Taking a Controlled Approach

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Controlled-release formulations have been around since 1952, after the first introduction by Smith Kline Beecham (1), and have seen continued growth and expansion thanks to technological advancements. According to market research, the controlled-release drug delivery market is anticipated to grow at a compound annual rate of nearly 8% between 2020–2027 (2). A drive in R&D to improve therapeutic efficiency for a variety of chronic diseases and the acknowledged improvements in medication adherence that can be gained through controlled-release formulations are key aspects to market growth in the field. 

“A distinction of controlled-release, compared with other modified-release formulations, is that it not only prolongs action of the drug but it attempts to maintain drug levels within the therapeutic window to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency,” notes Ali Rajabi-Siahboomi, vice-president and chief scientific officer, Colorcon. “So, controlled release is generally understood to mean where the drug delivery technology delivers the drug at a predetermined rate; other modified release technologies may not have a specific rate defined.”

There are a multitude of formulation concepts that may be used in order to control drug release and duration, and dependent on the API and its action in the body, tailored solutions are required to gain innovative drug products, explains Thorsten Cech, manager European Pharma Application Lab, BASF Pharma Solutions. “Application concepts range from topical patches to injections, which form subcutaneous pockets (depots) lasting for several hours, or even days. Furthermore, there are implants, which provide application windows of several years, although this is a very specific dosage form requiring trained medical staff for application,” he says. “Drug products that can be applied by the patients themselves are typically found in the field of oral solid dosage forms, meaning they are either delivered as tablet or capsule. Rarely seen are liquid formulations, as this concept is quite demanding and not suitable for many APIs.” 

Main concepts

There are two main concepts in the formulation of controlled or sustained-release oral solid dosage forms: matrix systems and reservoir systems, specifies Krizia M. Karry, global technical marketing manager, BASF Pharma Solutions. “In matrix systems, the drug is embedded in an insoluble, sometimes swellable excipient core, containing the actual matrix-former and additional components for tailoring the drug release rate. Drug release is either initiated by swelling or erosion of the core and diffusion of the API through the matrix,” she says. “These systems are most straightforward in terms of their formulation and manufacturing.” 

Rajabi-Siahboomi suggests that the most commonly used oral solid-dosage controlled-release technology, out of all oral solid dosage types, is hydrophilic matrices, due to the fact that tablets are easy to develop and produce, while also being versatile for a broad range of solubility and dosage strengths. “With matrix tablets, high viscosity hydrophilic polymers such as hypromellose are used as the rate-controlling polymer,” he explains. “Multiparticulate systems are also versatile for achieving different release profiles and dosage design, suitable for capsule forms. Non-ionic, water insoluble ethylcellulose is also commonly used in achieving extended-release formulations, usually multiparticulates for capsule formulation.”

The other formulation concept, reservoir systems, are represented by coated dosage forms, Karry continues. “Hereby, insoluble or soluble core substrates (e.g., pellets, mini tablets) are film coated with insoluble polymers to obtain a sustained-release functionality,” she states. “Independent of the substrate’s formulation, drug release results from permeation of dissolved API from within the core through the membrane.” 

Critical considerations

“In the field of immediate-release dosage forms, general formulation concepts can be applied to a variety of different drugs. API features, such as solubility kinetics, pH-value, particle size distribution, osmolarity, dose, and many more, merely provide minor challenges during the development,” emphasizes Cech. “In contrast, the understanding of all these characteristics is essential when aiming for controlled drug release. In this case, every drug requires a customized formulation concept to address its unique features.”

The advantages gained through controlled-release dosage forms, such as convenience of dosing, better therapeutic management of conditions, and lower side effects, can override the potential challenges associated with development and manufacture, asserts Rajabi-Siahboomi. Each approach offers its own set of advantages and challenges, he states; hydrophilic matrices, for example, are the simplest technology to use for controlled-release formulations but in cases of high-dose and high-solubility ingredients can result in an oversized tablet or a fast, initial “burst” release profile, respectively.

“Matrix excipients that ensure a controlled drug release independent of pH, have a lower ratio of soluble to insoluble pore formers, and have binder properties for strong tablet compacts are highly sought for,” notes Karry. “Matrix systems are advantageous because they employ direct compression processes-the least complex of all platforms-and can be easily scaled-up, transferred, and validated. There is the disadvantage, however, that some amounts of API will be present on the surface of the tablet. These quantities are immediately dissolved after administration.”

