Sponsored content from Roquette
By: Talles Ernica, Global Technical Developer
Controlled or modified-release dosage forms are no new breakthrough, but the pharmaceutical industry has yet to fully embrace them as a mainstream delivery format. Despite the health growth rates predicted for the global controlled-release segment up to 2032, the continued dominance of immediate-release medications across the oral dosage market provides compelling evidence. With instances of chronic disease worldwide on the rise and patient preferences on a constant cycle of evolution, it's high time to highlight the immense potential of controlled-release technologies. Read on as we discuss the why, what, and how of these under-adopted dosage forms and reveal the latest formulation solutions helping manufacturers combine process efficiency with patient centricity.
The why: Putting a price on pill fatigue
According to some estimates, 415 billion US dollars is how much medication nonadherence costs countries across Europe and North America each year. An arresting number on its own, this figure does not account for the very real human cost of treatment noncompliance – a phenomenon that often stems from pill fatigue. Patients facing long stints of polypharmacy (or the simultaneous use of multiple medications) can struggle to keep up with complex daily dosage schedules, leading many to skip doses or discontinue treatments altogether. Geriatric patients and those living with chronic conditions are most at risk. Still, regardless of age or health status, anyone can find themselves impacted by the damaging effects of pill fatigue. By reducing the number of individual doses a patient is required to take daily, controlled and modified-release treatments are an incredibly effective tool in the fight against pill fatigue and associated noncompliance. Despite this, however, they remain a surprisingly underutilized strategy. To explore this contradiction, we need to go back to basics – is there anything in the core definition of modified-release medications that points to their potential, and why it is yet to be fully realized?
The what: Defining "modified release"
Modified, delayed, extended, and sustained – all these terms and more are used interchangeably to describe controlled-release dosage forms, but this is not necessarily accurate. All formats classed as "modified release" are fundamentally different from "immediate release" formulations, where the goal is to deliver the active pharmaceutical ingredient (API) as quickly as possible. Within the broader category of "controlled release," there are further nuances. "Delayed release," for instance, refers to a drug formulated to release an API minutes or hours after administration, whereas "extended release" describes formats where the API is continually released over a prolonged period.
A point of similarity between the distinct types of modified-release dosage forms is their constituent ingredients. Drugs of this type almost always feature a highly soluble BCS (Biopharmaceutical Classification System) Class I or Class III API, combined with a specialized excipient, capable of slowly diffusing the active throughout the day with just one or two doses. In recent years, producers have begun to investigate the benefits of gradual release beyond the realm of oral dosage forms through delivery formats like multiple-day transdermal and subcutaneous depot formulations administered via transdermal microneedle patches. Technologies like these offer an effective, painless method for overcoming the gastrointestinal (GI) barrier when delivering large molecule biologics, making them an attractive alternative to traditional multi-dose vaccine or tablet regimens. However, the principal application for modified release firmly remains in the realm of oral dosage, where it has been shown to support improved bioavailability, safety, and effectiveness, as well as better patient compliance. Considering this obvious potential, the relative lack of new controlled release drugs seems puzzling until we consider the complex formulation requirements surrounding these dosage forms.
The how: Key formulation considerations and challenges
A host of factors are at play in the development of modified-release medications, many of which are unique to delivery forms of this type. First, the specific API dissolution and diffusion technique must be considered. The rate of dissolution determines the speed at which the active ingredient is released from an oral dosage form, while diffusion describes the movement of the dissolved drug molecules from areas of higher concentration (i.e., bodily tissues close to the drug) to regions with a lower concentration, allowing the pharmaceutical active to reach its intended site of action. In modified-release dosage forms, the former process is typically controlled by an enteric tablet coating such as methacrylate. At the same time, the diffusion mechanism is determined by the choice of polymeric excipient.
