AAPS 2014 Design of an ElectroNanospray

Design of an ElectroNanospray™ Formulation of Itraconazole
to Improve Dissolution in Fasted State Simulated Intestinal Fluid (FaSSIF)
T3117
Mourad F. Rahi, Huijing Fu, Andrew J. Goode, Doua Thao, James E. Lasch, Robert A. Hoerr
Nanocopoeia Inc. 1246 University Ave W, Saint Paul, MN 55104
Results
Purpose and Approach
Itraconazole (ITZ) is a BCS-Class II antifungal agent with extremely low solubility. Formulation
efforts to address this commonly report that test formulations show enhanced ITZ solubility in
acidic media, but precipitate rapidly in neutral media.[1] Our primary objective was to identify a
formulation that would sustain ITZ solubility in FaSSIF at pH 6.5, using a novel cone-jet mode
electrospray process, ElectroNanospray™ (ENS), which can produce amorphous, submicron
particles of drug and excipient. To determine how ENS-processing would affect ITZ
formulations made with common solubility-enhancing excipients, we selected a range of
materials representing anionic, cationic and neutral classes . These included Kollidon K30,
Gelucire 44/14, Eudragit E100- and Eudragit L100-55, d-alpha tocopheryl polyethylene glycol
1000 succinate (TPGS), sodium dodecyl sulfate (SDS), olive oil and poloxamer 188. Physical
mixtures were prepared as controls. We characterized the physical properties of test
formulations and tested their dissolution in FaSSIF at pH 6.5.
Particle size in powders generated by cone-jet mode electrospray process is controlled by the
properties of the spray solution and critical machine operation parameters. Our D-series
nozzles spray from a liquid sheet instead of a liquid filament like capillary electrospray nozzles;
however, the particle size and size distribution produced by these two different nozzle types are
similar. SEM images show spherical- and rod-like submicron particles in various sizes.
DSC thermograms of ENS-processed ITZ : PVP : Gelucire formulations (1:1:1, 1:2:1, 1:4:1)
compared to physical mixes. The percent crystallinity decreased as PVP increased.
1 1
1 1
c
Multi-jet High Throughput Electrospray
1:1:4
ITZ : Gel : PVP-K30
1 1
1:1:4:1
ITZ : Gel : PVP-K30 : TPGS
1 1
1 1
1 1
1 1
1:1:4:0.25
ITZ : Gel : PVP-K30 : SDS
1 1
1 1
1 1
A 24-jet per nozzle, 8-nozzle ENS system (Nanocopoeia, Inc., St. Paul, MN) was used to
generate multiple dry powder nanoformulations of ITZ, in combination with 1 or more excipients.
Spray solutions with dissolved ITZ and excipients were fed to the multi-jet nozzle array using a
constant feed syringe pump and sprayed with high voltage at ambient temperature. Powder was
collected on a stainless steel plate located beneath the nozzle array. Samples for imaging were
collected on small stainless steel coupons placed in various locations on the collector plate.
Powder was gently scraped off the plate and stored in dessicant until further use.
DSC thermograms of ENS-processed ITZ : Eudragit L100-55 and ITZ : Eudragit E100
compared with physical mixtures. ITZ was entirely amorphous for all formulation ratios with
Eudragit L100-55 indicated by the absence of the melting endotherm for crystalline ITZ at
~169°C which is detected in the physical mixtures of crystalline ITZ. However, ITZ
formulation with Eudragit E100 required 1:4 ratio for complete conversion of crystalline to
amorphous. The conversion was progressive as the ratio was increased from 1:1, 1:2 and 1:4.
1 1
ITZ: Eudragit L100-55
1:1:4:0.5
ITZ : Gel : PVP-K30 : olive oil
1 1
1 1
1 1
1:1:4 :1
ITZ : Gel : PVP-K30 : poloxamer
1 1
1 1
1 1
1 1
ITZ: Eudragit E100
1:4
ITZ : PVP-K30
1:2 ITZ : Eudragit L100-55
1 1
1:2 ITZ : Eudragit E100
13C-NMR
1% PVP-K30
Description
F1-% w/w
F2 -% w/w
F3 -% w/w
1
ITZ:Gelucire 44/14
1:1
--
-
2
ITZ:PVP K30
1:1
1:2
1:4
1:1:1
1:2:1
1:4:1
3
ITZ:PVP K30:Gelucire 44/14
4
ITZ:PVP K30:Gel 44/14:TPGS
1:4:1:1
5
ITZ:PVP K30:Gel 44/14:SDS
1:4:1:0.25
6
ITZ:PVP K30:Gel 44/14:Olive oil
1:4:1:0.5
7
ITZ:PVP K30:Gel 44/14:Poloxamer 188
1:4:1:1
X-ray powder diffraction. Spectra are
shown for ITZ raw powder, as received,
ENS-processed ITZ : Eudragit E100 and
ITZ : Eudragit L100-55 powders paired with
their physical mixture controls. ENSprocessed formulations for both Eudragit
versions were largely amorphous, while the
PM were crystalline. Only L100-55 can form
hydrogen bonds with ITZ.
