Sustained Release Suspension Aerosol Formulations with Oligolactic Acid (OLA)
Zhili Li and James S. Stefely
3M Drug Delivery Systems, 3M Center, 260-3A-05, St. Paul, MN 55144
Introduction
In-Situ generated microspheres
Oligolactic Acid (OLA)
O
O
O
O
Aerosol droplet
n
OH
Impact of OLA structure on drug release profile
Visual evidence for OLA- coatings
Suspension formulation
..
..
OLA, an excipient designed for use in HFA-MDIs
!Biodegradable and biocompatible
120
.…. ..
.... .... .
100
!Subclass of PLA (suture/implant constituent)
% drug released
O
Results
Results
Introduction
Solution formulation
!Multiple applications
Methods
!Solubilizer
A method [2] allowing comparison of drug release profiles from different
formulations in vitro, and the impact of OLAs on the drug release profile from
solution formulations [3] has been reported. Here we report the impact of OLAs on
the release properties of suspension formulations containing albuterol sulfate.
Albuterol sulfate was selected because it’s high water solubility provided a
stringent test of the technology’s ability to alter the release profile. OLA structural
characteristics such as molecular weight and end-group functionality, and
formulation parameters such as concentration can affect the drug release profile.
We examined the impact of these factors on the percent drug release in order to
further understand the benefits and limitations of this approach.
OLA-B
60
OLA C
40
0
Drug without OLA
Albuterol sulfate MDI suspension formulations were prepared with a
range of OLA concentrations (0.1%, 0.3%, 0.5% w/w OLA) and with
OLAs that varied in terms of molecular weight or end group (but
referred to as OLA A, B and C). Control formulations without OLAs
were also prepared. Aerosols were collected in an ACI and the drug
dissolution profile was determined using the method pictured below [2].
Aerosol particles were also directly observed under SEM to visualize
the nature of the coating.
Drug with OLA, in situ coated
28.3
L/min
Filter
HPLC
analysis
OLA-B, 0.1
80
OLA-B, 0.3
OLA-B, 0.5
60
40
total drug at time t
Drug release% = ————————
total drug (solvent released)
water
water
Water
Bath
37C
water
80
100
This study indicated that drug particles suspended in HFAs were effectively
coated by the excipient OLA after actuation from the HFA-based MDI. The in
vitro drug release profiles of these respirable OLA-coated particles could be
control by both OLA structural characteristics and OLA concentrations.
References
0
water
60
OLA free
0
After 90 min, Add
solvent to dissolve
matrix = 100%
released
40
Conclusions
120
20
Sample at 0, 4, 30,
60, 90 min
20
The impact of OLA concentration on the release profile
100
Hollow
Rings
0
Time, min
% drug released
Sustained release formulations have potential advantages, such as increased local
drug release time and reduced peak systemic drug levels when compared to
immediate release formulations. Oligolactic acids (OLA) are a family of designed
excipients which can be used in either solution or suspension aerosol formulations
[1]. As shown in accompanying cartoon, when a suspension formulation
containing OLA is actuated, propellant evaporates from the sprayed aerosol
droplets leaving a OLA-coated drug particles. When solution formulations are
actuated, a homogeneous microsphere composed of drug and OLA is generated as
evidenced by the absence of the original drug or OLA transitions in modulated
DSC scans. In either case, in-situ generated microspheres are formed and either
approach may modulate the drugs release profile. Compared to MDI formulations
that utilize preformed microspheres, these in situ generated microspheres are likely
to be simple and economic to produce.
OLA A
20
!Suspension aid
!Sustained release
OLA free
80
20
40
60
80
100
1.
time, min
2.
3.
Design and utility of a novel class of biocompatible excipients for HFAbased MDIs, J.S. Stefely et al, Respiratory Drug Delivery VII, Volume I,
p.83-90, 2000;
In vitro test method development for aerosol sustained release
formulations, Zhili Li, et al, AAPS, Oct 2003, Denver;
Oligolactic acid (OLA) biomatrics for sustained release of asthma
therapeutics, C. L. Leach et al, Respiratory Drug Delivery VII, Volume
I, p.75-82.
3 Drug Delivery Systems