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Oral solid dosage (OSD) forms are commonly used to administer small molecule drugs to patients, facilitating ease of administration to result in rapid delivery and benefit. This modality is most commonly used for immediate release (IR) formulations, where the drug instantly dissolves and is released. Despite the advantages of experiencing an immediate effect, this instantaneous release can lead to a short duration of action, requiring frequent dosage and resulting in release peaks and troughs in the bloodstream, which can lead to side effects or reduce therapeutic efficacy.
Dr. Asma Patel
Modified release (MR) OSD formulations enable control over the rate and location of drug release in the gastrointestinal (GI) tract, to achieve specific therapeutic benefits in comparison to IR formulations and can be better tailored to patient needs.
In this article, Dr. Asma Patel, Vice President of Integrated Development Services at Quotient Sciences, explores the benefits of MR formulations, highlighting the importance of an effective strategy for MR development.
Harnessing MR Therapeutic Benefits
Building in this inherent control over drug product release in the body allows for tailoring of therapeutic effects, including:
Designing the rate and location of drug release in the gastrointestinal (GI) tract, allowing for targeted delivery of drugs to specific regions.
- Introducing a time lag into formulation release to extend the time frame with a beneficial effect.
- Maintenance of drug plasma concentrations over a prolonged period to reduce dosing frequency.
- Reducing the incidence of peak-related adverse events (AEs) by attenuating peak-to-trough ratios.
In addition to these therapeutic benefits, altering the formulation from IR to MR can also provide a strategic advantage, with the ability to extend the patent exclusivity of the drug product. This can help originator companies maintain a competitive advantage in the market.
Development Challenges Hinder MR Formulation
Navigating the development of an MR formulation is complex, with multifaceted considerations for effective design and manufacture, including:
The examination of GI physiology: Successful OSD MR development requires consideration of the multiple GI environments the formulation will encounter across different anatomical regions. Factors such as GI transit time, absorptive surface area, permeability, GI fluid volumes and composition, pH, enzyme and transporter expression must all be considered.
- The active pharmaceutical ingredient (API) physicochemical properties: The properties of the API heavily impact how the drug behaves when administered. For example, if an API is highly soluble, then it will generally have a much quicker release rate. If the drug is a weak base or acid, its solubility is pH-related and hence the in vivo drug release can be different throughout the GI tract.
- The choice of formulation technology: A clear target product profile (TPP) can be essential to help guide the development of a formulation and ensure that the desired characteristics are achieved. The TPP is based on the drug product requirements including intended clinical use, dosage strength(s), drug release characteristics, stability and other product quality criteria. Many MR formulation technologies can be used to control the rate and time of drug release to achieve a particular TPP. A developer is therefore faced with the need to select the strategy that will provide optimal results most efficiently and cost-effectively.
- Effective analytical development: Successful development of MR solutions hinges on effective analytical methods. Assuring that safety and quality regulations are met, analytical methods are also essential to ensure that the MR formulation will perform as expected.
Attaining an effective MR formulation requires the selection of the right excipients and drug delivery technologies to meet the needs of the product and the patients. Having an effective strategy in place that takes into account all considerations at the earliest stage of development is essential to prevent the failure of the drug later in the pipeline as a result of efficacy problems.
A Strategy for Translation Success
Traditional formulation development relies on the successful testing of several formulations, which have been developed in vitro, within a preclinical in vivo model, before entering into human clinical testing. As there are key and complex biological differences between in vitro and in vivo models compared to human clinical testing, poor translation between preclinical and clinical studies often occurs, with approximately 40-50% of candidates failing due to a lack of clinical efficacy. To overcome this, the formulations entering human studies must have better translational efficacy.
Harnessing in silico tools can provide key insights early in MR development. By using modelling and simulation software, predictions of physiologically based PK (PBPK) and physiologically based biopharmaceutics modelling (PBBM) can be made, which can lead to better-informed decision-making throughout formulation development at the “wet lab” level.
In addition, adopting an appropriate formulation platform that harnesses human data allows for the optimisation of key variables of the formulation based on clinical data to achieve the desired TPP. This better positions the translation of in vitro formulations into human studies for success.
Meeting MR Formulation Needs
Concerning MR formulations, utilising a platform that considers the “design space” as outlined in ICH Q8 allows for a quality-by-design (QbD) development approach to be adopted. With this method, a formulation “design space” is defined that considers that in vivo product performance in humans will shift as compositions are altered. The “design space” may consider the following critical parameters that influence formulation release rate and PK profile:
- API dose/concentration
- Functional excipient content
- Drug:polymer ratio
- Surface area volume ratio
- Coating composition/thickness
By first determining the extremes (minimum and maximum), the “design space” can be mapped. Adjustments can then be made to trial medications as clinical results develop to optimise the drug-release pattern and increase or decrease the dose accordingly.
The flexibility a design space concept affords is only beneficial to the extent that manufacturing can keep pace with clinical trial dosing modifications. Seamlessly integrating a manufacturing facility with the clinical testing organisation running the study can shrink the time between decision points and restart the trial with the next iteration of the drug product. With this strategy in place, formulation components that have been deemed critical for performance can be used as variables for precise and accurate formulation design at accelerated rates.
The Future is MR
Navigating complex MR formulation development is vital for targeted and precise delivery. Opting for a platform that considers the critical parameters in MR formulations early in development is essential to overcoming development challenges, driving efficiency and implementing cost savings.