Reservoir systems, which are primarily attained via film coating processes, also offer simplicity for developers, but the coating process is less forgiving than direct compression, continues Karry. “An imperfect tablet coating can lead to fast water uptake and uncontrolled API diffusion out of the defective film,” she says. “Even if the coating process is flawless, elastic recovery of the tablets post-compression or during stability can crack the polymer film and render the system inadequate.” 

As a disadvantage, reservoir systems can produce a lag phase before the API can be dissolved, which is caused by the fact that the dissolution media needs to permeate the coat to dissolve the drug so that it can diffuse out, Cech adds. “Polymers that can readily meet the latter conditions or require lower concentrations of additional components to reach them are preferred,” he says.

Cech emphasizes the decisive role process parameters can play in the manufacture of controlled-release dosage forms. “Variations in the compression force during tableting or an alteration of product temperature during coating can result in a distinctive change of the dissolution pattern,” he notes. “When conducting the risk analysis as part of the quality-by-design (QbD) process, the list of potentially critical material attributes and process parameters appears to be endless.”  

“Furthermore, it’s not only about the reliable manufacturing of a controlled-release dosage form, where each individual tablet provides exactly the same dissolution pattern; the dissolution is also not allowed to change during shelf-life, even if the dosage form is stored at elevated temperature and humidity,” Cech asserts.

“The advantages of barrier membrane-coated multiparticulate extended-release systems may be related to the flexibility of achieving different release profiles and co-formulating more than one drug or release profile into one dosage formulation,” Rajabi-Siahboomi notes. “The challenge for this technology is fine-tuning drug release and maintaining stable performance over the shelf-life of the product.” 

However, Rajabi-Siahboomi also stresses the need for consideration of specific critical formulation and processing parameters during development and manufacture of extended-release multiparticulates. “In general, the choice and level of polymer, plasticizer, and pore-former, for example, all impact drug release performance,” he says. “Additionally, coating process conditions, such as spray settings, air humidity, and post-coating processing also affect drug release performance.”

Important innovations

The use of multiparticulate systems rather than single-dose systems was clearly a milestone in the field of controlled-release dosage forms. “Even though the idea is much older than a decade, there is hardly any other formulation concept that provided so many advantages,” Cech says.

Listing the advantages gained through the use of multiparticulate systems, Cech begins by highlighting the inherent risk of dose dumping that may occur with tablets coated with a sustained-release polymer. “Dose dumping may occur either because of a defect in the coat or because the patient decided to break the tablet before administration,” he comments. “If the dose is split among hundreds of pellets (e.g., filled in a capsule or compressed to a tablet), defects of a small number of single compartments bear no safety risk.”

Further to the safety benefits, particles below a threshold of approximately 2–3 mm behave as fluids in the stomach, which eliminates the potential effects of diet and food during drug absorption as the particles are able to freely move to the intestine, Cech confirms. “Additionally, developers are not obliged to develop one product that precisely matches the dissolution profile required,” he says. “Combinations of pellets coated with different coating formulations are often seen in these multiparticulate systems. The different dissolution patterns sum up to the required one, if the pellets are mixed in the right ratio.” An added advantage of using a combination of pellets is that if there is a variation in one coating batch, there is only a minor impact on the overall dissolution pattern. Conversely, if there is a variation in coating of a product based on one pellet formulation, the products are instantly out of specification, Cech stresses.

“Finally, multiple pellet formulations enable oral delivery of combination therapies without the interaction risk, and they reduce first-pass effects for acid-sensitive drugs,” Karry adds. “The formulations can either be swallowed or suspended in water to release the API-loaded pellets. The pellet nucleus can be a placebo bead coated with API and a suitable controlled-release polymer.”

Although many of the technologies available for controlled-release formulations have been around for a long time, such as matrix tablets and multiparticulate formulations, there have been line extensions and reformulations made to expand the potential applications of the technologies that are enabling developers to achieve different release profiles or formulate challenging drugs, continues Rajabi-Siahboomi. “A good example is the application of a barrier membrane coating to a hydrophilic matrix,” he notes. “By adding this top-coat, formulators have been able to overcome the so-called initial burst release for highly soluble drugs, which is important to maintaining controlled release.”

Push-pull osmotic pump (PPOP) technology is very robust in providing a zero-order release profile, which is critical for certain drugs with a narrow therapeutic index or those with undesirable side effects related to blood plasma C_max, Rajabi-Siahboomi asserts. “The manufacturing technology is multi-step; hence, experience and access to expertise in the different unit operations is very important,” he says. 

