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Effective Ocular Drug Delivery

27/09/2011


Dr Eileen McBride of the University of Strathclyde examines the advances being made in delivery technologies, including the use of MEMs, and the issues yet to be resolved.

Advances in the treatment and management of cardiovascular disease and cancer are contributing to an ageing population, which has resulted in an increase of 1.5 million people over the age of 65 in the last 25 years in the UK alone.1 This has significantly increased the prevalence of age related ophthalmic conditions and neovascular (wet) age-related macular degeneration (AMD), the leading cause of adult vision loss and visual impairment worldwide. Diseases affecting the back of the eye, including AMD, diabetic retinopathy and glaucoma present a challenge for effective treatment due to inefficient drug delivery to the regions affected.

The barriers to overcome

Traditionally, the most common approach to treating ocular conditions is with topical application to the cornea with eye drops. However, this is a highly inefficient means of delivering drugs to the back of the eye. A large percentage of the dose is lost through reflex lacrimation, overspill from the conjunctival sac, nasolacrimal drainage and systemic uptake via the conjuctiva. Poor contact and residence time limits absorption through the cornea although advanced delivery systems such as Timoptol-LA, an eye drop that gels in situ at the corneal surface and has an increased residence time, provides a means of overcoming this limitation. However, the drug must still overcome the corneal barrier itself, which is a lipophilic–hydrophilic matrix made up of a series of tight junctions limiting uptake. This barrier controls the rate at which a drug partitions through the cornea into the aqueous chamber where compounds possessing zwitterionic properties are optimal, but absorption is still slow and limited. Less than 5% of an instilled dose reaches the anterior chamber. Here, rapid clearance from the aqueous humour and melanin binding further limits the transport and therapeutic capability of drug in the posterior regions of the eye. Poor bioavailability limits treatment with topical therapy to conditions affecting the anterior chamber, and alternative routes of administration are sought for access and effective delivery to the posterior tissues.

Current approaches

The most direct and non-invasive means of treating conditions affecting the back of the eye is with systemic drug delivery. However, the high oral doses required to achieve therapeutic levels in the ocular tissues often result in toxicity and severe adverse effects.

Direct access to the posterior eye overcomes the barriers present in the front of the eye, although it generates a new set of issues. Currently, the only licensed treatment for wet AMD in the UK is a monthly intravitreal injection of ranibizumab (commercial name Lucentis), a vascular endothelin growth factor inhibitor. This is an expensive and relatively inefficient treatment in which more than 50% of the injected dose rebounds back out through the needle hole. Of more importance are the safety concerns associated with regular intravitreal injections. Patients can experience pain at the site of injection, an increased risk of infection, increased intraocular pressure, risk of retinal detachment and inflammation of the intraocular tissues. Rapid clearance of the dose from the vitreous through the blood–retinal barrier and the anterior chamber further limits the efficacy of this approach and demonstrates the need for improved delivery approaches.

Controlled release implants

To overcome the short lived effect of individual injections and to prolong the interval between injections, controlled release implants have been developed for intraocular use. The implants are both biodegradable and non-biodegradable. In the latter the implant is anchored within the sclera and releases into the vitreous. Biodegradable implants can be monolithic or can be micro- and nanoparticulates. They are commonly made using a mixture of degradable polylactic and glycolic acid esters, which control the rate of release.

Although they release over a period of months, the release profile is often difficult to control. They exhibit triphasic release profiles with a burst release at the beginning and at the end, which may fall outside the required therapeutic range and result in toxicity. An additional hurdle is that the particulates can be rapidly cleared depending on their size and sub-therapeutic concentrations are achieved in the target tissues. As foreign bodies, the implants may trigger an inflammatory immune response, and their administration remains an invasive process that possesses the same safety concerns as those outlined for intravitreal injections.

There are clear advantages to the implants, but more advanced technologies that overcome the barriers to delivery and provide a safer, less invasive and better controlled and targeted means of drug delivery are essential.

Advanced technologies

Progression of technologies for ophthalmic drug delivery relies on adapting a range of established technologies that are more readily applied to alternative sites of delivery. These include subcutaneous implants, transdermal patches and microneedles and microelectromechanical systems (MEMS) as delivery devices. These approaches address the concerns over control of release and targeting to specific areas of the back of the eye at therapeutically relevant concentrations.

Microneedles

As a well-established technology to aid transdermal drug delivery, microneedle arrays offer a range of opportunities for development as periocular delivery approaches, particularly applied to the sclera. The needles create a pain free and minimally invasive portal of entry in the tissue, destructing the outermost barriers of the tissue, and generating a more direct route of absorption for drug instilled in the pores created. 

They can be fabricated using a range of materials including stainless steel, glass and biocompatible polymers, and their size and shape can be adjusted depending on their use and the tissue in which they are to be positioned. The design specifications are dependent on the desired delivery approach where they can take on a number of forms:
  • solid microneedle arrays of specific dimensions used to create pores and then removed, after which drug can be applied in the form of a liquid or patch and absorption is increased
  • solid microneedle arrays where the tips are coated with a drug substance that allows poration of the relevant tissue and immediate dissolution of the coating in the space and permeation of the drug through the tissue
  • hollow microneedles that are fabricated in the same way as solid microneedles, but have a hollow core in their centre; a drug solution or a suspension containing micro- or nanoparticles can be channelled through the core into the portal created by the microneedles to create a drug depot in the tissue that permits repeated application into the same area
  • solid, biodegradable microneedles fabricated from polymers loaded with drug and left in position to degrade and gradually release the drug into the tissue pocket for absorption.
A combination approach

The latter approach is of particular interest when repeated access to a tissue is not desired and a controlled release depot is necessary such as in delivery to the eye. It has been demonstrated that combining two delivery technologies to control the kinetics of release is advantageous. Park and colleagues2 first encapsulated drug in microparticles and then dispersed these within a polymeric microneedle. They demonstrated an almost zero order release profile of calcein when encapsulated as microparticles in microneedles in contrast to a phased release profile with a large initial burst release observed with direct encapsulation within polymeric microneedles.

