Improved drug delivery and understanding patient needs are driving innovation in today’s oral solid dose market.
Biopharmaceuticals may be surging, but small molecule, solid dose medications are far from on their way out. In 2015, over 50% of the 45 new molecular entities (NMEs) approved by the FDA were solid dose products—15 tablets, 8 capsules. Despite significant improvements in drug development, as well as groundbreaking discoveries in the larger pharmaceutical market, oral solid dose (OSD) remains both popular and effective, with the OSD manufacturing process largely the same as it has always been. That reality alone speaks volumes about solid dose, but it also means there is room for innovation. However, this innovation will involve more than manufacturing efficiencies and packaging solutions.
In the face of today’s large molecule drugs, the future of OSD will likely rely heavily on high-potency compounds, niche drug forms and generics. With that, it is likely that innovation will come in the areas of improved drug delivery, enhanced efficacy and, most importantly, a deeper understanding of patient needs and wants. This includes psychological associations related to a drug’s physical appearance. Manufacturing improvements will play an important role as 3D printing continues to evolve at an astounding pace, with the larger healthcare industry expected to account for as much as 21% of the 3D printing market over the next 10 years, but improvements to the pills themselves will be key. Unfortunately, there is not a one size, shape or color fits all solution.
Time to Think Outside the Round
Exploring myriad shape options for OSD drugs can be daunting for manufacturers especially as shape impacts dissolution profiles. More specifically, the surface area to volume ratio is important and even the placement of a logo can affect dissolution. Due to concerns regarding this critical property and the added cost of exploring alternate shape options, most companies focus solely on standard round or oval shapes until around phase III of clinical trials. Shape changes become more difficult as development progresses, when the shape of a pill does more than affect dissolution.
While symbols, lines, or other imprinted markings can help patients distinguish between different size doses or other medications they may be taking concurrently, these symbols can also become confusing. The physical shape of a tablet can help alleviate this potential confusion and be an effective way to communicate some of these differences, while also improving brand memorability. In fact, the FDA guidance document, “Safety Considerations for Product Design to Minimize Medication Errors,” highlights the importance of size, shape and product appearance alongside other factors, collectively referred to as product design or user interface elements such as strength and dosage form. Psychologically speaking, a tablet’s shape can also impact a patient’s perception of size, which can help encourage adherence and improve the patient experience. However, shape cannot be arbitrarily selected because several additional factors—required size, intended purpose, manufacturability—must also be considered.
With high-potency products, smaller pill sizes allow for more shape options as swallowing is less of an issue. Switching to something like a heart, kidney or triangle shape, for example, can make the pill easier to identify and easier to handle. Both size and shape can impact swallowability independently, but ideally both should be considered simultaneously. Poor physical design may lead to delayed or incomplete esophageal transit of the tablet due to adhesion; in addition to causing discomfort, this issue can lead to injury.
Though studies focused specifically on geriatric and pediatric populations are currently limited, it is generally assumed that smaller tablets may be easiest to swallow. However, these tablets can be difficult for geriatric patients to pick up from a pill-box or flat surface. Though unrelated to swallow-ability, it is worth noting that pediatric caregivers also have concerns regarding small tablets, mainly due to fears that the pills will be lost during dosing. Fortunately, modifications to the shape of a smaller tablet can often improve handling without negatively affecting ease of use. Larger tablets do not typically have as many viable shape options, but these should be explored as some may make the tablet appear smaller and more streamlined, which can improve the patient’s perception of the overall experience. Alternately, understanding patient/caregiver interactions with the tablets may reveal that taking two smaller pills is preferred over one larger pill, changing the manufacturing direction and offering increased flexibility in regards to shape.
As OSD options increasingly become more novel or niche with the inclusion of bi-layer, tablet-in-tablet, and quick dissolve tablets, tableting tools and more complex manufacturing may limit shape options. This can obviously be mitigated with new equipment, but that comes at a cost and doesn’t necessarily help with development. Offering reasonable costs and flexibility, 3D printing might be one of the most promising options for clearing these hurdles and, with Aprecia Pharmaceuticals’ first-of-its-kind 3D printed Spritam, the technology has already worked its way into the industry and though the FDA. Though printing may not yet be a viable option for mass production, it’s an easy way to quickly manipulate shapes to assess feasibility and patient response. Additionally, for niche medications with unique profiles such as the rapidly dissolving Spritam, produced with the company’s patented ZipDose technology, 3D printing is an ideal tool. If shape changes are limited due to manufacturing restrictions, brand recognition, or other barriers, color alterations might prove worthwhile, but even color should be carefully evaluated.
More to Color Than Meets the Eye
Like shape, color should be manipulated to achieve a specific visual result alone. Though the list of hard scientific data to support color psychology might not be as quantitative as the shape-dissolution correlation, the qualitative data is significant and far reaching. In addition to factors that might exist regarding the branding and marketing of the drug, color can affect a patient’s perception of a drug’s taste, purpose and efficacy while also triggering varying emotional responses, all of which can affect adherence. For example, one study found that pink tablets were viewed as sweeter than red, while yellow tablets were often perceived as salty regardless of the actual ingredients used. Further, studies have shown a perceived connection between color and both specific ailments and the efficacy of a medication, with a color change found to contribute to non-adherence in adult epilepsy patients. Even something as simple as darker hues for evening medications and lighter hues for daytime medications can help patients better understand, remember and accept their treatment regimens.
To further complicate these associations, color perception can also vary by gender, age and culture, meaning different forms of the same drug may need to be produced for different regions. Typically, pediatric patients prefer bright colors that are, stereotypically gender dependent, while geriatric patients tend to favor white, a color that is often associated as “safe.” Similarly, colors such as red may mean “danger” in one country and “power” in another.
Though bold, vibrant tablets may currently be less common than more subdued tones such as the off whites and pale hues produced with iron oxide-based dyes, this is likely to change as OSD manufacturers look for ways to distinguish themselves and establish brand recognition in an ever competitive and generic-heavy market. However, it is worth noting that, if the FDA guidance documents regarding the physical characteristics of generic medications are any indication of things to come, differentiation may become difficult. Finally, color selection is further complicated by differing regulations that may exist in some countries. These perception issues are purely psychological—dyes do not affect drug performance or taste—but because they can lead to real-world problems if adherence is affected as a result, color becomes a powerful attribute.
With solid dose medications continuing to exercise their relevance and flexibility for niche drugs, a thorough understanding of the psychological effects of size, shape and color and the relationship between them is an important way of encouraging adherence and improving the patient experience, while potentially strengthening brand recognition.