Product Development of High-Dose Ambroxol HCl Capsules for an n-of-1 Clinical Trial Involving Dutch Patients with Gaucher Disease Type 3

Hoang Lan Le; Natalja Bouwhuis; Carla E M Hollak; Abraham J Wilhelm; Anne-Loes E Gerards; Yuma A Bijleveld; Eleonora L Swart

doi:10.3390/pharmaceutics17040417

Product Development of High-Dose Ambroxol HCl Capsules for an n-of-1 Clinical Trial Involving Dutch Patients with Gaucher Disease Type 3

Pharmaceutics. 2025 Mar 25;17(4):417. doi: 10.3390/pharmaceutics17040417.

Authors

Hoang Lan Le^{1

2

3}, Natalja Bouwhuis^{1

2

3}, Carla E M Hollak^{2

4}, Abraham J Wilhelm¹, Anne-Loes E Gerards¹, Yuma A Bijleveld¹, Eleonora L Swart¹

Affiliations

¹ Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
² Medicine for Society, Platform at Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
³ Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
⁴ Department of Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Abstract

Background/Objectives: Ambroxol hydrochloride (AMB) is a promising chaperone for treating neurological manifestations in Gaucher disease type 3 (GD3). The Amsterdam University Medical Center planned to conduct an n-of-1 clinical trial using high-dose AMB (25 mg/kg/day). As an adequate commercial AMB formulation is unavailable for this high target dosage, we aimed to develop high-dose AMB capsules and assess the formulated capsule's quality. Methods: AMB API was sourced and tested according to the requirements of the European Pharmacopoeia. Capsule formulations of 75 mg and 200 mg AMB were developed. Drug product specifications were set following international guidelines (ICH Q6A) and the European Pharmacopoeia. Analytical methods were developed and validated, and three validation batches of each capsule strength were produced and analyzed. Results: The contents and the Acceptance Values (AVs) of the initial AMB batches (both strengths) varied between 89.1% to 92.7% (specification: 90% to 110%) and 12.4 to 17.6 (specification ≤ 15.0), respectively, indicating non-uniform AMB distribution. Consequently, the production of 200 mg capsules was discontinued, and modifications were made to the 75 mg capsule formulation, followed by the production of three optimized 75 mg validation batches. These batches met the specified criteria, with an AMB content and AV values ranging from 93.9% to 96.5% and 12.4 to 14.9, respectively. Furthermore, rapid dissolution profiles were observed (>80% dissolution within 15 min). No degradation products or microbiological impurities were detected after production. Conclusions: The optimized formulation of 75 mg AMB capsules formulated within the hospital pharmacy setting resulted in qualitative and uniform capsules which can be used in clinical trials.

Keywords: Gaucher disease; active pharmaceutical ingredient (API); ambroxol hydrochloride; drug product specification; good manufacturing practices (GMPs); n-of-1 clinical trial; pharmaceutical quality; product development; product validation; rare diseases.