Enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case study.
Amorphous solid dispersions (ASD) of a poorly soluble water-soluble VR1 antagonist (AMG 517) were explored for improving physical stability and in vivo exposure. AMG 517 was incorporated at 15 or 50 wt % into polymeric microparticles of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC) by spray-drying. Solid particles having a collapsed, corrugated structure were observed by SEM. Median particle size ranged from 29 to 40 microm by laser light scattering, and residual solvent levels were below 2% by thermal gravimetric analysis. ASD powders exhibited single glass transition temperatures (Tg) in the range of 98-117 degrees C by modulated DSC and were amorphous by XRPD. Amorphous stability, characterized at 40 degrees C/75% RH (open dish) by XRPD, was at least six months for ASD formulations. Drug dissolution and supersaturation testing in a USP-2 apparatus indicated superior performance of ASD formulations over micronized AMG 517. PK of an ASD formulation in capsule (15 wt % AMG 517 in HPMCAS blended with 5 wt % SDS) in cynomolgus monkeys (n = 6, crossover) increased AUC 163% and Cmax 145% in comparison to an OraPlus suspension control. The study demonstrates the ASD approach provides improved amorphous physical stability and oral bioavailability for a poorly soluble development-stage molecule.
Kennedy
Michael
M
Small Molecule Process & Product Development, Amgen Inc., Thousand Oaks, California 91320, USA. kennedy@amgen.com
Hu
Jack
J
Gao
Ping
P
Li
Lan
L
Ali-Reynolds
Alana
A
Chal
Ben
B
Gupta
Vicki
V
Ma
Chandra
C
Mahajan
Nidhi
N
Akrami
Anna
A
Surapaneni
Sekhar
S
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002021:Buffers; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D008970:Molecular Weight; D010710:Phosphates / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D012995:Solubility; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D044366:Transition Temperature; D014867:Water / Q000737:chemistry
D052160:Benzothiazoles; D002021:Buffers; D002214:Capsules; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D010710:Phosphates; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014867:Water