The future will see more prescription products in multi-dose preservative-free formats, both in highly regulated and less regulated markets. Matthias Birkhoff, VP Business Development, Aptar Pharma and Dr Degenhard Marx, Director Scientific Affairs, Aptar Pharma Consumer Health Care Division, reveal more in an e-mail interaction with Viveka Roychowdhury
What are the pain points experienced by patients using ophthalmic medications?
There are several factors which contribute to eye problems, especially for elderly patients with impaired dexterity or vision. Many complaints relate to the eye drop primary packaging; sometimes patients find the bottle or container hard to open, or it is difficult to accurately deliver a drop into the eye. This issue varies from brand to brand, but really depends on the packaging design and the material with which it is made.
For example, the actuation force required to generate a drop from single-dose and multi-dose droppers may range from 4-5 N to 45 N. Another issue is difficult dosing schedules. If a patient is taking more than one medication, it could potentially be paired with unrealistic dosing recommendations. Although it is recommended for patients to wait five to ten minutes between eye drop administrations, this is not always the case and patients tend not to adhere. They may also confuse the order in which the medications are meant to be administered.
This issue can be addressed by simple, visualised dosing schedules or a prescription of combination products, if available and affordable. It is also important to consider the side effects related to the medication. Side effects may be caused by the active ingredient, and in many cases come from the preservatives used, particularly in common multi-dose bottles. Benzalkonium chloride is used for most preserved eye drops.
Clinical evidence suggests that especially during long-term treatment, or if two or more preserved eye drops are used, side effects can accumulate and become severe. This is now well-recognised and common knowledge. Pharma companies have responded by manufacturing preservative-free eye drops, mainly in single dose dropper availability.
What are the levels of patient compliance observed with eye care treatments?
Examining the literature for non-compliance and adherence, a wide range of patient compliance is reported. Serious studies report non-adherence of patients somewhere between 23 per cent and 60 per cent. In most cases, this data is based on questionnaires filled in by patients, which may not be always reliable, as the data may be better than reported, or possibly worse. Studies with intelligent monitoring technology may generate much better data. Besides this, there are several influencing parameters, such as severity of symptoms, education and training of patients, and social environment. Nonetheless, it is clear that non-compliance is a real problem that should be addressed by all stakeholders.
What role does the choice of a packaging format play when it comes to solving patient pain points and improving patient adherence?
The packaging system plays a key role and many issues can be addressed if the right combination of dropper and formulation is used. The packaging supplier needs to consider critical points early on during the development of a new packaging design. Claims of easy handling and other advantages of a new packaging system should be based on user studies with patients. However, this is just one part of the story. Any new packaging system needs to be compatible with the formulation to keep it safe and effective.
Single unit-dose systems which are free of preservatives do not tend to be easy to handle; they are often difficult to open or hard to squeeze. Furthermore, the formulation is not always easy to handle during the blow-fill seal (BFS) process in examples such as temperature-sensitive products or interaction with packaging material.
The side effects associated with preservatives, such as ocular surface changes, discomfort, inflammation and more, can be avoided by using novel multidose preservative-free packaging formats, such as Aptar Pharma’s Ophthalmic Squeeze Dispenser.
Multi-dose systems offer a range of technologies to tackle the preservatives issue, including pure mechanical systems, valve systems, filtration systems, the use of oligodynamic elements and others. For any system, the major challenge is to demonstrate the microbial integrity of the packaging.
Since the vast majority of patients receive little or no training at all, any design should be intuitive and as close to existing solutions as reasonably possible.
What are the guidelines that manufacturers of preservative-free ophthalmic applications need to comply with on the microbiological safety side?
European Authorities support the use of preservative-free eye drops whenever possible, yet to the best of our knowledge, there are no specific guidelines for preservative-free multi-dose presentations in place. The reason may be that this is a rather new technology and establishing new guidelines is a lengthy and complicated process.
On the other hand, ophthalmic preparations must be sterile. The bottle content has to remain sterile during the entire life of such a dropper, especially while in use. Sterilisation of the packaging components, sterile filling and line qualification, and sterility testing strategies are well-established in the pharma industry and can be applied to preservative-free products. Therefore, the wheel does not need to be reinvented. The preservative-free technology does not need an unfamiliar manufacturing environment, which is a clear advantage.
Not using any debatable additives, Aptar Pharma’s Ophthalmic Squeeze Dispenser allows for an easier pathway through the regulatory approval process as compared to competing systems. Some of these systems release silver ions into the fluid pathway, which interact with the formulation to inhibit microbial growth. For good reason, regulatory bodies such as the US FDA ask sponsors to explain how the silver is incorporated into the delivery system. The agency will want to know whether the silver leaches out into the formulation and, if so, what it does to the patient. The generation of additional data required to answer these questions certainly adds a level of complexity to any regulatory filling process.
What are the latest trends to watch out for in 2018 in intuitive eye care drug delivery formats?
Our population is ageing rapidly. Consequently, with the increasing numbers of elderly people, the occurrence of ophthalmic diseases will stimulate demand for ophthalmic drugs. The future will see more prescription products in multi-dose preservative-free formats, such as Aptar Pharma’s Ophthalmic Squeeze Dispenser, both in highly regulated and less regulated markets. In particular, products for the treatment of increased intraocular pressure will be using this technology, as any long-term treatment should come without the potential side effects of preservatives. In parallel, patients and consumers will be looking for convenient and intuitive packaging formats which will not require too much learning and, not to mention, too much space.
Could you give examples of the successful use of Connected Health within the field of drug delivery systems for eye care applications?
The first clinical studies have been initiated in Europe utilising connected devices. The idea is to replace assumptions with real-time data in order to save time and effort for clinicians as well as improve study accuracy. This is a relatively new technology though, so it will be very interesting to watch this evolve in the near term.