The Guide to Formulating Oral Extended-Release Tablets

Extended-release tablets, also known as sustained-release, controlled-release, or time-release tablets, have become increasingly important in the healthcare sector due to their ability to maintain consistent drug levels in the body over a specific period. This drug delivery system provides various benefits, including enhanced patient compliance, minimized side effects, and improved therapeutic efficacy.

Definition of Extended-Release Tablets

Extended-release tablets are medications designed to release an active ingredient over a specific duration gradually. Instead of being immediately released and absorbed once ingested, the drug in these tablets is distributed steadily in the body, ensuring a prolonged therapeutic effect. The goal is maintaining a constant drug concentration in the bloodstream, potentially reducing the dosage frequency and minimizing peaks and troughs in plasma drug levels (Figure 1).

Figure 1: Drug Plasma Level for Immediate Release and Extended-Release Tablets

Importance and Benefits of Extended-Release Tablets

The development and use of extended-release tablets are critical in modern medicine. These formulations provide several advantages that improve patient care:

1. Improved patient compliance: Patients often need extended-release tablets to take their medication less frequently than conventional immediate-release medications. This can improve adherence to treatment regimens, particularly in chronic conditions requiring long-term medication use.
2. Reduced side effects: By maintaining steady drug levels in the body, extended-release tablets can minimize the risk of side effects often associated with high peaks in drug concentration.
3. Enhanced therapeutic effect: Extended-release tablets ensure a consistent medication delivery over time, which can enhance the overall effectiveness of the treatment by ensuring maximum absorption and extending the duration of action.

The following sections will delve deeper into the mechanics, development, applications, and patient considerations associated with extended-release tablets. This complete guide aims to provide an in-depth understanding of this crucial aspect of pharmaceutical science and its significant impact on healthcare outcomes.

Mechanism of Action

The primary objective of extended-release tablets is to control the rate at which the drug is released into the system after ingestion. Various techniques, including matrix systems, encapsulation, and coating methods, achieve this. In all cases, the drug is embedded into a system that slowly dissolves or breaks down in the body, allowing a steady release of the medication. The specific mechanism of action varies depending on the type and design of the tablet.

Different Types of Extended-Release Tablets

Extended-release tablets can be broadly categorized into two types:

1. Diffusion-Controlled Systems: These include reservoir devices and matrix devices. In reservoir devices, the drug core is surrounded by a polymer membrane that controls the drug release rate. In matrix devices, the drug is distributed throughout an insoluble polymer matrix, and the drug diffusion rate governs its release (along with matrix erosion at later time points).
2. Dissolution-Controlled Systems: These systems control drug release by modifying the rate of dissolution of the drug in the gastrointestinal tract. This is usually achieved through special coatings or the incorporation of the drug in a water-soluble matrix.

Common Examples of Extended-Release Medications

Many medications come in extended-release formulations. Some common examples include certain cardiovascular drugs (e.g., metoprolol succinate), pain relievers (e.g., pregabalin CR), antidiabetic drugs (e.g., metformin ER), and psychiatric medications (e.g., dextromethorphan/bupropion ER).

Table 1: Common Examples of Extended-Release Tablets

Pharmaceutical Formulation Techniques

The formulation of extended-release tablets involves a variety of pharmaceutical techniques. The choice of technique largely depends on the properties of the drug, the desired release profile, and the intended route of administration. Some commonly used techniques include:

1. Matrix Formulations: The most common approach to achieving oral extended-release, in which drug is mixed with a polymer matrix and compressed into a tablet. The tablet is formulated to release the drug at a controlled rate as the matrix slowly dissolves or erodes in the body.
2. Coating Techniques: These involve applying a thin polymer layer to the drug particles or tablets. The coating material and thickness are selected to achieve the desired release rate.
3. Encapsulation Techniques: The drug is enclosed within a capsule that dissolves at a controlled rate, releasing the drug over time.

