Development of level A, B and C in vitro-in vivo correlations for modified-release levosimendan capsules

Int J Pharm. 2002 Jul 8;241(1):87-95. doi: 10.1016/s0378-5173(02)00137-0.

Abstract

The aim of this study was to investigate the possibility of developing different levels of correlation between in vitro release and in vivo absorption rate for four modified-release levosimendan capsule formulations. Differences and similarities in the in vitro dissolution curves were compared with pharmacokinetic parameters describing absorption rate. Formulations F, G, H and I differed in the amounts of the delaying excipients alginic acid and HPMC. In vitro release rate was studied by the USP basket method using the following conditions: pH 5.8 or 7.4 and a rotation speed of 50 or 100 rpm. In vivo bioavailability was tested in nine healthy male volunteers and the fractions absorbed were calculated by the Wagner-Nelson method. Dissolution conditions pH 5.8 and a rotation speed of 100 rpm predicted best the similarities and differences in absorption rates among different formulations, and levels C and B correlation coefficients were 0.85 and 0.97, respectively. For formulation H level A correlation (r=0.997) was found when in vitro lag time was 0.2 h and time scale factor 1.9. This study indicated that dissolution tests developed can be used as a surrogate for human bioequivalence studies, for development processes of final commercial products, to ensure batch to batch bioequivalence and in the future in possible scale-up and post approval change cases for modified-release levosimendan formulation H.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • Anti-Arrhythmia Agents / administration & dosage*
  • Anti-Arrhythmia Agents / chemistry
  • Anti-Arrhythmia Agents / pharmacokinetics*
  • Biological Availability
  • Capsules
  • Chromatography, High Pressure Liquid
  • Delayed-Action Preparations
  • Excipients
  • Female
  • Gelatin
  • Humans
  • Hydrazones / administration & dosage*
  • Hydrazones / chemistry
  • Hydrazones / pharmacokinetics*
  • Hydrogen-Ion Concentration
  • Male
  • Models, Biological
  • Pyridazines / administration & dosage*
  • Pyridazines / chemistry
  • Pyridazines / pharmacokinetics*
  • Simendan
  • Solubility
  • Spectrophotometry, Ultraviolet
  • Therapeutic Equivalency

Substances

  • Anti-Arrhythmia Agents
  • Capsules
  • Delayed-Action Preparations
  • Excipients
  • Hydrazones
  • Pyridazines
  • Simendan
  • Gelatin