Application of PRINT Microparticle and Nanoparticle Technology –
Toward Preparation of Ophthalmic Suspension Formulations with
Improved Tolerability and Efficacy
Benjamin Maynor, Andres Garcia, Janet Tully, and Benjamin Yerxa
Liquidia Technologies, P.O. Box 110085, RTP, NC 27709
Corresponding Author: Benjamin Maynor, ben.maynor@liquidia.com, (919) 328-4354
Abstract
Purpose:
To use PRINT technology, a novel particle engineering approach, to produce micro and nanoparticles of
controlled microstructure and nanostructure that are suitable for the preparation of aqueous ophthalmic
suspension formulations without use of solubilizing excipients (e.g. cremaphor, oils, cyclodextrins).
Platform Capabilites for “Hard to Formulate”
Small Molecules and Biologics
Dissolution Testing of Itraconazole Particles
The dissolution protocol and medium was
optimized in order to ensure maintenance
of sink conditions throughout the course of
dissolution testing. Dissolution medium
consisted of 0.1N HCl, and 0.3% SDS at
pH 1.2, consistent with previously
published work (1). In addition, PVOH was
used as a dispersing agent, which did not
affect solubility at the concentrations
tested.
Based on these data, samples
were tested at 10 µg/mL, a level sufficiently
below the solubility limit of itraconazole.
Methods:
PRINT technology, a novel drug/excipient micromolding approach, was used to produce monodisperse
nonspherical particles of itraconazole, cyclosporine, and tacrolimus. Dissolution characteristics of
itraconazole suspensions were evaluated and compared to bulk and micronized itraconazole using
standard dissolution test methods.
Cyclosporine
Results:
Monodisperse, shape-specific microparticles and nanoparticles were successfully prepared of
cyclosporine, tacrolimus, and itraconazole. Characterization of these particles using scanning electron
microscopy confirms that monodisperse populations of particles were produced of cyclosporine,
tacrolimus, and itraconazole, respectively. The sizes and shapes of these microparticles and
nanoparticles are suitable for use in ophthalmic suspension dosage forms. Dissolution studies of
itraconazole cylinder suspensions indicate that these particles dissolve faster under sink conditions than
traditional micronized itraconazole (50% dissolution at 5 min for PRINT-itraconazole cylinders vs. 15
minutes for micronized itraconazole), suggesting that itraconazole PRINT formulations may have greater
ocular surface bioavailability than traditional micronized formulations.
Tacrolimus
PRINT-Itraconazole has Increased Dissolution Rate
Polymer nanoparticles
Monoclonal Antibody
Minimal Aggregation/Degradation of “Delicate” Actives
PRINT® Technology
• Brings the precision and control of semiconductors to life sciences
and other markets
• Proprietary design and manufacturing platform to produce
nanoparticles and films
• Monodisperse feature morphology designed into master template
• Readily scalable using proven roll -to-roll manufacturing process
Active Ingredient
Relative Purity
Steroids (various)
> 99%
Prostaglandins (various)
> 98-99%
Monoclonal Antibodies
(bevacizumab, others)
> 90-100 %
siRNA
> 99%
Enzymes/proteins
> 99%
PRINT-itraconazole
particles
display faster dissolution than jet
milled and bulk itraconazole, as
evidenced by the time required to
achieve 50% dissolution. This time
was l5 min, 10 min, 20 min, and 45
min for the PRINT cylinders, jet
milled-F1, jet milled-F2, and bulk
itraconazole
preparations
respectively.
Example: Itraconazole Microparticles
Scanning Electron Micrographs
(SEM) of particles generated
from pure itraconazole.
Top, left panel:
1 µm PRINT cylinders*
Top, right panel:
Jet milled powder (F1)*
PRINT Process. A precise mold having micro- or nanoscale cavities (upper middle) is then filled
with drug product and formed into particles (top row, right). Particles can be removed (bottom row,
middle) from the mold and isolated as stable dispersions or free flowing powders (bottom row, left).
1 µm PRINT pollen
3 µm PRINT torus
Bottom, left panel:
1 µm PRINT pollen;
Bottom, right panel:
3 µm PRINT torus
* Adapted from Garcia et al, 2012 (2)
Benefits of the PRINT Platform for Ocular Drug Delivery
2 µm
Implants
 Extended release formulations of biologics and small
molecule drugs
 Reproducible implant size, dose and cost-effective
manufacturing
 New targets for tissue delivery in the eye
 Simple delivery
Micro/Nano Particles
 Topical delivery with fewer doses
 Sustained release
 Targeted drug delivery
2 µm
PRINT Dexamethasone PLGA implants
Particle type
Particle Size (VMD)
Jet milled itraconazole (F1)
3.63 µm3
Jet Milled itraconazole (F2)
2.52 µm3
PRINT hydrogel microparticles
PRINT 1 µm cylinders
1.42
µm3
Summary of particle sizel characteristics for PRINT versus jet milled pure itraconazole measured by
laser diffraction (VMD) and cascade impaction. These data demonstrate a reduction in volume
median diameter (VMD), as well as an increased emitted dose (ED) and fine particle fraction (FPF),
for the PRINT inhalation powder.
Conclusions
•
•
•
Small molecules, biologics, and polymer microparticles and nanoparticles were formulated
with high monodispersity and controlled geometry using PRINT technology
PRINT process preserves biochemical activity and physical structure of API
Enhanced dissolution kinetics were observed of microfabricated itraconazole particles,
compared to traditional crystalline or micronized forms, which may enhance bioavailability of
poorly soluble compounds
Methods:
• Itraconazole PRINT particles were fabricated using a proprietary molding process, as previously described (2).
Jet milled itraconazole was prepared using a Glen Mills Laboratory Jet Mill.
• Particle physical morphology was characterized by scanning electron microscopy.
• Volume median diameter (VMD) was determined by laser diffraction.
• The dissolution profiles were measured using an itraconazole suspension containing 0.1% w/w polyvinyl alcohol,
acting as a wetting agent, and at a final drug concentration of 10 µg/ml. The dissolution medium consisted of 0.1N
HCl and 0.3% w/w SDS and was maintained at a stirring speed of 100 RPM, as previously described for the
evaluation of itraconazole formulations for pulmonary delivery (1). Sink conditions were maintained throughout.
Dissolution test samples were removed and filtered using a 0.22 µm PES filter (Millipore) every 5 minutes for 30
minutes, then at 45, 60, 90, 120 and 240 minutes. Itraconazole content was measured using a RP-HPLC isocratic
method and Waters Symmetry Shield RP18 column, 3.5 µm particle size, 4.6 x 150 mm analytical column. Mobile
phase consisted of 20 mM hexanesulfonic acid and methanol (20:80) and a flow rate of 1mL/min was used. UV
absorbance of itraconaozle, with a retention time of 4.5 minutes, was measured at 260 nm.
Conflict of Interest
B. Yerxa, J. Tully, A. Garcia, and B. Maynor are alll employees and shareholders of Liquidia Technologies,
References:
1. McConville et al. (2006), “Targeted High Lung Concentrations of Itraconazole Using Nebulized Dispersions in a
Murine Model,” Pharmaceutical Research, 23(5), pp 901-911.
2. Garcia et al. (2012), “Microfabricated engineered particle systems for respiratory drug delivery and other
pharmaceutical applications,” Journal of Drug Delivery