Several studies have investigated the effectiveness of high-dose ambroxol in treating patients with Gaucher disease type 3. Since there are no registered high-dose ambroxol preparations available, information on the development of this preparation can be important to improve access. The pharmacy and clinical pharmacology department of Amsterdam University Medical Center has developed a simple 75 mg ambroxol hydrochloride (HCl) capsule formulation for this purpose. The aim of this study was to investigate the stability of 75 mg ambroxol capsules. Three batches (n=1000) of 75 mg ambroxol HCl capsules were produced and stored in climate chambers for 6 months under accelerated (40±2°C and 75% relative humidity (RH)±5% RH) and long-term (25±2°C and 60% RH±5% RH) conditions. At 0, 3 and 6 months, appearance, identity, related substances, assay, uniformity of dosage units (content uniformity (CU)), dissolution and microbiology were evaluated. The specifications and acceptance criteria were derived from the European Pharmacopoeia and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. All parameters met the predefined specifications from t=0 to t=6 months for both the accelerated and long-term stability studies. There were no visible changes in appearance of the capsule content, no degradation products above 0.05%, and no decrease in ambroxol content. Furthermore, the capsules met the criteria for CU with an acceptance value ≤15.0. The dissolution was rapid, with ≥80% of ambroxol released from the capsules within 30 min, and no microbiological growth was observed. The 75 mg ambroxol HCl capsules are stable for at least 6 months at room temperature. This paper provides guidance to pharmacies for compounding of high-dose ambroxol HCl capsules to ensure the availability of ambroxol for patients in need.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder resulting from pathogenic variants in the GBA1 gene, which encodes the enzyme glucocerebrosidase. We describe a child with neuropathic GD (type 3) associated with an uncommon GBA1 variant, p.Ser276Phe. A four-year-old girl, born to non-consanguineous parents, presented with gradually progressive neurological symptoms accompanied by systemic involvement. Examination revealed marked splenomegaly. Bone marrow biopsy demonstrated extensive infiltration by macrophages with characteristic wrinkled, fibrillary cytoplasm, partially replacing the marrow spaces, raising suspicion of GD. Antiepileptic therapy with levetiracetam resulted in partial improvement of neurological manifestations. Whole-exome sequencing identified a homozygous missense variant in exon 7 of the GBA1 gene, leading to the substitution of phenylalanine for serine at codon 276, within the PF07714 protein kinase domain. On follow-up at six months, the child continued to exhibit myoclonic jerks, progressive ataxia, and cognitive decline, consistent with a neuropathic disease course. While p.Leu483Pro is the most frequently reported mutation in the Indian population and is often associated with severe neurological disease in homozygous individuals, the p.Ser276Phe variant has been documented only rarely in the literature. This case highlights an uncommon GBA1 mutation and further illustrates the wide phenotypic variability and unpredictable clinical expression seen in neuropathic GD.

Gaucher disease (GD) is a lysosomal disease caused by mutations in the GBA1 gene, leading to glucosylceramide and glucosylsphingosine accumulation. GBA1 mutations are also the most common genetic risk factor for Parkinson's disease (PD). Increased expression of glycoprotein non-metastatic melanoma protein B (gpNMB), a potential biomarker of inflammation and neurodegeneration, has been reported in PD, GD and other LSDs. Plasma concentrations of gpNMB are correlated with the accumulation of bioactive lipid substrates in several chronic inflammatory diseases and gpNMB stimulates lipogenesis in white adipocytes. To explore its potential significance in GD we measured plasma gpNMB in patients with Gaucher Disease type 1 (GD1), Gaucher Disease Type 3 (GD3), GD1-PD, PD and GBA heterozygous PD and in different clinicopathological subtypes. The study enrolled participants the GAUCHERITE Cohort in the UK (172 GD1 and 20 GD3 patients) and the Biopark Cohort (72 IPD patients) in Sweden. Plasma concentrations of gpNMB were significantly higher in patients with Gaucher disease (mean: 200.9; range: 9.8-1643 ng/ml) compared with healthy controls (mean: 35.1; range.: 10.1- 125 ng/ml), including those receiving enzyme replacement therapy (ERT). Notably, gpNMB concentrations remained elevated in GD1 patients who had received ERT for more than 5 years. The biomarker was particularly elevated in patients who had been splenectomized, those with known pulmonary or liver disease, and those with monoclonal gammopathy, despite enzyme therapy. No statistical difference was found in plasma gpNMB concentrations between treated patients with GD1 and GD3. On average, there was no difference in plasma gpNMB concentrations between Gaucher patients with or without Pakinsonism. As expected however plasma gpNMB concentrations among patients with Parkinsonism were higher in those with type 1 Gaucher disease than either GBA1 heterozygotes or those with idiopathic PD (p=0.0001). Our findings indicate that the association of plasma gpNMB with liver cirrhosis, gammopathy and pulmonary disease in Gaucher disease warrants further investigation. Additionally, plasma gpNMB may serve as a supportive biomarker in the evaluation and clinical monitoring of residual disease activity. However, plasma gpNMB neither differentiated between the neuronopathic subtypes of Gaucher disease nor idiopathic Parkinson's disease.