Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties

J Pharm Sci. 2004 Sep;93(9):2214-21. doi: 10.1002/jps.20127.


R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Animals
  • Biopharmaceutics
  • Capsules
  • Chemical Phenomena
  • Chemistry, Pharmaceutical
  • Chemistry, Physical
  • Cross-Over Studies
  • Drug Evaluation, Preclinical / methods
  • Female
  • Gelatin / administration & dosage
  • Gelatin / blood*
  • Gelatin / chemistry
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / blood*
  • Muscarinic Antagonists / chemistry
  • Pharmaceutical Solutions / administration & dosage
  • Pharmaceutical Solutions / chemistry
  • Pharmaceutical Solutions / pharmacokinetics*
  • Swine
  • Swine, Miniature
  • Vitamin E / administration & dosage
  • Vitamin E / blood
  • Vitamin E / chemistry


  • Capsules
  • Muscarinic Antagonists
  • Pharmaceutical Solutions
  • Vitamin E
  • Gelatin