Ask the Expert: Are Controlled Release Tablets the Future of Patient-Centric Dosage Forms?

Modified, delayed, extended and sustained – controlled release oral dosage forms go by many names, but how well do we as an industry actually know them? All ‘modified release’ formulations stand in contrast to ‘immediate release’ formulations¹ , but there are also nuances within the controlled release category. ‘Sustained release’ describes drugs that release an active pharmaceutical ingredient (API) over a specific period but not at any pre-determined rate, whereas ‘extended release’ formulations continually release actives at a predetermined rate over a prolonged period of time.²

Regardless of their specific functionality, dosage forms like this typically feature a highly soluble BCS (Biopharmaceutical Classification System) Class I or Class III API, alongside a specialized controlled-release excipient. These baseline definitions help explain the phenomenal promise of controlled release dosage forms and highlight how they are currently being underutilized across the sector.

Patients living with chronic conditions--especially geriatric patients³-- can struggle to take multiple daily doses of several medications, leading many to skip doses or discontinue treatments altogether⁴, a scenario nicknamed “pill fatigue”. Controlled release drugs fight pill fatigue by reducing daily dosage requirements and supporting a more measured approach to drug delivery, helping curb API fluctuations that can cause under- or overdosing. Therefore, by requiring fewer doses, controlled release drugs encourage patients to adhere to their medication regime.

Given their clear potential to improve patient experience, why haven’t we seen more controlled-release formulations entering the market? The answer could lie in their complex formulation requirements. Modified release drugs require a specific form of polymeric excipient, an enteric protective coating, or a combination of both. The most commonly used excipient is currently hydroxypropyl methylcellulose (HPMC), a cellulosic compound that works by forming a gel-like hydrophilic matrix when it encounters the aqueous environment of the gastrointestinal (GI) tract.

For years, wet granulation was the only processing method available for HPMC-based formulations, bringing with it a multi-step, costly and time-consuming production process. This picture is changing however, thanks to emerging excipient technologies that are taking controlled release tablets into the process-efficient world of direct compression.

Pharmaceutical ingredients suppliers have recently begun exploring the potential of co-processing to revolutionize controlled release formulations. By physically combining two or more excipients, co-processing means formulators can create a filler-binder solution with the functional characteristics of its constituent parts, all in a single ingredient.

In theory, this would allow the controlled dissolution profile of HPMC to be combined with the processing efficiency-boosting benefits of a directly compressible excipient, like spray-dried mannitol. For an example of such a solution in action, we can turn to Roquette’s recently launched PEARLITOL^® CR-H, a co-processed mannitol-HPMC excipient. During product testing, this new excipient returned a good flow time on the flow-through-orifice test and good Hausner ratio, meaning it exhibits excellent flowability and compressibility properties. It was equally able to steadily release 40 mg of the API propranolol hydrochloride and 500 mg of metformin hydrochloride over the course of 12 hours.

Arnaud Verhaeghe, Marketing Director Pharma Oral Dosage, Roquette

References

1 Wheless JW, Phelps SJ. A Clinician's Guide to Oral Extended-Release Drug Delivery Systems in Epilepsy. J Pediatr

Pharmacol Ther. 2018 Jul-Aug;23(4):277-292. doi: 10.5863/1551-6776-23.4.277. PMID: 30181718; PMCID: PMC6117810.

2 NCBI, PubMed, ResearchGate Paper 1, ResearchGate Paper 2, Primary Research, Evalueserve Analysis

3 Keppel Health Review, Pill fatigue, 25 February 2022,

https://www.keppelhealthreview.com/winter2022/pillfatigue#:~:text=Pill%20fatigue%20is%20when%20a,they%20have%20to%2

0take%20them.

4 Kleinsinger F. The Unmet Challenge of Medication Nonadherence. Perm J. 2018;22:18-033. doi: 10.7812/TPP/18-033. PMID:

30005722; PMCID: PMC6045499