Excipient-mediated supersaturation stabilization in human intestinal fluids.
It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development.
Laboratory for Pharmacotechnology and Biopharmacy, O&N2, Herestraat 49-Box 921, 3000 Leuven, Katholieke Universiteit Leuven, Belgium.
Jan
J
Bevernage
Thomas
T
Forier
Joachim
J
Brouwers
Jan
J
Tack
Pieter
P
Annaert
Patrick
P
Augustijns
D000081:Acetamides / Q000737:chemistry; D000098:Acetophenones / Q000737:chemistry; D000328:Adult; D001826:Body Fluids / Q000737:chemistry*; D003613:Danazol / Q000737:chemistry; D005079:Excipients / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D011345:Fenofibrate / Q000737:chemistry; D006801:Humans; D007422:Intestines / Q000737:chemistry*; D008297:Male; D009570:Nitriles; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry; D011743:Pyrimidines; D019438:Ritonavir / Q000737:chemistry; D012995:Solubility; D055815:Young Adult
D000081:Acetamides; D000098:Acetophenones; D005079:Excipients; D009570:Nitriles; D004364:Pharmaceutical Preparations; D011108:Polymers; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; C080073:loviride; D003613:Danazol; D019438:Ritonavir; D011345:Fenofibrate