TY - JOUR
T1 - Investigating the effects of amphipathic gastrointestinal compounds on the solution behaviour of salt and free base forms of clofazimine
T2 - An in vitro evaluation
AU - Bannigan, Pauric
AU - Stokes, Killian
AU - Kumar, Ajay
AU - Madden, Conor
AU - Hudson, Sarah P.
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Interactions between hydrophobic drugs and endogenous gastrointestinal substances have the potential to manipulate drug concentration in the human gastrointestinal system, and thus likely play an important role in determining the rate of absorption for hydrophobic drugs. The effects of phospholipids, bile salts and digestive proteins on the solution behaviour of clofazimine in biorelevant media was demonstrated here using dissolution experiments and solid state analytical techniques. Clofazimine is a hydrophobic, anti-mycobacterial agent with virtually no detectable water solubility in its free base form. Salt forms of the drug offer improved aqueous solubility but are unstable in solutions at low pH (pH 1.6) or high pH (pH 6.5). At low pH and high chloride ion concentrations, CFZ in solution experiences a high driving force to crystallize from solution as a hydrochloride salt, which is insoluble, while at high pH CFZ does not dissolve to any extent. In this study, it is demonstrated that amphipathic compounds present in the gastric and intestinal systems can overcome the instability experienced by CFZ at these pH values. This is done by encapsulation of the hydrophobic drug in mixed bile salt phospholipid micelles in both the gastric and intestinal fluid, and by the drug actively binding with the digestive enzyme pepsin in the gastric system. Pepsin binds and solubilises the drug at even relatively low concentration (0.1 mg/mL). When pepsin concentration is increased in the gastric media, a corresponding increase in the solution stability of CFZ is observed.
AB - Interactions between hydrophobic drugs and endogenous gastrointestinal substances have the potential to manipulate drug concentration in the human gastrointestinal system, and thus likely play an important role in determining the rate of absorption for hydrophobic drugs. The effects of phospholipids, bile salts and digestive proteins on the solution behaviour of clofazimine in biorelevant media was demonstrated here using dissolution experiments and solid state analytical techniques. Clofazimine is a hydrophobic, anti-mycobacterial agent with virtually no detectable water solubility in its free base form. Salt forms of the drug offer improved aqueous solubility but are unstable in solutions at low pH (pH 1.6) or high pH (pH 6.5). At low pH and high chloride ion concentrations, CFZ in solution experiences a high driving force to crystallize from solution as a hydrochloride salt, which is insoluble, while at high pH CFZ does not dissolve to any extent. In this study, it is demonstrated that amphipathic compounds present in the gastric and intestinal systems can overcome the instability experienced by CFZ at these pH values. This is done by encapsulation of the hydrophobic drug in mixed bile salt phospholipid micelles in both the gastric and intestinal fluid, and by the drug actively binding with the digestive enzyme pepsin in the gastric system. Pepsin binds and solubilises the drug at even relatively low concentration (0.1 mg/mL). When pepsin concentration is increased in the gastric media, a corresponding increase in the solution stability of CFZ is observed.
KW - Clofazimine
KW - Gastrointestinal solubility
KW - Oral drug delivery
KW - Pharmacokinetics
KW - Poorly water soluble drugs
UR - http://www.scopus.com/inward/record.url?scp=85054192293&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2018.09.012
DO - 10.1016/j.ijpharm.2018.09.012
M3 - Article
C2 - 30236646
AN - SCOPUS:85054192293
SN - 0378-5173
VL - 552
SP - 180
EP - 192
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 1-2
ER -