Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib by Solid
Lipid Dispersions
Yajun Liu1, Gino M. Salituro2, Keun-joong Lee2, Annette Bak1, Dennis Leung1*
1. Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New
Jersey, USA, 07065; 2. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck &
Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, USA, 07065
* Corresponding author: Email address: dennis_leung@merck.com
Tel.: 1-732-594-6982
Supplemental Information
1. Screening stabilizers for producing solid lipid nanoparticles (SLNs) via acoustic milling
Around 2 mg of solid lipid microparticles (SLMs) was weighed and added to each well of 96 well
plate together with 800 mg of zirconia YTZTM milling beads (500 µm, Tosoh Corp., Tokyo, Japan). 146
µL of five surfactant solutions (Pluronic F127, Pluronic F68, Cremophor EL, Tween 80 and Tween 20)
was added to each well at the concentration of giving ratio of SLMs/surfactant at 1: 0.25, 1: 0.5, 1:1, and
1:2 (w/w), respectively. The well plate was thermally sealed and then placed on LabRAM mixer
(Resodyn Acoustic Mixers, Inc., Butte, MT, USA) and agitated at 40% of intensity for 1 hour. At the end
of the experiment, 5 µL of slurry was withdrawn and diluted with 35 µl of water, which was subject to
particle size analysis by dynamic light scattering (DynaPro Plate Reader, Wyatt Technology Corp., Santa
Barbara, CA, USA).
600
1: 0.25
1:0.5
1:1
1:2
Particle size (nm)
500
400
300
200
100
0
27
c F1
oni
Plur
n ic
o
Plur
F68
r EL
n 80
n 20
pho
wee
w ee
o
T
T
m
Cre
Figure S1. Effect of surfactant type and ratio of particles to surfactant (w/w) on the particle size of SLNs
produced from acoustic milling.
2. Particle size analysis of SLMs dissolution medium
The study was conducted using dissolution testing apparatus (Distek Model 2100c, Distek, Inc.,
North Brunswick, NJ, USA) at 37 °C. Around 12 mg of torcetrapib-loaded SLMs precipitated at 45°C
was added to 50 mL of phosphate buffer (25mM, pH 6.8) containing 0.17% of sodium dodecyl sulfate
(SDS). The dissolution medium was stirred with a paddle at 50 rpm. After 1h, 3h, 6 h and 24 h, 80 µl of
dissolution medium was withdrawn and analyzed for particle size using dynamic light scattering.
700
600
Particle Size (nm)
500
400
300
200
100
0
1
3
6
24
Dissolution time (h)
Figure S2. Particle size kinetics of dissolution medium containing torcetrapib-loaded SLMs at 37 °C
3. Particle size analysis of torcetrapib-polymer dispersion
The particle size of the spray dried amorphous solid dispersion of torcetrapib was
measured by laser diffraction (SYMPATEC, Sympatec Inc., Pennington, NJ, USA). The
instrument is equipped with a dispensing unit RODOS/M, a vibratory feeder VIBRI, and a laser
diffraction sensor HELOS. Dry powders were measured directly with a dispersing pressure of
1.0 bar and a laser measuring range of 0.5 µm to 350 µm. A D50 particle size of 19.13 microns
for the solid material was determined.