Stress-relieving: printing personalized cortisol for patients with adrenal insufficiency.

The treatment goal for patients with adrenal insufficiency (AI) is to mimic physiological cortisol plasma concentrations. The current cortisol replacement therapies are suboptimal due to their drug release profile, fixed-dose character and the inability to cover nocturnal cortisol plasma concentrations. There is a high inter-individual variability in the cortisol need within this patient group, which comes with the unmet need for personalized cortisol formulations. 3D printing is a suitable technology for manufacturing oral dosage forms which allows us to easily adjust the drug dose and release profile based on patient needs. The aim of this research is to develop novel tailor-made 3D printed hydrocortisone formulations covering the daily as well as nocturnal physiological cortisol plasma concentrations.


Two sustained release (SR) formulations were printed using hydroxypropylcellulose based polymeric matrix filaments prepared by hot-melt extrusion. Formulation 1 (F1) and 2 (F2) were loaded with 20% and 30% hydrocortisone respectively. Tablets were printed with a height of 1 mm, 2 mm and 3 mm in order to assess the relationship between tablet height and drug dose. A dissolution study was performed to compare drug release profiles of the printlets with the release profile of the commercially available Plenadren©.
Dissolution study data demonstrates that 3D printed SR formulations have a similar drug release profile compared to the Plenadren© 5 mg tablets (Fig. 1). Tablet height was correlated to tablet dose (R2 0.996).

In this work we have demonstrated that hydrocortisone formulations can be printed in any desired dose by adjusting the tablet height. Furthermore, the novel 3D printed formulations have a similar sustained drug release profile compared to the commercial Plenadren© formulation. 3D printed SR formulations provide more dose flexibility compared to fixed-dose commercial formulations while maintaining the same drug release profile. The high inter individual difference in the cortisol need can be addressed by printing the desired dose for the unique patient which is essential in the treatment of patients with AI.

A presentation by Sejad Ayyoubi, PhD candidate at Erasmus University Medical Center.

Interview

Question 1: What drives you?
3D printing is an amazing, versatile technology which can be used to print tailor made medicines based on specific patients’ needs. Many concepts have been shown and it is now the right time to move forward and really bring 3D printed medicines to the patients to improve their pharmacotherapy, quality of life and to achieve better health outcomes. What gives me a lot of energy is the fact that we at the Erasmus Medical Center are working together with patient associations, reimbursement organizations, health care professionals and GMP production specialists to research the first FDM-based product in our knowledge in a clinical study which is planned in Q4 2022.

Question 2: Why should the delegate attend your presentation?
As mentioned before, 3D printed products have been researched extensively in a non-clinical setting, and in some cases with products that have no urgent unmet need. In my presentation
I will guide the attendees through our journey starting from the unmet medical need, to product development and ending with some remarks on our planned clinical study. My goal is to translate the pharmaceutical 3D printing concept from an abstract topic to a realistic clinical setting, showing the true added value of this technology.

Question 3: What emerging technologies / trends do you see as having the greatest potential in the short and long run?
There are many 3D printing technologies in the market with their own advantages and disadvantages. I believe in the concept of an API-printer relationship in which a suitable printing technology should be selected based on API characteristics and the intended clinical purpose. There are two examples I can share; (1) melt-based technologies are for instance not suitable for thermo-labile APIs and (2) multi-nozzle printers enable us to integrate multiple active pharmaceutical ingredients into one dosage form. More research is needed to elucidate which of the many available printing techniques are suitable for a hospital or community pharmacy.

Question 4: What kind of impact do you expect them to have?
3D printing can have a huge impact in two patient groups specifically, patients with rare (metabolic) diseases and pediatric patients. Pediatric patients need drugs with low and adjustable doses rather than drugs with discrete doses, which are typically developed for adults, in order to be able to adjust to rapid changes in their physiological and metabolic functions. 3D printing technology allows pharmacists to tailor the medication based on the specific needs of pediatric patients. Furthermore, the unmet need within the heterogeneous group of patients with rare diseases is very high due to several reasons. For instance, the desired drug plasma concentration in patients with rare metabolic disorder can be very complex and are not always adequately addressed with existing treatment strategies. We are developing novel 3D printed products for patients with adrenal insufficiency with drug release profiles which better fit the desired drug plasma concentrations, improving their quality of life and health outcomes.

Question 5: What are the barriers that might stand in the way?
I am very enthusiastic and think that the existing barriers can be managed well. More research in the suitability of printing techniques in hospital pharmacies or compounding pharmacies are needed and ongoing. Reimbursement will follow when clinical evidence shows that 3D printed drugs are safer and more effective compared to standard of care treatments. Some might say that there are regulatory challenges that might be a barrier for this innovation to reach the patient. I think that within the existing regulatory framework, at least in the Netherlands, there is plenty of room to bring this innovation to the patient as magistral formulations. The main benefit of 3D printing is the customization of existing APIs for a specific patient, registration is therefore not particularly needed. The greatest barrier may be the development of GMP proof equipment to facilitate the implementation of this technology into hospital pharmacies. At the Erasmus Medical Center we are working with all the relevant stakeholders to ensure the successful implementation of this technology for the benefit of the patients.

About Sejad Ayyoubi
Sejad Ayyoubi is a pharmacist by training. He became familiar with 3D printing during his research project at the Complutense University of Madrid. After obtaining his master’s degree in early 2020 he started working as a production pharmacist at Apotheek Haagse Ziekenhuizen. Around the same time, due to his fascination on 3D printing, Sejad started looking for an unmet medical need which could not be solved using conventional production techniques. Shortly after, he set-up a research project regarding the 3D printing of hydrocortisone for patients with adrenal insufficiency. A PhD position at the Erasmus university Medical Center followed in 2021.

About Erasmus University Medical Center
We are Erasmus MC. Every day our staff, volunteers, and students work with dedication and commitment and are passionate about everything that we stand for.

We work on
(1) top-clinical care for patients with complex care needs, rare diseases, or acute needs for care and treatment.
(2) distinctive, high-quality education that appeals to ambitious, inquisitive, and talented students and addresses the healthcare issues of tomorrow.
(3) cutting-edge, world class international medical research that helps to understand, predict, treat, and prevent diseases and health conditions.

Like every university medical center, our three core tasks are: patient care, education, and research.

Sejad Ayyoubi is speaker at the 2022 edition of the 3D Pharma Printing Conference, which is part of the 3D Medical Printing Series.

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