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Better drug delivery devices needed to improve patient outcomes
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The application of an eye drop remains the primary method for treating a vast array of eye diseases, primarily of the anterior segment, including infection, inflammation and glaucoma.
Eye drop application to treat eye disease dates back to ancient times, when ingredients such as milk, wine and even urine were used to treat diseases of the eye. As one can imagine, many of these treatments were harmful rather than therapeutic, and many eyes were infected and made worse with their use.
Before World War II, most therapeutic drops were compounded by ophthalmologists themselves or in compounding pharmacies. Again, quality control was variable and therapeutic efficacy unpredictable.
In the U.S., Alcon was founded in Fort Worth, Texas, by two pharmacists, Robert Alexander and William Conner, in 1945. These two innovative pharmacists developed the “Drop-tainer” in 1953, and this bottle delivery system remains the most widely used worldwide 60-plus years later. About the same time, Allergan was founded by Gavin Herbert’s father in Los Angeles, and Alcon and Allergan have grown side by side into key providers of a broad array of key topical therapeutics used every day worldwide. Santen, another major provider of topical therapeutics, especially in Asia, began focusing on eye drops in 1952. Other major providers, such as Bausch + Lomb, evolved later, but eye drops in a “Drop-tainer” delivery model remain the primary therapeutic prescribed worldwide for the treatment and prophylaxis of eye disease.
A few innovative alternatives have been tried, such as an attempt at spray bottles to apply drops to the eye, but spray bottles never gained popularity because of annoyance with the medication being spread over the eyelids and face and secondary issues with dermatitis medicamentosa. Today, drops and ointments remain the majority of the market.
So, what is wrong with drops? The primary issue, once one gets past the pharmacokinetics of developing a solution, suspension, gel or ointment that can penetrate to the target tissue in an effective concentration to be therapeutic, remains the unfortunate reality that they rely on the patient to apply them properly and consistently as instructed.
Study after study shows that patients simply do not take their drops as directed, in regards to both method and frequency. To be direct, patient compliance is very poor. Patients do not shake their drops to ensure proper distribution of medication when a suspension, they do not close their eyes after application, they do not apply nasal lacrimal compression to reduce systemic absorption, they do not wait 5 minutes between drops, and they do not take the drops in the frequency required for a good therapeutic response.
In self-limited diseases such as allergy or viral conjunctivitis, poor patient compliance does not lead to permanent ocular morbidity, but in chronic blinding diseases such as glaucoma, poor compliance is a major cause of permanent damage to the eye. Many alternatives exist, but all have their own drawbacks. Systemic medications can be effective but often are associated with significant side effects and also suffer from issues of poor compliance. Subconjunctival, sub-Tenon’s, intracorneal, retrobulbar and intraocular injections are widely used and eliminate issues with patient compliance, but they are significantly more invasive and usually not very patient friendly.
Thus, much investment of financial and human capital is being expended to develop successful, patient-friendly methods of extended ocular drug delivery. We have a few early examples on the market, including, in the anterior segment, the Ocusert delivery system for pilocarpine in glaucoma and the Lacrisert insert (Valeant) for dry eye. In the posterior segment, we have Retisert implants (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan), Iluvien (fluocinolone acetonide, Alimera Sciences) and Triesence (triamcinolone acetonide injectable suspension, Alcon). Each has found some application, but none have had a significant impact on indications that call for drops for glaucoma or for the treatment of anterior segment inflammation or infection, or reduced the ever-growing number of intravitreal injections for posterior segment eye disease.
A better method of extended drug delivery is a significant unmet need in each of these areas and, if developed, will be a disruptive change in how we treat patients. Many approaches are being studied, including punctal plugs, contact lenses, flexible rings implanted in the conjunctival fornices, implanted refillable reservoirs and various pump systems, to name a few. Many are promising, but none have yet achieved regulatory approval and significant commercial success.
The pharmacokinetics of long-term drug delivery are complex, and what makes sense in the laboratory does not always work well when tested clinically. A reasonable duration of therapy, perhaps 3 months at a minimum for a disease such as glaucoma and ideally 6 months, with assurance that the device does not extrude or fall out and that therapy is consistent over the entire time period are daunting challenges. Nonetheless, challenges such as these are almost always overcome with adequate investment of human and financial capital.
A better method of delivering drugs to the eye that eliminates patient compliance is a major and critical unmet need, and the innovation cycle and competition are in the midst of working their magic. I believe we can expect meaningful products in this arena by 2020, and these products will change the way we practice and our patients’ outcomes for the better.