Manufacturing of Extended-Release Tablets

There are several ways to manufacture extended-release tablets, namely:

1. Wet Granulation: a process by which dry powders are agglomerated in the presence of a granulating fluid. The mixture is then dried, leaving behind granules of API and excipient(s). These granules are blended with additional ingredients, such as fillers and binders, and compressed into tablets.
2. Dry Granulation: a process by which powder mixtures are compressed into granules without the use of liquid. These granules are then blended with additional ingredients, such as fillers and binders, and compressed into tablets.
3. Direct Compression: a streamlined process by which powder mixtures of API and specialized excipients are weighed, blended, and compressed into tablets.

In recent years, direct compression has gained traction as an alternative to traditional granulation processes due to its many economic- and resource-based benefits, including:

• Minimized processing steps
• Reduced energy use
• Decreased labor costs
• Higher throughput

Quality assurance and control are critical in manufacturing extended-release tablets to ensure that they meet the desired specifications and release profiles. This involves rigorous testing of the raw materials, in-process materials, and finished products using methods such as dissolution testing, hardness testing, and friability testing.

Regulatory Aspects in the Production of Extended-Release Tablets

The production of extended-release tablets is subject to stringent regulatory requirements to ensure safety, efficacy, and quality. These requirements include Good Manufacturing Practices (GMPs), stability testing, bioequivalence studies, and appropriate labeling.

When selecting excipients an extended-release formulation, it is important to reference the FDA’s Inactive Ingredient Database (IID), which lists excipients found in approved drug products. The IID lists the highest amount of the excipient per unit dose in each dosage form in which it is used. This database is often used by manufacturers when developing new drugs and generic medications because it provides data on inactive ingredients that the FDA has previously vetted.

How the Body Processes Extended-Release Medications

Pharmacokinetics is how the body absorbs, distributes, metabolizes, and excretes a drug. In the case of extended-release tablets, the drug is typically absorbed in the gastrointestinal tract over a prolonged period. This slow absorption process, combined with subsequent distribution, metabolism, and excretion, contributes to maintaining steady levels of the drug in the body.

Effects of Extended-Release Medications on the Body

Pharmacodynamics deals with the effects of a drug on the body. Extended-release tablets are designed to provide a steady, therapeutic effect over time. By maintaining consistent drug levels, these tablets can ensure that the drug continues to exert its desired effect without causing peaks that may lead to side effects or troughs that might render the medication less effective.

Factors Influencing the Absorption and Distribution of Extended-Release Tablets

Several factors can influence the absorption and distribution of extended-release tablets. These include the patient's age, body weight, genetic factors, overall health status, the presence of food in the stomach, the pH of the gastrointestinal tract, and the use of other medications. Some APIs may also have properties that introduce challenges, such as poor absorption outside the stomach/upper gastrointestinal tract or short half-lives. These drugs often require a combination of extended-release technology with another approach, such as gastroretention, to extend the absorption window.

Conditions Treated with Extended-Release Tablets

Extended-release tablets are used to treat various conditions, particularly those requiring long-term medication management. These include chronic diseases such as hypertension, diabetes, chronic pain conditions, and psychiatric disorders like depression and anxiety.

Comparisons to Immediate-Release Medications

Compared to immediate-release medications, extended-release tablets provide several advantages, such as reduced dosing frequency, improved patient compliance, and a more consistent therapeutic effect. However, they may not be suitable for conditions requiring rapid onset of action or drugs that need to be absorbed quickly into the system. In these situations, bi-layer tablets provide an appealing solution.

Bi-Layer Tablets for Multiple Release Rates

In a bi-layer tablet, an immediate release layer and an extended-release layer and pressed into a single unit, allowing tailored release profiles for multiple APIs. Bi-layer tablets also enable fixed-dose combinations of APIs, wherein an immediate and extended effect are achieved from a single dosage form. The popular over-the-counter cough and cold medicines Mucinex and Mucinex DM (Figure 2) are examples of bilayer tablets with an immediate- and extended-release component.

Figure 2: Mucinex® bi-layer tablets, which feature an immediate-release layer for fast relief and an extended-release layer for prolonged drug delivery.

