Small molecule drugs still make up the majority of newly approved medicines. In 2022, 57 percent of FDA drug approvals were for small molecules (1, 2). The global small molecule drug discovery market size is also expected to increase from $75.96 billion in 2022 to $163.76 billion by 2032 – a compound annual growth rate of 7.97 percent (3).
Traditionally, molecules for oral administration have been formulated into immediate release (IR) products with a rapid onset of action. Although instantaneous relief can be advantageous for the patient in some therapeutic areas, these formulations can suffer from a short duration of therapeutic effect, resulting in the need for more frequent dosing regimens. And because the drug immediately enters the bloodstream, it can cause significant peaks and troughs in circulating drug concentrations, leading to side effects and variation in therapeutic efficacy.
To overcome these limitations, modified release (MR) formulations can be designed that allow more control over the rate and location of drug release in the GI tract. MR formulations can also provide added therapeutic benefits, including i) the maintenance of drug plasma levels, wherein a prolonged period of release stabilizes drug plasma levels, reducing the dosing frequency requirements, ii) attenuation of peak-to-trough ratios, which can lead to lower peak-related adverse effects and improve therapeutic efficacy, and iii) targeted delivery or the specific release of a drug at a particular site in the gut tract (to either target gastrointestinal disease or reduce the impact of delivering a drug to absorptive regions).
With MR formulations, drug delivery can be optimized, taking into account drug product dosage, target, and patient needs.
Under the broad MR term, there are many formulation technologies that provide individual benefits and support different release profiles.
- Sustained or extended-release. Prolonged-release profile of the drug allows for minimal dosing of 1–2 times per day. Technology: matrix or film-coated tablets or multiparticulates can achieve this.
- Delayed release. A lag time of release can be achieved, allowing the drug to reach an intended site in the GI tract before release for more targeted delivery. Technology: pH or time-dependent coating systems can be used.
- Gastric bypass. The drug can pass through the stomach without being released to overcome any stability limitations in the harsh environment of the stomach. Technology: Enteric coating.
- Biphasic/pulsatile release. Allows for both instantaneous and extended-release profiles, reducing the need for repeat dosing. Technology: introducing IR and MR layers in a bilayer tablet or multiparticulates with different release profiles.
- Gastro-retention. Formulating the drug to delay the natural gastric emptying of the stomach allows for a prolonged time frame to the upper GI tract when an absorption window exists. Technology: swellable, floating, and bioadhesive systems.
Although increasingly used for the development of new chemical entities, MR technologies have traditionally been adopted for life cycle management strategies. This modest reformulation of changing from an IR to an MR allows for the extension of drug product patents and provides continued market exclusivity.
Navigating MR, however, can be a complex process as differences in the regional absorption of the GI tract, which are not normally a consideration for IR dosage forms, come into play. An example of this is a sustained-release formulation that transits to the GI tract while continuously releasing the drug. Therefore, the drug must be sufficiently absorbed in the lower GI tract to maintain a therapeutic effect. Accordingly, the development team will typically need to conduct multiple cycles of formulation development, in vitro screening, preclinical, and clinical studies to find the balance of drug release rate and dose to achieve the target plasma concentration profile for the MR formulation to succeed.
One way that development teams can improve this optimization process is to employ a “translational pharmaceutics” approach and evaluate a “design space” within a clinical study. The design space concept is rooted in ICH Q8 quality-by-design principles and allows a range of drug release rates and doses to be advanced to clinical assessment. The research team can therefore conduct a series of “make” and “test” cycles to iteratively explore a range of doses and drug release rates. This method considers using the in vivo product performance in humans alongside the ability to correspondingly support changes in drug product composition to identify the optimal formulation composition to deliver the target profile, and quickly and precisely identify the formulation that is effective while meeting patient needs.
Images credit: author supplied
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References
- “FDA Novel Drug Approvals 2022 — Nearly 60% Small Molecules”, CCDC (2023). Available at: https://bit.ly/3SbsyH2
- DB Tiz et al, “FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis”, Pharmaceutics, 14, 11. (2022) DOI: 10.3390/pharmaceutics14112538
- “Small Molecule Drug Discovery Market Size, Report By 2032”, Precedence Research (2022). Available at: https://bit.ly/3u1Sdtx
