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

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.

Figure 1

Scatter plots illustrating ambroxol hydrochloride (AMB) content distribution of the selected capsule samples across validation batches: (a) initial capsules of 75 mg AMB; (b) initial capsules of 200 mg AMB; (c) optimized capsules of 75 mg AMB. The black lines indicate the mean of the AMB content per batch, the horizontal dashed line represents the target content for the produced capsules, and the dashed-and-dotted lines together with the grey area represent the acceptable range for mean capsule content.

Figure 2

Dissolution profiles of the initial product validation of 75 mg and 200 mg AMB.

Figure 3

Scatter plots illustrating the content distribution of the initial product validation and after 3 months of storage of (a) 75 mg AMB capsules in the same bottle analyzed by two laboratory technicians; (b) 200 mg AMB capsules reanalyzed by another laboratory technician. The black lines indicate the mean of 10 capsules, the horizontal dashed line represents the target concentration, and the dashed-and-dotted lines together with the grey area represent the acceptable range for mean capsule content. t = 0: Analysis during the initial product validation. t = 3: Analysis after 3 months of storage. L1: Laboratory technician 1. L2: Laboratory technician 2.