Overcoming Challenges in Transdermal Formulations: How AI Improves Patient Experience

The transdermal (TD) route of administration is a promising method for drug delivery for several reasons. It can provide a sustained and controlled dose over prolonged periods, enable treatment efficacy directly at the site of administration, avoid gastrointestinal drug degradation and first-pass liver metabolism before reaching the site of action, and is non-invasive and painless, leading to better patient compliance. However, there are several challenges associated with TD drug delivery. These challenges include the fact that only small molecules (~< 500 Da) can effectively penetrate the stratum corneum and slow permeation of drug through the stratum corneum. In order to address these challenges, chemical permeation enhancers are typically added to transdermal formulations. However, these permeation enhancers can cause skin irritation. In view of this, the challenge is to develop formulations that provide improved drug delivery without the need for harsh permeation enhancers. The development of such desirable formulations is very challenging as it involves a complex interplay of API and excipient interactions with each other and with the stratum corneum and the underlying skin layers. For example, physicochemical properties such as solubility of the API in the formulation phase, API and excipient partitioning in to the stratum corneum, and the diffusivities of the API and excipients through the stratum corneum must be adequately accounted for in addition to physiological properties of drug disposition in the body to enable an informed formulation development program.

VeriSIM Life’s BIOiSIM^® platform can address the challenges of TD formulation development because its hybrid AI models capture the complex interplay between the API, excipients, and physiology. BIOiSIM uses a unique combination of mathematical and AI-driven techniques to analyze and predict a drug’s behavior in the human body. The platform's models provide deep insight into drug distribution in various skin layers and underlying tissues, such as joint synovial membranes, and capture a drug’s systemic exposure and clearance post-transdermal application.

In figures below, we compare anticipated drug exposure at the knee joint synovial membrane and in the plasma for three different transdermal formulations of diclofenac. Clearly, much higher local concentrations at the synovial membrane than systemic are afforded by transdermal formulations. Of course, the type of formulation can have a substantial impact on the time duration of the beneficial effects of the drug. For example, formulation 1 rapidly delivers a high concentration of API and almost twice the maximum local concentration at the site of action (synovial membrane), but its effect is not sustained over time.

In addition to determining the likely drug distribution and exposure both locally and systemically, BIOiSIM also incorporates hybrid AI models for predicting target engagement/efficacy, local and systemic/organ toxicity, and skin irritation potential for both the API and the excipients. These different models predict multiple outcomes that are combined and summarized to form a multimetric Translational Index™, which quantifies the overall likelihood of a formulation’s success. Of the three formulations below, the Translational Index score for treating inflammation at the synovial membrane was the highest for formulation 3, followed closely by formulation 2. However, the Translational Index score of formulation 1 was substantially lower, mainly due to the corresponding rapid decay of diclofenac at the site of action. The Translational Index scores for the three formulations are shown in Table 1 below.

Fig 1: Diclofenac concentration at synovial membrane for 3 different formulations as a function of time post transdermal drug application.

Fig 2: Diclofenac concentration in the plasma for three different formulations post transdermal application.

Fig 3: Translational Index multimetric components example.

Table 1: Translational Index scores for the three formulations. These scores balance drug disposition, efficacy, off- and on-target toxicity concerns for the formulations.

Using BIOiSIM’s platform, drug developers can quantify local and systemic drug exposure post application for different transdermal formulations. And with the Translational Index score for each formulation, developers can quantify the formulation’s likelihood of success in overall treatment/disease management. Such quantification is critical in assessing the suitability of a given formulation intended to engage with local targets without compromising patient safety. By harnessing these insights early in the drug development process, researchers can advance programs into in vivo experimental confirmation, regulatory evaluation, and first-in-human dosing clinical trials with confidence, while greatly improving the overall patient experience, and Phase 2/3 trial success potential.