Preformulation characterization and in vivo absorption in beagle dogs of JFD, a novel anti-obesity drug for oral delivery.
JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2-10 μm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK(a) (7.49 ± 0.01), log P (5.10 ± 0.02) and intrinsic solubility (S0) (1.75 μg/ml) at 37 °C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T(max), C(max), AUC(0-t) and absolute bioavailability were 1.60 ± 0.81 h, 0.78 ± 0.47 μg/ml, 3.77 ± 1.85 μg·h/ml and 52.30 ± 19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD.
Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology , Beijing , China .
Yunzhou
Y
Fan
Meiyan
M
Yang
Yuli
Y
Wang
Yanyou
Y
Li
Yuanda
Y
Zhou
Xiaoping
X
Chen
Li
L
Shan
Jun
J
Wei
Chunsheng
C
Gao
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D003503:Cyclobutanes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D016503:Drug Delivery Systems; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007532:Isoleucine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D010316:Particle Size; D011208:Powders; D012995:Solubility; D017155:Wettability
D019440:Anti-Obesity Agents; D003503:Cyclobutanes; D005079:Excipients; C000605329:N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorophenyl)-2-amylamine; D011208:Powders; D007532:Isoleucine
Absolute bioavailability; chemical compatibility; crystallinity; hygroscopicity; oral delivery; partition coefficient; preformulation; solubility