Chapter 13

Refillable Devices for Therapy of Ophthalmic Diseases

Alan L. Weiner

Abstract  As a subset of ophthalmic drug delivery systems, refillable approaches encompass a relatively new but growing field of study. This review will cover general design considerations in the development of refill devices for the eye. This will include acceptability of administration sites, body and injection port design, influences of vacuum and pressure, flushing and fluid replacement for active, passive and solid delivery devices, and potential for contamination. Historical influences leading to the current design concepts such as development of parenteral infusion pumps, glaucoma drainage devices, and pioneering ocular experiments will be discussed. Finally, specific studies and designs on refillable systems that have been proposed to deliver agents either to the vitreous through the pars plana, via trans-scleral delivery from episcleral implantation, to subretinal or suprachoroidal spaces from anterior location or to the anterior or posterior chambers from the lens capsule will be presented.

13.1  Introduction

Historically, the outcome of seminal events is usually a blossoming of major innovation. In the development of therapeutic approaches in ophthalmology, there have been a number of such notable turning points; the idea that the vitreous could be surgically invaded and manipulated, the discovery that concentrated sonic or laser energies could be used safely in the eye to destroy or stimulate only targeted tissues, and that the placement of very fine solid particles on the eye surface does not elicit significant foreign body response, to name a few. Thus, in retrospect, the concept of putting a refillable device on or in the eye must be linked to at least one epiphany

A.L. Weiner (*)

DrugDel Consulting, LLC, P.O. Box 173752, Arlington, TX 76003, USA e-mail: alweiner@drugdelconsulting.com

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 305 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_13,

© American Association of Pharmaceutical Scientists, 2011

with respect to practical ophthalmic therapy. Indeed, the idea to be able to treat ophthalmic patients via a device that allows for a refilling procedure has genesis in at least three unmet needs. The first is a matter of patient compliance; it has become increasingly clear that patients are simply noncompliant with medications, whether for reasons of age (physical or mental limitations), inconvenience, or intransigence in dealing with intolerable side effects that stem from dosing drug excesses to achieve necessary target tissue levels. As such, giving the physician better tools to automate a patient’s dosing regimen removes those variables. The second is a function of the eye’s efficiency in eliminating foreign substances through a compartmentalized and well-regulated pressurized plumbing system. The ability to apply a convenient repetitive regimen to counteract the clearance mechanisms gives a practical way for the physician to interact with the patient at regular predetermined intervals to assure maintenance of vision. In addition, the device may better regulate the tissue efficacy response through its mechanism of release or efficiency in delivery to the target. But the third unmet need is the key; an ability to combine the above two needs in a way that is as minimally harmful to the patient as is practicable. Through refilling, the requirement for repetitive invasive surgical re-intervention is thus eliminated by the ability to utilize simple injections, improving overall safety to the patient.

Beyond the unmet needs of the patient and physician, there are additional needs that are fulfilled as defined by the engineers and pharmaceutical scientists who design the refilling devices. First, a refill system offers opportunities to overcome drug stability issues (and associated loss of potency) following administration to the patient. Because the frequency of refill can be designed to accommodate regular shorter visit intervals of the patient to the practitioner, a requirement that the drug remain stable at body temperature for periods corresponding to the longer intervals of device re-implantation surgery is thus eliminated. Second, it offers the opportunity to develop a more stable form of the drug for purpose of storage prior to use. So for example, drug could be stored in lyophilized or frozen state prior to a reconstitution step in advance of the administration. This is particularly important with newer labile drug products such as proteins which are notoriously unstable to higher temperatures. Finally, by allowing for a dissociation of the device from the drug substance, both components can be subject to different sterilization methods. In systems which are manufactured as a single unit containing both the device and the drug, application of terminal sterilization methods such as irradiation or heat can impact the stability of either the device itself or the contained drug. In a refillable approach the drug product can for example be sterilized by a sterile filtration method and stored in its own sterile container, while the delivery device is sterilized separately by a technique such as gamma irradiation.

Even with the promise of significant advantages for the developers and users of refillable ophthalmic devices, the challenges to achieve commercialization and adoption are still significant. The factors which must be accounted for include longterm compatibility with tissue, size of the device and corresponding drug loading capacity, issues of comfort and cosmetic acceptability for the patient, complexity of implantation and corresponding reimbursement to the physician, and longterm delivery accuracy and performance. The current research and development