Innovations and Future Directions in Extended-Release Tablets

Current Research and Innovations

The field of extended-release tablets is continually evolving, with research focusing on creating more efficient drug delivery systems. Some of the recent advancements include:

1. Gastroretentive Drug Delivery Systems: Gastroretentive Drug Delivery Systems (GRDDS) are oral dosage forms that are designed to prolong residence time in the stomach/upper gastrointestinal tract. GRDDS are useful when formulating drugs that are best absorbed in the stomach/upper gastrointestinal tract, exhibit poor solubility at alkaline pH, or suffer from poor stability in the lower GI tract. Several commercial drug products utilize GRDDS, and there are many in the development pipeline. When combined with extended-release technology, GRDDS can improve absorption of drugs while minimizing doses and side effects for patients. Common approaches to gastroretention include floating systems, swelling/expandable tablets and capsules, and mucoadhesive systems, all of which may also incorporate extended-release elements[1].
2. Mucoadhesion: Mucoadhesion is the ability of a formulation to adhere to a mucous membrane (oral, ophthalmic, vaginal, intestinal, etc…). This technology is used in drug delivery to increase retention of active ingredients at a target site for local or systemic delivery. Some oral drug delivery researchers have leveraged mucoadhesive excipients, such as carbomers, to develop patches and particles that adhere to the intestines to enhance bioavailability and provide extended release of drug over time[2]. Similar to GRDDS, this approach ensures higher absorption of drug and increases bioavailability.
3. New Formats for Extended-Release: Dysphagia, or difficulty swallowing, is a common and growing problem in drug delivery. It is estimated that over 16 million people in the United States and over 40 million people in Europe have difficulty swallowing, which can lead to challenges delivering traditional oral tablets and capsules[3]. In addition to tablet size reduction and coating technologies, formulators are looking to incorporate extended-release properties to more patient-friendly dosage forms, such as oral liquids, granules, and rapidly disintegrating tablets. These approaches will ensure dysphagic groups, such as pediatric and geriatric patients, can still access the benefits of extended-release.

Future Trends and Opportunities in the Field

Looking ahead, the development of personalized medicine, where treatments are tailored to individual patients' needs, will likely impact the field of extended-release tablets. Furthermore, advancements in technology and materials science could lead to more sophisticated controlled-release systems, such as systems that can respond to changes in the body and an increase in “multi-API” dosage forms to reduce the pill burden on patients.

Extended-release tablets are crucial in modern healthcare, offering several benefits, such as improved patient compliance, reduced side effects, and enhanced therapeutic effectiveness.

This guide has explored the basics of extended-release tablets, their development and manufacturing processes, pharmacokinetics and pharmacodynamics, clinical applications, and patient considerations. We also discussed current innovations and future trends in the field.

Given the benefits of extended-release dosage forms, continued research and development in this area is essential. Advances in the materials, formats, and manufacturing of extended-release drug products will continue to drive more effective treatments, better patient outcomes, and overall improvements in healthcare delivery.

If you are formulating an oral extended-release product, contact our team of experts to learn how Lubrizol can support your development with best-in-class excipients and formulation expertise.

[1] Vrettos NN, Roberts CJ, Zhu Z. Gastroretentive Technologies in Tandem with Controlled-Release Strategies: A Potent Answer to Oral Drug Bioavailability and Patient Compliance Implications. Pharmaceutics. 2021 Sep 30;13(10):1591. doi: 10.3390/pharmaceutics13101591. PMID: 34683884; PMCID: PMC8539558.

[2] Kaur G, Arora M, Ravi Kumar MNV. Oral Drug Delivery Technologies-A Decade of Developments. J Pharmacol Exp Ther. 2019 Sep;370(3):529-543. doi: 10.1124/jpet.118.255828. Epub 2019 Apr 22. PMID: 31010845; PMCID: PMC6806634.

[3] Sabry, A., Kyriakou, K. and Moerman, M. Fast facts: Neurogenic dysphagia. 2022. https://doi.org/10.1159/isbn.978-3-318-07216-7.