Modified-Release Dosage Forms: Expertise is Essential
Author: Yihong Qiu, Ph.D., Sr. Research Fellow Drug Products Operations Science and Technology, AbbVie
Whether your goal is to increase patient compliance, improve clinical outcomes, or to extend a product’s lifecycle, modified-release dosage forms present a solution to myriad challenges. The trick is to understand the influence of both drug property and delivery technology on drug design, and to give you enough time to select and introduce the ideal release form for both therapeutic and economic advantage.
Unlike immediate-release forms, which act quickly, modified-release forms are intended to act over a longer time period or delay action until they have reached a specific area – the stomach, small intestine, or colon, for example. There are different names for different modifications:
- delayed release for specific sites or times
- extended release for sustained or controlled drug exposure
- programmed release such as pulsatile or biphasic
The products also take many forms, from oral solid tablets, capsules, and liquid gels to transdermal patches, depot injections, and even infusions. There are matrix, reservoir, osmotic pump, and coating systems to alter the delivery pattern of drug products, as well as various mechanisms to extend, delay, or program drug action. This variety helps drug companies select the best possibly delivery system for the specific drug product to yield the best possible therapeutic result.
Why Modify Drug Release?
Among the therapeutic advantages for altering absorption characteristics of a drug is patient convenience and compliance. With nearly five in 10 Americans reporting taking at least one prescription drug in the previous 30 days, medical adherence is important to overall health. If a drug can be taken once a day instead of three or four times, the patient is more likely to find it easy to comply with dosing instructions. Studies on medical adherence have found that compliance for once-daily medication is nearly 80 percent, dropping to only 50 percent for medication taken four times a day.
Modified-release dosage forms can also improve the efficacy and safety of a drug and/or reduce adverse events. This is because drugs targeted to reach a specific region or to be released in smaller doses over time may improve efficacy and/or help reduce or diminish unwanted side effects for certain class of drugs. Different delivery systems can help mask unpleasant taste or odor, or, for example, ease nausea or irritation by delaying release until after passing through the stomach. This, too, improves patient compliance and outcomes. The different MR dosage forms can also increase selectivity of drug activity, or be used to treat new indications – e.g., the management of neuropathic pain in addition to severe or chronic pain -- or provide new therapeutic benefits – e.g., improving tolerability.
There are commercial advantages, too, from modifying the release of drugs through different dosage forms. The therapeutic advantages help maximize the drug’s medical benefit and potential – for example, reformulating for pediatric or geriatric dosing, or to extend market exclusivity. MR can help differentiate a drug product in the marketplace, and improve its cost effectiveness. In the case of converting immediate-release generic doses to modified-release, the clinical pharmaceutical rationale and feasibility for the drug product have already been proven. Switching to a modified-release version of an existing product can also extend that product’s lifecycle.
The cardiovascular drug Cardizem is one example of how MR can extend a product’s lifecycle and increase sales. In the late 1980s, as a three-times-a-day drug, it reached peak revenues of $260 million. The introduction of twice-a-day Cardizem SR grew revenues to $400 million. Once-a-day Cardizem CD more than doubled sales to almost $900 million by 1996.
Considerations for Contracting MR Manufacturing
The decision to outsource development and manufacturing of a modified-release dosage form should factor in the CMO’s experience with delayed-, extended- and programmed-release drugs. This includes extensive knowledge, experience, and capability required for fundamental understanding of the MR product and process development, including:
- characterization of drug properties
- different types of MR delivery systems and design
- understanding of impact of GI drug release/absorption and residence time on product design
There is a wide array of drug delivery technologies and mechanisms to consider for oral and parenteral delayed- and extended-release dosage forms. Knowledge of the physiochemical, biopharmaceutical, pharmacokinetic and pharmacodynamics properties of the API must be integrated with understanding of dose, available delivery systems, and the processes to manufacture the MR drug product. The interplay of the drug and the dosage form with physiological and biological variables must also be considered.
A rational design process would include the following actions:
- Define the clinical rationale and the quality target product profile. A PK simulation should be used to define the required drug input and desired outcome.
- Conduct a feasibility assessment to understand API properties – from solubility and lipophilicity to stability, ADME, and therapeutic window.
- With confirmed feasibility, select the appropriate modified-release technology to be used, the manufacturing process, and test methods.
- Design and test prototypes in vitro and in vivo to identify the target commercial formulation. In vitro and in vivo study results can be used to refine the design, and their relationship should be concurrently explored.
In our decades of experience with modified-release dosage forms, we have found there is no “one-size-fits-all” delivery technology. For feasible APIs, there is more than one well-established technology available for addressing various modified release delivery needs. The successful design and development of commercially viable MR products relies primarily on drug properties, though delivery technology is also an important or factor.
For help developing and manufacturing your modified-release dosage forms, talk to AbbVie Contract Manufacturing. We’ll work with you to understand the API properties, target MR properties, determine dose, strength, and delivery technology, select cost-effective and robust manufacturing processes, create a workable development schedule, and move quickly to commercial manufacturing.