FUNCTIONAL EXCIPIENTS - Much More Than Filler: Solving the Challenge of Patient Non-Compliance

INTRODUCTION

The pharmaceutical industry currently faces one of its tough­est challenges to date – the epidemic of patient non-compliance. Recent research suggests medical non-adherence accounts for half of all treatment failures in the US, with serious consequences.¹ This phenomenon is the cause of at least 100,000 preventable deaths and generates unnecessary medical costs of up to $100 billion each year.² The stakes could not be higher, yet progress to tackle the root causes of medication mis­use has been frustratingly slow. In this article, we want to intro­duce the pharma industry’s secret weapon in the fight against non-compliance – functional excipients. Much more than just fillers that hold tablets together, these ingredients could help man­ufacturers do their part to turn the tide and drive improved health outcomes for patients around the world.

INNOVATIVE DOSAGE FORMS UNLOCKED

Alongside medical professionals, pharmaceutical drug man­ufacturers have an equally important role to play in encouraging improved medication adherence. For drug producers, this vital responsibility is usually discussed in the context of active pharma­ceutical ingredient (API) efficacy and effectiveness, but excipient selection is just as fundamental a consideration for formulating patient-centric delivery forms.

Choosing the right functional excipient allows brands to cre­ate innovative products – from orally disintegrating tablets and films to effervescent and modified-release tablets – designed to meet both patients’ medical needs and personal preferences. Ul­timately, high-quality excipients make convenient, tailored, and effective dosing methods possible, unlocking new horizons in drug delivery.

Armed with these solutions, pharma manufacturers can re­duce medical waste, boost their commercial bottom lines and – most importantly – help patients feel the full benefit of their med­ications. By taking a closer look at some of the most exciting pa­tient-centric dosage forms available today, it becomes clear just how important functional excipients are for encouraging patient compliance.

DEVELOPING ORALLY DISPERSIBLE DRUGS

In any solid dosage form, swallowa­bility, ease of administration, and taste are critical considerations. These factors are imperative for all patient groups, but dou­bly so for geriatric or pediatric popula­tions, who typically struggle to swallow traditional medications. To address the is­sues of drug accessibility for patients suf­fering from dysphagia (difficulty swallowing), formulators have developed a range of disintegrating dosage forms: orally disintegrating tablets (ODTs), orally dispersible mini tablets (ODMTs), and orally disintegrating films (ODFs). Dissolv­ing rapidly when placed on the tongue, these delivery methods simplify the process of taking medication, making it safer, eas­ier, and more convenient for the patient. Because they disintegrate quickly in the oral cavity, taste and overall sensory expe­rience are extremely important. This is where high-quality functional excipients can really add value.

When selecting an excipient for use in ODTs and ODFs, manufacturers must pay close attention to processability, resultant mechanical strength, dispersibility, and palatability. Beyond just checking these features off a list however, balance is a crucial factor in dispersible formulations. This is particularly true when considering mechanical strength and rapid disintegra­tion. While it is important the chosen ex­cipient delivers good strengthening and binding capabilities, this should not hinder the rapid disintegration of the tablet or film. With such a delicate balance to achieve here, multifunctional excipients rapidly become a necessity. Solutions that combine ideal texture properties, with a pleasant flavor and ease of handling allow manufacturers to concentrate on ensuring their ODTs and ODFs can live up to their primary functional advantage – dis­persibility.

Based on extensive testing, formula­tion scientists at Roquette developed PEARLITOL® Flash, a mannitol-starch com­pound, specifically designed to produce dispersible dosage forms that hit the spot for pharma producers and patients. A di­rect compression excipient with superior disintegrant properties, PEARLITOL® Flash offers excellent chemical inertness and consistently rapid disintegration time. Ad­ditionally, its mild taste and texture make it an ideal choice for swallowable and orally dispersible tablets.

MODIFIED RELEASE, IMPROVED RESULTS

Another significant barrier to patient compliance is pill fatigue. This phenome­non is triggered when patients feel over­whelmed by the number of drugs they must take, something that is more preva­lent in geriatric populations who typically require more medications for chronic con­ditions.³ For most patients, compliance starts to wane beyond a certain pill count. However, some medications with a rela­tively short half-life require 2-4 doses daily to be effective. Traditionally, pill fatigue has been characterized as a “patient problem” by medical professionals, without taking into account just how challenging it can be to form the habits required to take multiple daily doses of several different medica­tions.⁴ To help bridge the gap between ef­ficacy and patient compliance, pharma formulators are investigating the benefits of reducing dosing frequency through con­trolled-release dosage forms.

Broadly categorized as extended-re­lease formulations, these dosage forms typically feature a highly soluble BCS (Bio­pharmaceutical Classification System) Class I or Class III API, combined with a specialized excipient, that slowly release the required amount of drug throughout the day with just one or two doses. Apart from the obvious benefit of reducing dos­ing frequency, controlled-release drugs offer a host of advantages. By maintaining a more consistent level of medication in the body for example, this delivery method curbs the fluctuations that can cause under or overdosing, providing therapeutic effi­cacy with reduced risk of potential side ef­fects. In recent years, producers have also begun to extend the benefits of gradual re­lease formats beyond the realm of oral dosage forms. Multiple-day transdermal and subcutaneous depot formulations ad­ministered via transdermal microneedle patches, for instance, offer an effective, painless method for overcoming the GI barrier when delivering large molecule bi­ologics. They are therefore gaining popu­larity as an alternative to traditional multi-dose oral regimens. Such features may result in improved bioavailability, safety, and effectiveness, as well as better patient compliance.