1 1
1 1
8
ITZ:Eudragit L100-55
1:1
1:2
1:4
9
ITZ:Eudragit E100
1:1
1:2
1:4
ENS-sprayed ITZ
FormulaProcess
ITZ1:1PVP1:1Gel
1:4:1- 1:4:1- 1:4:1- 1:4:1ENS ENS ENS ENS
660x 1320x
ITZ1:1Eudragit L100-55
FormulaProcess
1:1:1- 1:2:1- 1:4:1ENS ENS ENS
FormulaProcess
1:1PM
1:1ENS
1:1ENS
xES
250x
250x
250x
xES
82x
82x
125x
TSC (µg/mL)
20
20
20
TSC (µg/mL)
6.6
6.6
10
Tmax (min)
5
5
5
Tmax (min)
240
60
120
0.32
0.94
3.5
Cmax (µg/mL) 0.092
2.9
4.6
43
34
224
AUC
790
1241
xES
66x
250x
TSC (µg/mL)
5.3
20
53
106
Tmax (min)
30
20
20
5
Cmax (µg/mL)
1.6
4.2
4.5
3.6
Cmax (µg/mL)
AUC
297
186
178
134
AUC
19
• ENS yields flowable powder with 800-1200 nm particles, even with waxy or oily
secondary excipients such as Gelucire 44/14 and olive oil.
• DSC thermograms and XRPD show that ENS-processed formulations made
with Eudragit L100-55 formed amorphous particles at all ratios studied, but
this occurred with PVP and Eudragit E100 only at higher polymer:drug ratios.
• ENS-processed 1:1 ITZ : Eudragit L100-55 provided the most favorable
results in this set of experiments, providing high ITZ concentrations that
were sustained for 5h and AUC that were 40- to 60-fold greater than the
physical mixture. Hydrogen bonding may help stabilize supersaturated ITZ
drug at intestinal pH levels. In contrast,1:2 ITZ : Eudragit L100-55 prepared
by heat melt extrusion was reported to precipitate at neutral pH[1]. The
comparative impact of ENS or HME processing on formulation performance
differences such as these merits further investigation.
• Multi-jet ENS provides a new processing alternative for improving the dissolution
performance of poorly soluble drugs for intestinal delivery.
1 1
1 1
Spray solutions for ENS-processing were prepared in a blend of ethanol and acetone (3:2 v/v)
at different percent solids (w/v). ITZ was first dissolved in dichloromethane, then added to the
solution mix. Compositions prepared for these studies are summarized below.
ITZ1:1PVP1:1Gel
Conclusions
1 1
Cone-jet mode electrospray plumes
from D-24 nozzle (below)
Formulation#
Dissolution profiles in FaSSIF (pH 6.5). Test doses were set as multiples of the equilibrium
solubility (xES) of ITZ in FaSSIF, which is 80 ng/mL at 37ºC. Data for E100 formulations are not
reported; they flocculated in neutral media, trapping ITZ in the precipitate.
ITZ and Eudragit L100-55
hydrogen bonding. ENSprocessed ITZ combined with
Eudragit L100-55 had a pale
bluish color, while the powder
with E100 was white. Color
shifts can accompany
hydrogen bonding. These
13C-NMR and FTIR spectra
are consistent with H-bonding
for the ITZ in combination with
L-100-55 but not with E100.
.
FTIR
References
[1] Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO 3rd. 2008. Targeted Intestinal Delivery
of Supersaturated Itraconazole for Improved Oral Absorption, Pharm Research. 25:1450-1459.
Acknowledgements
Collaborators J. Warner and G. Haugstad at University of Minnesota Characterization Facility (CharFac)
assisted with method development. XRPD was performed at CharFac, which receives partial support from
NSF through the MRSEC program. J. Wyman and B. Koelman at Nanocopoeia produced ENS samples.