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Modified Release Dosage Forms: Giving New Life to Drugs

Considerations for developing modified release versions of an immediate release product.

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Released By Bend Bioscience

Developing a modified release (MR) formulation of an existing immediate release (IR) dosage form is a frequent request. There are a number of therapeutic and business advantages for why a company would modify the release of a drug and expand development beyond the IR predecessor including patient compliance, extended duration of action, and extension of product lifecycles.
 
On the therapeutic front, modified release drug products enable drug release over a defined period of time or at specific locations within the gastrointestinal (GI) tract for prolonged or targeted drug delivery.
 
“This allows for less frequent dosing, which can increase patient compliance and result in fewer side effects by reducing peaks and troughs in blood levels,” said Brittany L. Hayes, Ph.D., applied technology director at Societal CDMO, a pioneer in modified release technology. “This is a huge therapeutic advantage for patients if the debilitating effects of a disease appear quickly once the drug concentration falls out of the therapeutic window.”
 
Other therapeutic advantages of MR drugs include improved efficacy, optimized clinical performance, a greater selectivity of activity, or possibly new indications.
 
From a business advantage perspective, a successful MR drug product can provide a company with market expansion, intellectual property, and extension of exclusivity as pharma companies face patent loss. Reformulated drugs can have improved characteristics that will attract patients and they may help the innovator company to ward off generic competition and maintain market share for as long as possible.
 
Modifying Dosage Forms
 
Modified release formulation development and manufacturing are notoriously challenging. According to the experts at contract development and manufacturing organization (CDMO) Societal CDMO, achieving an effective formulation requires a holistic, well-researched view of:
 

  • API characteristics;
  • Desired pharmacokinetic (PK) profile;
  • Appropriate excipients;
  • Dosage form selection; and
  • Manufacturing techniques.
 
As a pioneer in the field, 
Societal CDMO has been developing modified release dosage forms for over 35 years, since the 1980s, at one of the first U.S. sites to apply this technology.
 
The key differences between MR and IR products include drug absorption rates and the location of drug release. There are multiple options for delivery forms including tablets, capsules, and multiparticulates. Which one you choose for your MR product depends on the target release profile and the physicochemical properties of the API(s).
 
“Matrix tablets are among the most common oral solid MR products. The API is dispersed within a polymer matrix, and it is released gradually either by diffusion across the matrix or as the matrix erodes. Matrix tablets may be difficult to formulate with multiple APIs and/or incompatible APIs,” said Hayes. “A bilayer or trilayer tablet and/or enteric coatings may be more suitable here. Capsules are an option, and once the soluble capsule dissolves, it will release its components. The release profile is determined by the formulation and/or the capsule shell itself, both of which can be specially formulated for MR characteristics.”
 
Another capsule product that could be used in MR products is a multiparticulate formulation, according to Hayes. “Here, the capsule contains one or more populations of pellets in an easily dissolved, hard gelatin or HPMC shell,” she explained. “API dosages are easily adjusted by increasing or decreasing the various bead contents. This delivery system can be created with complex dissolution patterns by making bead populations that release at different rates.”
 
Knowledge of your API’s physicochemical properties like pH solubility, solubility in solvents, crystallinity, particle size, solid and solution state stability profiles, PK data, GI profile, and bioavailability are imperative when considering formulation approaches in early development.
 
“Answering questions like, ‘What is the target PK profile and why?’ and ‘What tools and technologies are available to strategically design the formulation that will achieve this PK profile?’ are needed before plunging ahead,” said Hayes. “Conducting an excipient compatibility study (ECS) with suitable MR excipients and a forced degradation study (FDS) are also important.”
 
In terms of technology, the greatest advances have been improvements in applications of existing materials and in processing equipment, such as automation. “Our understanding of how to formulate or reformulate molecules continues to evolve as does our ability to engineer processes to produce them,” said Hayes. “Newer equipment is more reliable, easier to operate, easier to clean, and quicker to change over. It also offers better data collection and security, which is key in today’s environment prioritizing data integrity.”
 
If a company decides to outsource their MR dosage form development and manufacturing needs, the most important thing to consider is the experience of the CDMO in working with the various delivery technologies and forms. “MR dosage forms present their own unique set of complications, nuances, and regulatory expectations that are not always apparent,” said Hayes. “There are specific strategic decisions that need to be made with respect to the desired in vivo behavior and final dosage form that critically impact formulation strategy and process selection.”
 
The essential elements to a successful partnership include open communication and trust. “It’s a two-way street,” said Hayes. “Both parties need to be open, honest, and transparent. It isn’t ‘if’ issues will arise but ‘when,’ and the key thing that matters is how they are managed.”

Learn more about Societal CDMO >>>>>

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