Getting down to practicalities, suc­cessful modified drug development hinges on selecting a polymeric-based excipient, capable of allowing the API to be gradu­ally diffused from the tablet. Typically, these excipients, such as hydroxypropyl methylcellulose (HPMC), work by forming a gel-like matrix when they come into con­tact with the aqueous environment of the GI tract. This feature ensures the active in­gredient takes longer to diffuse out of the tablet, resulting in a slower drug-release profile. In addition to the excipient type, manufacturers must also consider the pro­portion needed to achieve the desired rate of drug release at the absorption or target site.

To complement the effect of these slow-release ingredients, Roquette offers a broad range of directly compressible excipients, such as magnesium stearate and MICROCEL® microcrystalline cellu­lose, which exhibit good flow and com­paction properties to help formulators de­velop successful controlled-release drugs. The superior stability exhibited by Roquette excipients offers another advantage – helping to ensure both reproducibility and reliability so patients experience the same outcome after each and every dose.

THE “SOFTER” SIDE OF DRUG DELIVERY

While delivery methods tend to dom­inate the conversation surrounding patient compliance, smart excipient solutions can go further than just addressing dosage preferences. By aligning their solutions with people’s values and ideals, as well as their physical needs, drug producers can ensure patients are not only capable of taking their medication but are actually comfortable doing so.

Take the rising demand for plant-based healthcare solutions as an example. The number of people following vegetar­ian and vegan diets, or simply seeking to consume fewer animal-derived products, has skyrocketed in recent years.⁵ As such, the widely popular softgel capsule format faces a serious issue. Due to its multifac­eted functional properties and natural po­sitioning, gelatin has historically been the excipient of choice for these applications. But with its origins as a byproduct of the meat industry, this well-known ingredient is unsuitable for veggie or vegan-friendly drug development.

Again, innovative excipients can cir­cumvent this problem by providing brands with new opportunities to create pharma and nutraceutical products powered by plant-based materials. First-of-a-kind pea starch technologies, like Roquette’s LYCAGEL® plant-based softgel solution, give brands the option to develop vegetar­ian softgels that perform equally, if not bet­ter, than gelatin-based solutions, while still adhering to the stringent quality standards required in the highly regulated pharma­ceutical and nutraceutical markets. Higher performing and more sustainable than other gelatin-alternatives, these plant-based solutions deliver transparent, shiny capsules with a neutral taste that are easy for patients to swallow – both literally and metaphorically.

IT ALL COMES BACK TO PEOPLE

In these technical discussions on poly­mer matrices, dispersibility, and optimal API delivery, it can be easy to forget the people at the center of the patient-compli­ance issue. Medical noncompliance is one of the most pressing issues facing the pharma industry today, but it is even more serious for patients who are not receiving the treatments they need, want, or de­serve. Ultimately, optimal medication lies in the intersection of efficacy and effective­ness – wherein efficacy refers to the ability to cause a therapeutic effect and effective­ness relates to its value in real-world use.⁶ A general rule of thumb is that drugs tend to score lower on effectiveness than effi­cacy because clinicians prioritize short-term discomfort over long-term health benefits.⁷ But to achieve truly ideal drug delivery, manufacturers should strive to re­dress the balance and put patient experi­ence on a par with a medication’s baseline efficacy.

As the range of excipients available to pharma brands increases, so do the op­portunities to tackle this challenge with smart drug delivery. Game-changing APIs are undoubtedly important for improving user acceptance, but innovative excipients also deserve a place in the patient compli­ance conversation. A trusted excipient sup­plier therefore has an extremely important role to play in helping pharmaceutical manufacturers solve their formulation and delivery challenges. Much like the process of combining the right API, excipient, filler, or binder – ingredients suppliers, pharma producers, clinicians, and patients can overcome these challenges by combining forces and working together to build a healthier future for all.

REFERENCES

1. Elephant in the Room, US Pharm. 2018;43(1)30-34, https://www.uspharmacist.com/article/med­ication-adherence-the-elephant-in-the-room.
2. Kleinsinger F. The Unmet Challenge of Medication Nonadherence. Perm J. 2018;22:18-033. doi: 10.7812/TPP/18-033. PMID: 30005722; PMCID: PMC6045499.
3. Keppel Health Review, Pill fatigue, 25 February 2022, https://www.keppelhealthreview.com/win­ter2022/pillfatigue#:~:text=Pill_fatigue_is_when_a,they_have_to_take_them.
4. Ibid, Kleinsinger F.
5. Food Revolution Network, Why the Global Rise in Vegan and Plant-Based Eating is No Fad (30x In­crease in US Vegans + Other Astounding Vegan Stats), 6 April 2022, https://foodrevolution.org/blog/vegan-statistics-global/.
6. Shalini S. Lynch, MSD Manual, Drug Efficacy and Safety, last reviewed May 2022, https://www.msd­manuals.com/en-gb/professional/clinical-phar­macology/concepts-in-pharmacotherapy/drug-efficacy-and-safety.
7. Ibid, MSD Manual.

Dr. Carin Siow is a Senior Pharmaceutical Application Scientist at the Roquette Applications Lab. She earned her Bachelor’s degree in Pharmacy and her PhD in Pharmaceutical Technology from National University of Singapore. As a registered pharmacist, she is passionate about leveraging the advantages of excipients to improve the design of dosage forms for patients. Her current role involves working on application studies and developing technical materials to broaden the formulation and processing understanding of the Roquette excipient portfolio.