title: Stability of refrigerated miglustat after preparation in InOrpha(®) flavored suspending excipient for compounding of oral solutions and suspensions.
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.
  
  
  CONCLUSIONS
  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.
authors: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Sofyen
authors: S
authors: Riahi
authors: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Michael
authors: M
authors: Ambühl
authors: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Jürgen
authors: J
authors: Stichler
authors: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Dirk
authors: D
authors: Bandilla
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical; D003080:Cold Temperature; D003116:Color; D004339:Drug Compounding; D004340:Drug Contamination; D004355:Drug Stability; D005079:Excipients / Q000008:administration & dosage / Q000737:chemistry*; D005421:Flavoring Agents / Q000008:administration & dosage / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D019999:Pharmaceutical Solutions; D012034:Refrigeration; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D005079:Excipients; D005421:Flavoring Agents; D019999:Pharmaceutical Solutions; D017485:1-Deoxynojirimycin; C059896:miglustat
keywords: Niemann–Pick disease type C; microbiological challenge; type 1 Gaucher disease
references: Int J Pharm Compd. 2014 Sep-Oct;18(5):427-31
references: 25577893
references: Trends Pharmacol Sci. 2004 Mar;25(3):147-51
references: 15019270
references: Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):955-60
references: 12803929
references: Trends Cell Biol. 1998 May;8(5):198-202
references: 9695839
references: Ther Clin Risk Manag. 2009;5:877-87
references: 19956552
references: Mol Genet Metab. 2012 Jul;106(3):330-44
references: 22572546