Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties.
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.
Department of Pharmaceutics, Roche Palo Alto, Palo Alto, California 94304, USA. karen.olocco@roche.com
Karen
K
Ramsay-Olocco
Ludmila
L
Alexandrova
Ranjani
R
Nellore
Robert
R
Killion
Li
L
Li
Patricia
P
Coen
Quynh
Q
Ho
Donald
D
Jung
Cynthia
C
Rocha
D000328:Adult; D000818:Animals; D001702:Biopharmaceutics; D002214:Capsules; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D018592:Cross-Over Studies; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005780:Gelatin / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D019999:Pharmaceutical Solutions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013552:Swine; D013556:Swine, Miniature; D014810:Vitamin E / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry
D002214:Capsules; D018727:Muscarinic Antagonists; D019999:Pharmaceutical Solutions; D014810:Vitamin E; D005780:Gelatin