This Small Business Innovation Research Phase I project assesses the feasibility of using a novel synergistic drug-polymer ocular film product based on a modified biopolymer hydrogel to deliver antibiotics directly, locally and continuously to the ocular surface over an extended weekly period. This film combines the pro-healing, anti-inflammatory effects hyaluronic acid with slow release of an ophthalmic antibiotic. Topical ocular antibiotics require frequent dosing (i.e., hourly for corneal ulcers), often resulting in improper administration, causing suboptimal bioavailability to the eye and considerable waste. This novel polymer film can be placed on the ocular surface topically to deliver a well-known ophthalmic antibiotic. We propose to expand on known benefits of topical hydrogels by delivering antibiotics to reduce bacterial infections locally while simultaneously accelerating and improving healing. Prototype films of hydrogel containing antibiotics will be produced and evaluated for film degradation, anti-bacterial efficacy, and drug release. Safety and tolerability of the antibiotic-containing films will be demonstrated in a preclinical rabbit model. We anticipate being able to produce a well-tolerated antibiotic-releasing film product prototype and demonstrate the desired characteristics. Such a film would allow us to progress to a Phase II SBIR to optimize a sterile and clinically useful commercial product.
The broader impact/commercial potential of this project is development of a new ocular drug delivery product that will improve patient care by providing a more efficient, effective, convenient, and consistent means of antibiotic delivery directly to the ocular surface. Using a known polymer carrier with intrinsic healing properties, this product will deliver continuous adequate doses locally, thus eliminating the frequent topical (up to every hour) and/or systemic doses of antibiotics for a wide range of infectious ophthalmic conditions. This improves patient compliance and patient outcomes, while reducing health care costs. Relevant eye diseases include active infections of the cornea and conjunctiva, as well as prevention of potential infections associated with various ocular surgeries and diseases. This topical extended release product addresses important unmet medical needs in the military and in civilian populations by providing healthcare provider-placed antibiotic product administered acutely. The antibiotic-containing films produced and evaluated in Phase I can ultimately lead to the development of a commercially viable ocular care product to address these unmet needs. Further, by demonstrating release of polybasic antibiotics, such a system could be expanded to deliver other antimicrobials to treat ophthalmic fungal or viral infections, which represent significant challenges in developing countries.
Corneal disorders are a leading cause of global blindness, with bacterial keratitis (BK) – also known as infectious corneal ulcers – being a leading contributor. This serious ocular emergency develops quickly and without warning. Characterized by intense pain, reduced vision, and extreme light sensitivity, this disorder often results in a scarred/cloudy cornea (the clear dome covering the eye’s iris and pupil) and subsequent loss of vision. The most common cause of BK is injury to the corneal surface, the eye’s natural barrier, with the main risk factor in the U.S. being improper and extended contact lens use. In particular, sleeping with contact lenses in place can leave the corneal surface starved for oxygen and prone to infection. No U.S.-approved product is marketed to treat this disease. The current course of treatment is topical antibiotics prescribed off-label and dosed via eye drops every hour around the clock for several days and then less frequently over a few weeks to clear the infection and allow the ulcer to heal. As a result of this difficult-to-administer regimen, a significant medical need exists for an improved corneal ulcer treatment. Jade Therapeutics’ sustained-release product holds the potential to provide an innovative solution to this problem. A flexible, biodegradable, antibiotic-loaded polymer film (similar in initial consistency to a soft contact lens) placed on the surface of the eyeball underneath the eyelid can deliver therapeutic levels of antibiotics in a patient-friendly manner over multiple days without the need for hourly eye-drop applications. Such a therapy would improve patient compliance and effectively eradicate the bacterial infection, thereby allowing the ulcer to heal and preventing permanent vision damage. Intellectual merit: Jade is developing ophthalmic applications of HyStem®, a proprietary version of a naturally occurring hyaluronic acid (HA), formulated into a topical film to deliver a variety of small-molecule and protein-based drugs directly to the eye. This NSF Phase I SBIR grant allowed initial development work to proceed through proof-of-concept of an antibiotic-eluting ocular product that addresses the unmet need for an extended-duration BK treatment. Advantages of this medicated film system over traditional multiple-dosed antibiotic eye drops are that the drug is delivered continuously over several days directly to the eye’s surface, eliminating the need for frequent hourly/daily application and decreasing the accompanying medication wastage that occurs with tearing and eye drop volume overflow. Additionally, the HyStem® polymer matrix may provide intrinsic healing benefits that can decrease the local inflammation and potentially reduce scarring. Work completed under this Phase I grant allowed Jade to demonstrate the ability to make an antibiotic-releasing, biodegradable, HA-based film prototype capable of delivering clinically proven ocular antibiotics in therapeutically relevant doses over three days, both in bacterial cultures and in vivo in rabbit eyes. In addition, support from the Phase I grant allowed Jade to apply for additional patents based on the antibiotic film formulation and to develop novel assays to measure antibiotic levels in rabbit tears. Based on these results, three abstracts have been submitted to the leading U.S. ophthalmology conference – the Association for Research in Vision and Ophthalmology (ARVO) annual meeting – for the spring of 2014. Broader impacts: The broader societal impact of this Phase I project is significant both within the U.S. and globally. Many BK patients around the world do not have ready access to specialty pharmacies capable of compounding the appropriate antibiotic eye drops. Furthermore, poor compliance with topical ophthalmic medication (i.e., inconvenient hourly dosing schedules required with eye drops) is well documented, resulting in sub-optimal therapeutic outcomes (e.g., corneal blindness) and associated human suffering and economic costs (e.g., frequent office visits, additional medications, lost productivity, and subsequent surgeries such as corneal transplants to restore vision). Beyond bacterial keratitis, Jade Therapeutics’ novel, polymer-based, drug delivery technology has the potential to establish the HyStem® polymer matrix as a general means of delivering various already-approved and clinically efficacious drugs – as well as novel new chemical entities – to improve outcomes and preserve vision. A number of technical, therapeutic, and manufacturing challenges required to translate such a drug delivery product into clinical/commercial use remain and will be addressed in the Phase II portion of this grant. The merit of this innovation has already been recognized by collaborators, including the U.S. Department of Defense and the Himalayan Cataract Project, as well as by a variety of potential corporate partners that have expressed interest in this approach. Thus, the knowledge gained in working with this antibiotic-delivering film formulation will help enable this unique and novel HyStem® technology to be further developed into a broad platform for ophthalmic drug delivery.
