.
The human eye contains a striking amount of intricacy for such a small organ; and disorders affecting the eye can affect its components in a wide variety of ways. Diseases like glaucoma and conjunctivitis attack the anterior regions of the eye, such as the cornea and conjunctiva; while disorders like macular degeneration (AMD) and diabetic retinopathy can damage the retina.
Delivery systems for ocular therapies are equally diverse, ranging from conventional topical instillations to ointments, contact lens delivery systems, and newer, more innovative systems like dendrimers and nanomicelles. Each of these delivery systems presents its own advantages and challenges, requiring pharmaceutical developers to carefully consider the implications of their intended delivery vehicle throughout the drug development pipeline.
This article presents an overview of several key delivery vehicles or ocular drugs, along with brief discussions of the benefits and potential concerns involved with each.
Topical instillations are non-invasive, but offer low bioavailability.
Perhaps the best-known form of ocular drug delivery is that of dosage forms like eye drops, which fall into the category of topical instillations; in other words, liquids administered directly onto the eye’s anterior surface. While these dosage forms are convenient, safe, and immediate, factors like reflex blinking and nasolachrymal drainage result in extremely low bioavailability. In fact, an average of less than five percent of a topical dose actually reaches the eye’s tissues.
To improve the bioavailability of active pharmaceutical ingredients (APIs) delivered via topical installations, a wide range of improvements have been developed. These innovations range from the usage of suspensions, emulsions and ointments, to more novel delivery technologies like the use of liposomes, dendrimers, nanomicelles and nanoparticles. These improvements will be covered in greater detail throughout the remainder of this article.
Suspensions provide tighter control over drug activity, but have high viscosity.
In contrast to traditional topical instillations, suspensions provide a longer contact period between the API and the cornea, and also provide greater control over the drug’s absorption rate. This is because a suspension consists of a dispersed insoluble API within a water-based solvent, resulting in a concentration of suspended particles that are retained in the precorneal pocket upon administration. Drug particles of smaller size are rapidly absorbed into ocular tissue, while larger particles remain in the precorneal pocket, releasing their contents over time.
While this extended absorption period significantly increases bioavailability, suspensions have higher viscosity than topical instillations, which can inhibit its tissue permeation and overall coverage of ocular surfaces. To counteract this issue, some drug manufacturers have begun introducing excipients that reduce the viscosity of the suspension, resulting in more effective delivery systems. Still, much work remains to be done on suspension viscosity.
Emulsions improve solubility and bioavailability, but remain poorly understood.
Another approach to circumventing the challenge of low bioavailability is to dissolve the API in oil and disperse the oil in water, or dissolve it in water and disperse it the water in oil, resulting in an emulsified formulation. Emulsions offer significantly greater bioavailability than topical instillations, while also remaining more soluble than highly-viscous suspensions. These delivery systems also tend to cause less irritation than either of the aforementioned vehicles.
But while research on emulsions is promising, conclusive results are so far scattered and disconnected. Some research has demonstrated that emulsions containing difluprednate can reduce ocular inflammation. Other studies have found that emulsions with lipid additives can enhance bioavailability of APIs. Still other researchers have used mucoadhesive polymers like chitosan to lengthen emulsions’ precorneal residence time. As potentially useful as all these techniques are, an overall set of best practices for emulsion delivery systems still remains to be developed.
Ointments provide high bioavailability and sustained release, but often cause irritation.
In cases where bioavailability and continuous release are crucial, ophthalmic ointments offer a possible alternative to liquid topical delivery systems. In these vehicles, the API is suspended in a hydrocarbon that melts at ocular surface temperature. This gradually melting compound loosely adheres to the ocular surface, delivering the API into tissues at a controlled rate, over an extended period of time.
As effective as emulsions can be, a number of key challenges remain. Like all topical formulations, ointments frequently cause irritation and redness, and may interfere with vision. In addition, an ongoing series of doses can cause a buildup of API within the patient’s tissues, potentially leading to systemic complications. For all these reasons, much current research on ophthalmic formulations is focused on obtaining tighter control over drug absorption, via an array of innovative delivery technologies. These technologies will be the focus of the next two sections.
Liposomes and dendrimers increase drug half-life, but remain little-studied.
A number of recent studies have shown promising results from liposomes, lipid vesicles enclosing an aqueous core containing the API. Liposomes have been demonstrated effective at delivering drugs to both anterior and posterior ocular surfaces, with precorneal residence times far longer than those typically achieved via conventional topical delivery vehicles. Some researchers have achieved even longer residence times through the use of positively charged liposomes, which bind directly to ocular tissues.
In addition to liposomes, a growing number of research teams are experimenting with dendrimers, nano-scale branching polymers available in a wide range of weights, sizes, geometries and functional groups. The high variety of dendrimers makes them potentially suitable for use with a wide range of drugs. They have been shown to increase mean ocular residence time, while enhancing bioavailability and half-life of several drugs. However, both liposomes and dendrimers remain poorly studied as ocular delivery vehicles, and require a great deal of further research.
Nanomicelles and nanoparticles provide precise control, but research is early-stage.
Beyond liposomes and dendrimers, a set of emerging therapies are based around even more innovative nano-scale delivery systems. One key field of research focuses on nanomicelles, self-assembling colloidal dispersions with hydrophobic cores and hydrophilic shells. These delivery vehicles promise extraordinarily high bioavailability, due to their extremely small size and high encapsulation of API molecules. Several studies have already demonstrated nanomicelles’ effectiveness in anterior ocular drug delivery, and further studies are currently investigating nanomicellular delivery of drugs to posterior ocular tissues.
Nanoparticles serve as another key focus for ocular drug delivery research. These colloidal carriers can be composed of lipids, proteins, or natural or synthetic polymers, enclosing drug particles within nanocapsules or nanospheres. While the small size of nanoparticles provides very high bioavailability, it also increases the likelihood that these particles will be eliminated from the precorneal pocket, just as particles in topical instillations are. Thus, researchers are now investigating the use of liposomes and dendrimers to extend nanoparticle residence times. Even so, research on both nanomicelles and nanoparticles remains very early-stage, and much exploration remains before these novel delivery systems are ready for large-scale clinical trials.
Many pharma developers are now pouring significant expertise and resources into refining novel ocular drug delivery systems, from liposomes and dendrimers to nanomicelles and nanoparticles. Still, topical instillations remain the backbone of ocular drug delivery, accounting for 90 percent of all commercial ocular drug vehicles. Pharma innovators aiming to capitalize on innovative delivery systems will need to solve the technical problems associated with conventional vehicles, including ocular irritation, short residence times, and low bioavailability. Only then will these novel vehicles be ready to enter the clinical and commercial spotlight.
