What are DTx Digital Excipients?
What do Digital Therapeutics (DTx) consist of? Digital Active Ingredients and Digital Excipients.
What are Active Ingredients and Excipients?
Few people have used these terms – of clear pharmaceutical origin – in the discussion on DTx. However, medicines – whether they are based on chemical or biological molecules or on software and algorithms – always need active ingredients and excipients.
In molecule-based medicines, the active ingredient is the constituent responsible for the biological activity and therefore the clinical effects, both therapeutic and undesirable. Excipients, on the other hand, are inactive components of the medicinal product which have no pharmacological action. Their function is to protect the active ingredient from external agents that could damage it (heat, cold, humidity or other chemicals), to increase its volume to allow the preparation of tablets or any other pharmaceutical form of acceptable size, to make stable solutions or suspensions by avoiding sedimentation of the active ingredient at the bottom of the containers and to facilitate absorption of the active ingredient into the body, to make the taste of medicines more pleasant, etc.
In the United States Pharmacopeia (USP), the legal definition of a “drug” includes the Active Pharmaceutical Ingredient (API) and excipients. APIs are the molecules providing the desired therapeutic effect (or active ingredients), and excipients – considered inactive ingredients – are the other substances intentionally included in the drug product and necessary for the active ingredients to have their intended therapeutic effect (1).
Both these elements are required to get a medicine that is able to provide a therapeutic action and not only pharmacological.
Why should software-based medicines be different?
Digital Active Ingredients
The digital active ingredient is the software component responsible for the therapeutic effect. In the case of Cognitive Behavioural Therapy (CBT) – based Digital Therapeutics, the sequence of activities foreseen by the CBT protocol once translated into software represents the digital active substance, for example.
The best active ingredient could not exert any therapeutic effect if it was not able to interact with the patient, i.e. to become “digitally bioavailable“. The function of making the active ingredient “digitally bioavailable” is that of digital excipients.
These are software with different purposes, which have the ultimate goal of engaging the patient in the therapeutic experience and allowing the patient to adhere to digital therapy for the time necessary to complete the therapy.
Digital Excipients and US Pharmacopeia
In 2018 John B Torous was the first – at least to our knowledge – to use the term “active ingredient” with reference to apps and their effect on patient outcomes. However, it does not refer to “digital excipients” and seems to indicate that the principle is the only component of the app design (2).
Much more detailed is the analysis of the significance of digital active ingredients and digital excipients carried out by USP in The role of public standards in assuring quality of digital therapeutics, issued at 6.2020 (1):
For DTx, we are not aware of an analogous framework considering active ingredients and excipients. Similar to traditional medicines, we propose that DTx also have an “active” code, or a digital Active Pharmaceutical Ingredient (dAPI), and other code that supports the dAPI or digital excipients. Digital excipients would include code that tends to be shared between applications, such as communications
stacks and graphics libraries.
A common practice by the software development industry is to obtain reusable or shared code (digital excipient code) from third parties, who are not always known or easily identifiable (e.g., due to the numerous individual contributors to open source projects). Given their potential to be used in multiple contexts, products, and combinations, and their frequent lack of known or controlled provenance, digital excipients and their use would benefit from quality standards. Ensuring the quality of ingredients is critical to any manufacturing chain, especially one resulting in the
manufacture of therapeutics, whether traditional or digital.
Ultimately, it is the DTx developer’s responsibility—as it is with any credible, trustworthy manufacturer—to assure that any code (ingredient) in the final product, including digital excipients obtained from third parties, meets appropriate
quality requirements before releasing it to patients.
Identifying and establishing critical quality attributes of digital excipients will help DTx developers confirm their integrity as well as the absence of harmful codes to patients.
The concepts of dAPIs and digital excipients establish a foundation for the pharmacopeial approach to standards development. This approach includes the development of documentary standards and appropriate physical reference
standards that provide the framework, guidelines, and best practices for testing the identified quality attributes of compendial articles (1).
We share the US Pharmacopeia position, although the concept of Digital Excipients should be more closely linked to the objective of Digital Bioavailability.
Digital Excipients and daVinci Digital Therapeutics
As a Digital Biotech Company committed to research, develop and delivery evidence-based, prescription Digital Therapeutics as software-based medicines, daVinci Digital Therapeutics approach is the same as that for any medicine, regardless of the technology behind the active ingredient. We research both digital active ingredients and digital excipients (3):
In general, the purpose of the excipient is to shape the active ingredient and promote its intake, making it as bioavailable as possible.
In the case of Digital Therapeutics (DTx), the digital excipients can include the virtual assistant able to communicate in natural language with the patient, modules for patient rewarding, reminders for the assumption of the Digital Therapeutic and complementary therapies, modules to connect the patient with his doctor and other patients and more, with the aim of ensuring the longest possible use of the Digital Therapeutics and thus to ensure maximum digital bioavailability of the active ingredient.
Among the various elements of the excipient, the user interface is fundamental, able to condition the user experience, the acceptability of the therapy, the adherence to the treatment and consequently the therapeutic outcomes.
Although there is no experience in this sense, it is to be expected that the same digital active ingredient may have different therapeutic effects depending on the digital excipients contained in the therapy, which may make it more or less bioavailable to the patient (3).
The Politecnico of Milan Digital Excipients Working Project
The Politecnico of Milan, in collaboration with daVinci Digital Therapeutics, has completed a project to identify, classify and make available to Digital Biotechnology Companies the most appropriate digital excipients in relation to the characteristics of the digital active ingredient and the therapeutic indication of Digital Therapeutic to be developed.
So far several Digital Excipients have been identified in literature, such as:
- Appointment Manager
- Automated Assistant
- Doctor Jump-in
- Health Literacy
- Data Integration
- Media Library
- Progress Tracking
- Social Support
- Social Comparison
grouped according to different categories, such as Community Involvement, Self And Clinical Assessment, Action Planning, Effort And Results Acknowledgment and others.
Results of the project will be presented at the Digital Therapeutics Day 2020, Milan 22 October 2020 and later published.
- M Ambrose et al. The role of public standards in assuring quality of digital therapeutics. US Pharmacopeia, 2020
- JB Torous. Focusing on the Future of Mobile Mental Health and Smartphone Interventions. Psychiatric Services 69:9, 2018
- G Recchia et al. Digital Therapeutics-What they are, what they will be”. Acta Scientific Medical Sciences 4.3: 01-09, 2020