An estimated 70% of people in the U.S. take one or more prescriptions¹, and many of these of course come in the form of solid dosage tablets. In addition, not only are people taking these prescribed and FDA-approved drug treatments, but also dietary supplements, a vast majority of which are solid dosage forms. So what are the trends and challenges shaping this aspect of the drug treatment market? What are we looking out for and ahead to? There are a few principal factors, which will influence the continued evolution of the solid dosage market: An aging population and increased interest in atypical pharmacodynamics, specifically differential-release or time-release technologies. The median age of the population in the U.S. is about 38 years, and continues to increase. A typical, simple, correlation shows that people tend to take more medications, and therefore more solid dose medications, as they increase in age.

The evolution of multi-layer tablets
Tablet makers have been trying with varying levels of success to achieve nuanced treatment profiles with bi-layer, or multi-layer, tablets. Multi-layer tablets have been produced for decades, and in fact somewhat humorously, the initial multi-layered tablets were originally created as more of a marketing perception feature, rather than a legitimate foundation for different materials to be consumed simultaneously. There is a certain consumer-level effect with layered tablets where there is an expectation of different benefits stemming from the different visual appearance of the dosage. Much of this had come down to the psychology of branding and consumer marketing, while harnessing the brand loyalty of the re-purchasers and perhaps even creating a categoric effect by placebo and the expectation that the different appearance would lead to a different result.

Now the industry has scientifically demonstrated solid dosages, which can affect drugs’ dissolution, half-lives, area under the curve, etc. So where do things stand? And where are they going?

Current challenges
Keefer et al. (2014) have noted some of the most frequent and pernicious challenges facing multi-layer tablet formulation. One of the most observable and catastrophic to the dosage is if they become axially debonded, where the differential layers separate. Though there are others, which include cross-contamination of the multiple tablet layers’ components, delamination of the various layers, where the various layers do not bond completely due to adherence issues between the granulation layers, and cost—part of, which includes the cost of yield loss due to enhanced dust collection, which is used to reduce cross-contamination of the different layers which removes (viable) product material from the process. All of these challenges rob the technology of some of its luster to those who would be interested in producing a multiple-layered solid dosage medication. So why pursue it?

Custom-tailored dissolution characteristics
Clearly, as the early marketers were onto as they developed multi-layer tablets even if they didn’t actually represent any differential effect was that a layered solid dose form first brings to mind that different things are happening within one dose. Of course, nowadays this is actually true—solid dosages are robustly engineered and developed so that they specifically combine different components into a single dose. All of this additional engineering and validation as well as in-line Process Analytical Technology (PAT) brings with it additional costs to production. So there needs to be a realistic value proposition to make it worthwhile to pursue this technology. Manufacturers can get different dissolution/absorption profiles out of the medication by going with multi-layered solid dosages, and Figure 1 shows an example of a bi-layer tablet’s differential dissolution performance in terms of percent dissolution (y-axis) over a period of time (x-axis).

The immediate-release layer becomes dissolved at over 97% within 1 hour, whereas there is a gradual dissolution of layer B (time-release) over a period of 12 hours. This allows for novel pharmacokinetics to be engineered into the solid dosage forms that can take advantage of these combinations of immediate- and delayed-release forms to augment differential effects of a drug treatment.

Evergreening drug therapies
Of course, there is a side of the solid dosage trend which has mixed perceptions, and that’s the concept of evergreening. Part of the lifecycle management of a drug therapy, evergreening refers to making modifications of an approved drug product’s forms of release, dosages, or variations to keep it on-patent and avoid competition from generics. The revenue loss from a patented treatment is enormous—prices fall up to 95% (and usually about 70%-90%) when drugs become generic. The appropriateness and level that it’s done at is a business decision and a value judgment, but clearly these solid dosage technologies can be developed and delivered both at the innovator-patent level and at the generic level, as well as with nutraceuticals and other OTC treatments.

Benefits of differential solid dosage layering
To be sure, there can be several very beneficial rationales for multi-layering, most importantly including a reduction of gastric upset and intolerance effects with some drugs, a more stable pharmacokinetic profile leading to sustained blood levels of the drug treatment, and attenuated adverse effects. Perhaps seemingly trivial but likely the most important benefit of all is increased patient compliance because the minimization of adverse effects, gastric issues, and some potential physiologic effects from rapid rises and falls of medication levels in the bloodstream are irrelevant to consider if the patient has elected to not take the dose in the first place. Multi-layer solid dosages can also improve patient compliance by reducing the number of daily doses required and simplifying regimens.3 This can be in the form of time-released treatments which, as described above, can eliminate the need for multi-dosing throughout the day, or it can be for multi-phasic combination treatments that are in one solid dosage. 

(Note: For a list of references visit the online version of this story at nitesh_cp.rodpub.com.)

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Ben Locwin
Healthcare Science Advisors

Ben Locwin, PhD, MBA writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He also provides advisement to many organizations and boards for a range of healthcare, clinical, and patient concerns.