The current “star” solution, when it comes to controlled drug diffusion, is hydroxypropyl methylcellulose (HPMC). This cellulosic compound works by forming a gel-like hydrophilic matrix when it encounters the aqueous environment of the GI tract. HPMC has long been valued for its controlled diffusion properties, but it is also famously difficult to work with on a large manufacturing scale. Its poor flowability and tabletability have meant that wet granulation was the only viable processing method available for HPMC-based formulations, bringing with it a complex, costly, and time-consuming production process. For years, drug manufacturers have searched for methods to convert their operations from wet granulation to the more process- and cost-efficient direct compression model. However, they have been hindered by the need to use HPMC for its superior diffusion profile at each turn. More recently, however, this picture has started to change. For the first time, the introduction of innovative, co-processed excipients has unlocked the capacity for manufacturers to produce modified-release dosage forms via direct compression.
The future: Innovative excipients take the lead
At its core, co-processing is an excipient production method in which two or more ingredients are physically combined to create a filler-binder solution with the functional characteristics of all its constituent parts. In the context of controlled release drug production, co-processing is the tool that can help manufacturers overcome one of the major barriers keeping these dosage forms from achieving mainstream success.
The enduring sticking point for drug producers working with HPMC is the molecule’s poor flowability and tabletability, necessitating the additional wet granulation step to prepare tablets for compression. In response to this issue, application experts at Roquette began exploring the possibility of combining the process efficiency benefits of spray-dried mannitol – an excipient ideal for direct compression – with HPMC’s uniquely effective diffusion properties. The end result was the launch of PEARLITOL® CR-H co-processed mannitol-HPMC, a one-of-a-kind excipient with significant potential to advance the development of new modified release drug formats.
During product testing, this novel solution returned a good flow time on the flow-through-orifice test and a good Hausner ratio, demonstrating its excellent flowability and compressibility capacity. The ultimate test was how the new excipient performed regarding API dissolution and diffusion. After extensive assessment, it was shown that tablets formulated with PEARLITOL® CR-H were able to steadily release 40 mg of the API propranolol hydrochloride and 500 mg of metformin hydrochloride over the course of twelve hours, proving this truly is a solution offering the best of both worlds.
Lightning round: FAQs for PEARLITOL® CR-H
Q: Can PEARLITOL® CR-H be used in multiparticulate formulations?
A: Yes, it is especially well suited to mini-tab applications thanks to its superior flowability and compatibility in direct compression processes. Dry granulation is also a viable production method for multiparticulates made with PEARLITOL® CR-H, but further testing is needed to assess its suitability for wet granulation.
Q: What is the glass transition temperature of PEARLITOL® CR-H?
A: In general, the glass transition of PEARLITOL® CR-H is comparable to that of conventional HPMC. However, as with any excipient, the dissolution profile can be adjusted in different ways – sped up by adding more soluble materials and reduced by changing the ratio of excipient to API (though the specific effect changes depending on the API used).
Q: What is the nominal particle size of a co-processed material, and what would its segregation tendency be with various APIs or other ingredients due to its relative surface smoothness?
A: PEARLITOL® CR-H features non-rounded, smooth particles (with some irregular shapes) at a size of around 150 microns. The risk of segregation when using this excipient is minimal, as particles of different sizes are easily trapped by the irregular surface, aiding with cohesion. Segregation tendency is only materially increased when the size of the different structures used in conjunction with PEARLITOL® CR-H is smaller than the interstitial space between its particles.
Q: Is the gelling capability of conventional HPMC affected by co-processing, and could aggressive processing conditions like milling or HME potentially separate the two co-processed materials?
A: No, co-processing HPMC and high-quality spray-dried mannitol to create PEARLITOL® CR-H does not affect the gelling capacity of HPMC, and there is no risk of separation between the two components – even during high-stress processing.
What comes next?
The powerful combination of controlled-release dosage forms and co-processed excipients has the potential to transform the treatments of thousands worldwide. Drug manufacturers now must choose the right partner to help them kick-start their next drug development journey.
With one of the world's most extensive excipient portfolios, a vertically integrated supply chain, and decades of science-backed expertise, Roquette is the partner for pharmaceutical innovation.
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