“Furthermore, the use of extended-release technologies for fixed-dose combinations (FDC) has allowed a significant number of new drug applications to be made under the 505(b)2 scheme with the US Food and Drug Administration,” Rajabi-Siahboomi says. “Some of these may be a combination of extended and immediate release in the same dosage form, like bi-layer tablets, or a mix of barrier membrane-coated multiparticulates that are loaded into a capsule. The FDC technology improves patient experience by reducing the pill burden (taking one dose rather than two or more) and enables synergistic treatment of a condition with a single dosage formulation.”

Regulatory hurdles

As is the case with all pharmaceutical products, materials used in the development of controlled-release dosage forms must be safe and ideally have precedence of oral use, asserts Rajabi-Siahboomi. “Regulators look for data to support stability, safety, and efficacy of the dosage form. It’s important that formulators select raw materials from suppliers with high quality standards and who fully understand the science and nuances of rate-controlling polymers to ensure consistency of the materials,” he says.

Rajabi-Siahboomi adds, “QbD can help to determine if there is any batch-to-batch variability of ingredients and how to manage these during manufacture at commercial scale. Demonstrating stability for any product is a key requirement (i.e., keeping the identity, purity, and performance of the drug and dosage unit consistent over the assigned shelf-life of the product). In addition, formulators must clearly demonstrate safety when drugs are administered orally as the drug load of many of these formulations are higher than their immediate-release dosage forms.”

“Especially in the field of controlled drug release, QbD-based formulation development can be quite demanding,” continues Karry. “Various process parameters and material attributes do not only have an impact on the resulting drug release, but also provide interactions pronouncing their effect.”

By way of example, Cech highlights that the film formation during coating is a thermodynamic process. “Consistently, the integrity of the coat depends on the product temperature during the process and process humidity,” he says. “Varying one of these parameters already has some impact on the dissolution, yet varying both at the same time has a major impact on the drug release kinetics.”

Concurrently, regulatory hurdles can be met when targeting specific patient populations, Karry explains. “Pediatrics and geriatrics are quite challenging to address,” she says. “It is more difficult to conduct clinical studies, and the age-specific metabolism provides additional challenges.”

A demonstration of stability for any product is also a key requirement, emphasizes Rajabi-Siahboomi. “In addition, formulators must clearly demonstrate safety when the drug is administered orally, because the drug load of many of these controlled-release formulations are higher than their immediate-release dosages,” he states. “There should not be any ‘dose-dumping’ due to exposure of the dosage form to gastrointestinal tract content, so fed and fasted studies need to be conducted, in addition to studies assessing the effect of alcohol.”

What the future holds

New technologies, such as three-dimensional (3D) printing, are gaining interest throughout industry. “The interest in 3D printing is because of potentially personalized medicine, but it also offers opportunities in the field of controlled-release dosage forms,” Karry highlights. “By employing 3D printing, rather complex tablet designs are possible. Concepts carrying several compartments with very specific drug-release features have already been tested successfully. Both technology and formulation concepts are still quite young in the pharmaceutical field, and we need to see in which direction we are proceeding. However, new opportunities support innovation that could lead to a paradigm shift.”

“In addition, there are various efforts in personalized medications leveraging new technologies or less frequent dosing, such as once a week therapy, which enhances patient adherence even further than current once-a-day formulation,” Rajabi-Siahboomi summarizes. Furthermore, he emphasizes the R&D work to achieve oral delivery of large-molecule drugs, which also has the potential to cause a paradigm shift in targeted and controlled-release formulations. 

References

1. P.I. Lee and J.X. Li, “Evolution of Oral Controlled Release Dosage Forms,” In Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice, H. Wen and K. Park (John Wiley & Sons, Hoboken, NJ, 23 August 2010) pp. 21–31.
2. Grand View Research, “Controlled Release Drug Delivery Market Size, Share, and Trends Analysis Report by Technology (Micro Encapsulation, Targeted Delivery), by Release Mechanism, by Application, by Region, and Segment Forecasts, 2020–2027,” grandviewresearch.com, Market Report (March 2020).

Article Details

Pharmaceutical Technology 
Vol. 44, No. 7
July 2020
Pages: 26–29

Citation 

When referring to this article, please cite it as F. Thomas, “Taking a Controlled Approach,” Pharmaceutical Technology 44 (7) 2020.