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      Stability of refrigerated miglustat after preparation in InOrpha ® flavored suspending excipient for compounding of oral solutions and suspensions

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          Abstract

          Background

          Miglustat (Zavesca ®) is an oral treatment for type 1 Gaucher disease and Niemann–Pick disease type C. Patients with Niemann–Pick disease type C often have difficulties swallowing, and miglustat has an unpleasant taste. The stability of miglustat at 2°C–8°C prepared in InOrpha ® suspending vehicle, a liquid taste-masking agent, was assessed.

          Methods

          The contents of Zavesca ® 100 mg capsules (a powder blend comprising miglustat and several excipients) were transferred into InOrpha ®. Although miglustat was soluble in InOrpha ® at all concentrations tested, some of the excipients were not. An InOrpha ® suspension containing 20 mg/mL miglustat was investigated initially. Subsequently, a pH-adjusted suspension of 20 mg/mL, and non-adjusted 10 and 5 mg/mL suspensions were evaluated. All suspensions were stored under refrigerated conditions. Physicochemical and microbiological challenge testing was performed at 0 hours and after 14 and 28 days. Degradation was assessed by high-performance liquid chromatography, appearance was assessed visually, and pH was recorded. Suspensions were inoculated with seven species of bacteria, yeast, and mold, and growth evaluated using membrane filtration.

          Results

          Miglustat 20 mg/mL suspension changed from yellow (0 hours) to brown (days 14 and 28); pH remained stable at 7.4–7.6. Pure InOrpha ® (pH 4.6) remained yellow throughout the study. Pure InOrpha ® adjusted to pH 7.5 displayed a brownish discoloration after 9 days. Miglustat 5 and 20 mg/mL suspensions, adjusted to pH 6.5 and 4.4, respectively, remained yellow at days 14 and 28. Miglustat 10 mg/mL suspension (pH 7.3) changed from yellow to brown on day 9. No degradates were detected for any of the concentrations tested. There was no proliferation of microorganisms over the study period; in all cases the level of contamination was clearly reduced.

          Conclusion

          InOrpha ® suspensions containing miglustat 5 mg/mL (without pH adjustment) and 20 mg/mL (with pH adjusted to 4.4) display stable physicochemical and microbiological properties over 28 days.

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          Most cited references 10

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          Glucosylceramide synthase and glycosphingolipid synthesis.

          In mammalian cells, there are two major classes of sphingolipids---sphingomyelin and glycosphingolipids (GSLs)--both of which are synthesized from the hydrophobic molecule ceramide. The synthesis of most GSLs begins with glucosylation of ceramide to form glucosylceramide (GlcCer), which, in turn, serves as the source of 300-400 GSLs. Although most of these GSLs have been characterized chemically, the biological functions of ceramide glycosylation and GSLs still remain enigmatic. The recent description of a GSL-deficient cell line and isolation of cDNA for GlcCer synthase provide new insights into GSL functions.
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            New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

            Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®), a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years) and in juveniles and adults (12 years and older), compared with those diagnosed in early childhood (younger than 6 years). Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder.
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              • Article: not found

              New directions in the treatment of Gaucher disease.

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                17 January 2015
                : 9
                : 561-566
                Affiliations
                Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
                Author notes
                Correspondence: Dirk Bandilla, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland, Tel +41 61 565 6004, Email dirk.bandilla@ 123456actelion.com
                Article
                dddt-9-561
                10.2147/DDDT.S74497
                4304488
                © 2015 Riahi et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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