A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs.
The applicability of the semi-fluorinated alkane 1-perfluorohexyloctane (F6H8) as a novel excipient in lipid based drug delivery systems was studied. Solubility studies of 11 poorly water soluble drugs (cinnarizine, danazol, estradiol, fenofibrate, griseofulvin, halofantrine, lidocaine, prednisolone, probucol, rolipram and siramesine) showed significantly lower equilibrium solubility in F6H8 compared to soy bean oil (long chain triglyceride). F6H8 was miscible with medium chain triglycerides (MCT) but not miscible with long chain triglycerides, neither was pure F6H8 nor the mixture F6H8:MCT (1:1) miscible with 7 commonly used surfactants (Cremophor EL, Span 20, Span 80, Labrasol, Softigen 767 and Gelucire 44/14, polysorbate 80). In vitro lipolysis studies confirmed that F6H8 was non-digestible. F6H8:MCT (1:1) showed initially faster lipolysis compared to pure MCT. Thus, final phase lipolysis was lower indicating that F6H8 may affect the lipolysis of MCT. However, in vivo bioavailability studies in rats showed the same plasma concentration-time profiles when dosing 10mg/kg halofantrine at two dose levels of F6H8, MCT or F6H8:MCT (1:1) (AUC ranged from 3058 to 3447hng/ml, T(max)∼6.0h, C(max) ranged from 168 to 265mg/ml). Generally, the addition of polysorbate 80 shortened the time to reach C(max) (T(max) ranged 1.3-4.5h), but had limited effect on the bioavailability from F6H8 or MCT in combination with polysorbate 80 (4:1) (AUC ranged from 3807 to 4403 (hng/ml)). Although a synergistic effect was obtained with halofantrine in F6H8:MCT:polysorbate 80 (2:2:1) (AUC 5574±675hng/ml; mean±SEM), it was not superior to dosing halofantrine in pure polysorbarte 80 (AUC 7370±579hng/ml; mean±SEM). The applicability of F6H8 as an excipient for future use in lipid based formulations for poorly water soluble drugs is therefore considered to be very limited.
Preformulation, H.Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. rhol@lundbeck.com
René
R
Holm
Erling Bonne
EB
Jørgensen
Michael
M
Harborg
Rune
R
Larsen
Per
P
Holm
Anette
A
Müllertz
Jette
J
Jacobsen
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005079:Excipients / Q000737:chemistry*; D005466:Fluorocarbons / Q000737:chemistry*; D008066:Lipolysis; D008297:Male; D004364:Pharmaceutical Preparations / Q000097:blood / Q000737:chemistry; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents; D014280:Triglycerides / Q000737:chemistry
D005079:Excipients; D005466:Fluorocarbons; D004364:Pharmaceutical Preparations; D010616:Phenanthrenes; D013501:Surface-Active Agents; D014280:Triglycerides; C118616:perfluorohexyl-octan; C023768:halofantrine