Transcript Final_Drug_Delivery_Poster_2006

Polymer Stabilized Emulsions For Drug Delivery:
Effect of Polymer and Oil Choice
Ashley Bourgault1, Michael Brunetti1, Matthew Regan1, Anne St Martin2,
Alain Durand3, Michèle Léonard3, Terri Camesano1, W. Grant McGimpsey2
1Department of Chemical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609
2Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609
3Laboratoire de Chimie Physique Macromoléculaire, Ecole Nationale Supérieure des Industries Chimiques
OIL PARTITION COEFFICIENT
A collaboration between WPI and ENSIC was undertaken to investigate the properties of emulsions as a
drug delivery system. The use of biocompatible amphiphilic polymers as emulsifiers for controlled drug
delivery is a relatively new technology. The emulsifier acts as a barrier between phases in oil-in-water
emulsions to increase stability. Oil soluble drug substances can then be encapsulated within the oil
nanoparticles where the polymer surfactants help to control the drug release into a biological system over
time. The goal of this project was to research the stabilization and drug release kinetics of two modified
amphiphilic polymers, dextran (DexC6) and alginate. The most stable emulsions were formed with a
DexC6 aqueous concentration of 40g/L in a system of 40% octyldodecanol oil volume. Experimentation
yielded consistent drug release kinetics for both polymers, that encapsulated lidocaine is released at a
much slower rate than free lidocaine. This conclusion encourages further research into drug delivery
through emulsion systems.
The partition coefficient (Kp) was determined using UV-visible spectroscopy. Four different types of oil
were used for this study. Saturated lidocaine in a dilute NaOH solution was mixed well with each oil, and
allowed to settle and reach equilibrium. Finally, the aqueous phase was analyzed for absorbance and the
results are as shown. Octyldodecanol showed the highest Kp in each case.
Partition Coefficient vs Oil:Lidocaine and Total Volume
Partition Coefficient Calculation
90
Kp = C drug in oil / C drug in solvent
80
Partition coefficient
ABSTRACT
70
dicaprylyl carbonate
60
caprylic/capric triglyceride
50
Octyldodecanol Verification
octyldodecanol
40
miglyol
30
4 more trials were run initially using 6
mg/mL lidocaine in octyldodecanol.
20
10
INTRODUCTION
Consistent results were obtained:
0
3:5, 4ml tot
Traditional Drug Delivery
Ideal Drug Delivery
 Intravenous and oral administration
 Controlled, slow release kinetics
 First order kinetics
 Zero order kinetics
 Problems with toxicity and repeated dosing
 Can be achieved through polymer stabilized
emulsions
1:1, 10ml tot
Kp (octyldodecanol) = 62 ± 3
3:5, 10ml tot
EMULSIFICATION
Emulsions made with either modified dextran or alginate polymers, 10-4M NaOH solution or 10-2M NaCl
solution, octyldodecanol, and lidocaine.
Dextran emulsions: aqueous polymer concentrations of 30g/L and 40 g/L, a 40% oil fraction, and an oil
lidocaine concentration of 25g/L.
Alginate emulsions: aqueous polymer concentrations varied from 0.1 g/L to 4.0 g/L and oil fractions that
ranged from 10% to 30% with an oil lidocaine concentration of 25 g/L.
EMULSION STABILITY
Emulsion degradation was marked by the increase in the particle size of the emulsion with time. Emulsions
were also artificially aged by use of a centrifuge and freeze dried and reconstituted to further test their stability.
Lidocaine Encapsulated
Emulsions, 40g/L DexC6
DexC6 Concentrations of 30g/L and 40g/L
OBJECTIVES
Synthesize dextran and alginate polymers for structural analysis and use in all project experiments
500
500
Lidocaine Encapsulated Emulsions
450
450
40% Oil, 25mg/mL Lidocaine in Oil, 40g/L DexC6
400
400
400
300
30g/L
250
40g/L
200
350
350
48 hrs
250
Centrifuged
200
Reconstituted
150
150
100
Emulsion 1
200
Emulsion 2
150
50
50
50
0
30g/L
0
24 hrs
48 hrs
Centrifuged
40g/L
0
Polymer Concentration (g/L)
Reconstituted
POLYMER PREPARATION
24 hrs
96 hrs
Alginate Emulsion Particle Sizes Over Time
Dextran is a natural polysaccharide molecule that was chosen for drug delivery research because it is
biocompatible and biodegradable. It is a hydrophilic molecule that is reacted with epoxyoctane to obtain a
amphiphilic polymer. The reaction substitutes hexane groups onto the monomer units. NMR is used to
determine the degree of substitution of the polymer. The molecule used for experimentation was
approximately 20% substituted DexC6.
Average Particle Sizes for Alginate Em ulsions, 10% Oil, NaCl in Aqueous
Average Particle Sizes for 1.4 m g/m l Alginate Em ulsions, 10% Oil
1200
1200
1000
1000
Size (nm)
800
800
600
Size (nm)
1.3mg/ml
1.4mg/ml
1.5mg/ml
1.4mg/ml 1
600
1.4mg/ml 2
1.4mg/ml NaCl
400
400
200
200
0
0
12 hr
Unsubstituted Dextran Monomer
250
100
100
Study drug release kinetics to confirm that polymer presence helps to control lidocaine release
300
24 hrs
300
Particle Size (nm)
Particle Size (nm)
Optimize parameters for emulsion particle stability
350
Particle Size (nm)
Determine best oil for emulsion preparation using partition coefficient data
34 hr
38 hr
centrifuged
freeze dried
initial
48 hr
centrifuged
freeze dried
Substituted Dextran Monomer
NMR spectrum for degree of substitution analysis
LIDOCAINE RELEASE KINETICS
Modified Dextran
Modified Alginate
• 10 mL emulsion with 40% oil
• 30 mL emulsion 10% oil
• 25 g/L lidocaine in oil, 40 g/L DexC6 in aqueous
• 25 g/L lidocaine in oil, 1.4 g/L alginate in aqueous
ALGINATE SYNTHESIS
Lidocaine Release Kinetics with Alginate
0.16
0.16
0.14
0.14
0.12
0.10
0.08
Lidocaine
Emulsion
0.06
0.04
Concentration (mg/ml)
Concenration (mg/mL)
Lidocaine Release Kinetics with DexC6
0.12
0.10
Alg + Lido
0.08
0.06
0.04
0.02
0.02
0.00
0.00
0
100
200
300
400
500
Emulsion
0
100
Time (min)
Alginate is a naturally occurring biopolymer consisting of linear, unbranched polysaccharides that is
extracted from brown algae. In addition, alginate matrices are very biodegradable and will eventually
dissolve under normal physiological conditions.
200
300
400
500
Time (min)
CONCLUSIONS
Most stable emulsion was formed with 40% oil volume, 40 g/L DexC6 (Particle sizes of approximately 300 nm)
Octyldodecanol was the best oil based on partition coefficient experiments
Goal was to obtain 8% fixation of
C12 chains on the alginate
backbone
Achieved at rate of fixation of 5%
C12 chains on alginate
Drug release kinetics were more controlled when emulsions were used
RECOMMENDATIONS
Discontinue the use of dilute NaOH as the aqueous phase
Model lidocaine release experiments based on convective mass transfer
Reevaluate dialysis purification step of dextran synthesis procedure