Efficacy of microneedles

The application of microneedles to ocular tissues and in particular to the sclera has been demonstrated using a range of approaches. The rationale behind using microneedles for scleral delivery is that it overcomes the physical barrier to diffusion created by the scleral tissue, while creating a more direct route to the underlying retinal tissues. Drug diffusion has been shown to be both transscleral and lateral via the choroidal neovasculature and provides a more targeted approach to the relevant tissues.3 In addition, controlled penetration of the microneedles into the ocular tissues in terms of force and depth can be achieved and safety is enhanced. It reduces the risk of disruption of the entire barrier, which in turn would subject the patient to intraocular risks of retinal detachment, infection or endophthalmitis.

The effect of microneedles on the permeation of drugs through the scleral tissue has been demonstrated by Prausnitz, Edelhauser and colleagues in several different forms. Their approaches include solid core, coated microneedles for immediate drug deposition in the scleral tissue, and hollow microneedles through which drug substances were delivered and a depot created.4,5 In these studies, they clearly showed the generation of a pore in the scleral tissue at a controlled depth with minimal disruption to the surrounding tissue. In the pores created, fluorescent labels accumulated to form a depot and began to diffuse through the scleral tissue.

A recent study by the same group demonstrated clear advantages to applying microneedles to the scleral tissue. They showed delivery of fluorescent polymeric nanoparticles through hollow microneedles directly into the suprachoroidal space of perfused ex vivo eyes where significant lateral diffusion away from the delivery site and towards the retina was observed.6 This study highlights the ability of this technology to overcome the barriers to delivery to the back of the eye, while delivering drug in a minimally invasive, controlled, and most importantly, targeted manner.

Ocular MEMS implant

A more recent advance in ocular drug delivery was the application of MEMS technology to control delivery of drugs intraocularly. One group in particular developed a wirelessly controlled ocular implant that was successfully trialled in vivo and overcame safety concerns associated with battery powered implants.7,8

The implant was silicon-based and consisted of 12 drug filled microreservoirs. Each reservoir was sealed with a gold membrane, which was dissolved electrochemically on activation to release the drug solution (Figure 1a). Control of the release was performed using control circuitry contained within the implant and an external dual-tone multi-frequency transmitter, which generated an external signal to trigger activation of each reservoir. The implantable chip was relatively small (3 x 3 mm) and contained in a customised package (Figure 1b). It was implanted in the vitreous cavity of a rabbit eye where the wireless communication device effectively controlled the individual release of fluorescein contained within each microreservoir and the fluorescence was observed diffusing throughout the vitreous cavity.
 
      

Figure 1:(a) Drug containing microreservoir sealed with gold membrane, (b) Prototype of silicone-based implantable device for ocular drug delivery

Images courtesy of Dr Stewart Smith, University of Edinburgh

This study demonstrated an improved method of control of delivery to the intraocular tissues and highlights the applicability of this type of technology for controlled and targeted delivery to the ocular tissues. MEMS technologies could be used in combination with other approaches such as microneedles to add another dimension to the kinetics of release. This would allow external control while the implant helps overcome physical barriers and is able to be replaced or replenished easily with minimum discomfort to the patient.

Future work
The barriers associated with inefficient drug delivery to treat diseases of the back of the eye can be overcome using a range of approaches. The advanced technologies described above show clear advantages through their ability to deliver drugs in a controlled and targeted fashion. However, there are still flaws associated with these technologies that need to be addressed. These include the incorporation of appropriate quantities of drug for delivery of therapeutic doses, the stability of drugs contained within the implants and their ability to withstand manufacturing processes, and most importantly, the issues surrounding the safe use of these devices and their patient acceptability. The ongoing advances in pharmacologic interventions for the treatment of prevalent diseases of the eye is important, but it is crucial that there is parallel development of delivery technologies to effectively deliver therapeutic doses to the target tissues.

References

1. Office of National Statistics, www.statistics.gov.uk/cci/nugget.asp?id=949, accessed October 2010.
2. J-H. Park, M.G. Allen, M.R. Prausnitz, "Polymer Microneedles for Controlled-Release Drug Delivery,” Pharm. Res., 23, 1008–1019 (2006).
3. J. Jiang et al., "Measurement and Prediction of Lateral Diffusion within Human Sclera,” IOVS, 47, 7, 3011–3016 (2006).
4. J. Jiang et al., "Coated Microneedles for Drug Delivery to the Eye,” IOVS, 48, 9, 4038–4043 (2007).
5. J. Jiang et al., "Intrascleral Drug Delivery to the Eye using Hollow Microneedles,” Pharm. Res., 26, 395–403 (2007).
6. S.R. Patel t al., "Suprachoroidal Drug Delivery to the Back of the Eye Using Hollow Microneedles,” Pharm. Res., 28, 166–176 (2011).
7. S. Smith et al., "Development of a Miniaturised Drug Delivery System with Wireless Power Transfer and Communications,” IET Nanobiotechnology, 1, 5, 80–86 (2007).
8. T.B. Tang et al., "Implementation of Wireless Power Transfer and Communications for an Implantable Ocular Drug Delivery System,” IET Nanobiotechnology, 2, 3, 72–79 (2008).


Dr Eileen McBride is a Postdoctoral Research Fellow in Pharmaceutics at the Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK,
tel. +44 141 548 3347




   

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