Jeong Woo Lee, Jung-Hwan Park, Mark R. Prausnitz
22 Oct 2008
Graduate Student Colloquium 2008
Chemical and Biomolecular Engineering
Georgia Institute of Technology
1.
2.
3.
4.
Drug Market
Transdermal Drug Delivery Route
Dissolving Microneedles
Conclusion
Public Biotech Sales and R&D
Sales ($ billions)
R&D Expense ($ billions)
Nat. Biotech. 23 (1466) 2005
Oral Delivery
Injection Delivery
Small
MWMW
andand
High
moderately
lipophilic
hydrophilic
Epidermis
(Stratum corneum +
Viable epidermis)
Dermis
Hypodermis
(Subcutaneous tissue)
From www.antbits.co.uk
 Patent by Alza Corp. in 1971
 Microfabrication technique
100 mm
“Dissolvable microneedles
encapsulating biomolecules”
Stratum Corneum
Viable Epidermis
Dermis
 Advantages
 Patient compliance
 Self-administration
 No sharp and biohazardous waste
 Solid platform for biopharmaceuticals
 Controllable delivery




Fabrication
Mechanical Strength
Drug Delivery
Drug Stability
 Material Selection
 Safety in use
• Biocompatibility
• FDA-approved for injection
 Mechanical property
• Reliable insertion
 Support for biomolecules integrity
• Capability of aqueous process
• Mild process conditions
Hydrogel
Centrifugal Force
Inverse
Mold
 Centrifugal casting
 Aqueous drying process
 External centrifugal force
 Reliable mass production
Solidified
Hydrogel
 Matrix
 Carboxymethyl
Cellulose (CMC)
 Amylopectin
 Drug only
 BSA
600 µm
A
B
C
D
A: Master Structure
C: Amylopectin
B: CMC
D: BSA




Fabrication
Mechanical Strength
Drug Delivery
Drug Stability
(A) Force-Displacement
Measurement
Metal Surface
(B) Thumb-Push
Demonstration
Pig Skin
 Force-Displacement
Sudden yield for high aspect ratio
Yield at lower force for CMC Microneedles
1.0
Cone PLA
Cone CMC
Force (N/needle)
0.8
0.6
0.4
0.2
0.0
0.0
0.1
0.2
0.3
Displacement (mm)
0.4
0.5
 Critical Buckling Load (Pcri)
 Low aspect ratio  16-fold increase
 Large cross area  2-fold increase
Conical (800 µm Length)
Diameter
(µm)
50
100
200
300
400
600
800
Pyramidal (600 µm Length)
Pcri (N)
Base (µm)
CMC
PLA
0.0004 0.0020
50
0.0061 0.0307
100
0.1021 0.5105
200
0.5266 2.6329
300
1.6813 8.4064
400
8.6032 43.0158
500
27.3415 136.7075 600
Conical (600 µm Length)
Pcri (N)
Pcri (N)
Diameter
(µm)
CMC
PLA
CMC
PLA
0.0020 0.0102
50
0.0007 0.0035
0.0255 0.1271
100
0.0109 0.0546
0.3639 1.8194
200
0.1815 0.9076
1.7798 8.8899
300
0.9362 4.6808
5.5223 27.6113
400
2.9889 14.9447
13.3433 66.7164
500
7.3438 36.7191
27.4795 137.3976
600
15.2945 76.4725
 Force-Displacement
 No sudden yield for low aspect ratio
1.0
(a)
Pyramid PLA
Pyramid CMC
Cone PLA
Cone CMC
2:1
Force (N/needle)
0.8
0.6
4:1
0.4
0.2
0.0
0.0
0.1
0.2
0.3
Displacement (mm)
0.4
0.5
 Force-Displacement
 Similar behavior with other material
1.0
(b)
PLA
Amylopectin
80/20 wt% CMC/BSA
BSA
CMC
Force (N/needle)
0.8
0.6
0.4
0.2
0.0
0.0
0.1
0.2
0.3
Displacement (mm)
0.4
0.5
 Thumb-Push
 Reliable insertion (Pig skin)
 150-200 µm insertion depth
 Rapid dissolution of microneedles
150 µm
Backside
Tissue Staining
Histology
Before
1 min
10 sec
15 min
60 min




Fabrication
Mechanical Strength
Drug Delivery
Drug Stability
 If drug is encapsulated in
 Microneedles  Bolus release
 Backing layer  Sustained release
Bolus Release
Sustained Release
 Bolus Release
 Two-step casting
 Limited dose (a few µg per needle)
 1 hour application time
stratum corneum
600 µm
200 µm
 Sustained Release
 Two-step casting
 High dose to milligrams
 Adjustable release kinetics
600 µm
After 12 h
1 mm
Cumulative
amountof
of the
the released
drugdrug
(mg) (mg)
released
amount
Cumulative
 Controllable Release
 Type of matrix material
skin
Sampling
Port
1.0
0.8
Receptor
Chamber
0.6
Stir bar
0.4
0.2
Carboxymethyl cellulose matrix
Amylopectin matrix
0.0
0
1
2
3
4
Time
Time (Day)
(Day)
5
6
7
released
amount
Cumulative
Cumulative
amountof
of the
the released
drugdrug
(mg) (µg)
 Controllable Release
 Loading amount
skin
Sampling
Port
10 wt% loading
30 wt% loading
40
Receptor
Chamber
30
Stir bar
20
10
0
0
1
2
3
4
5
6
Time
Time (Hour)
(hour)
7
8
9
10




Fabrication
Mechanical Strength
Drug Delivery
Drug Stability
 Lysozyme
 Circular Dichroism (Secondary Structure)
 Functional Activity (Tertiary Structure)
 Human Growth Hormone (hGH)
 Functional Activity (Tertiary structure)
 Pharmacokinetics (In vivo)
 Heat Denatured, Negative control, Lysozyme
microneedles, Lysozyme Microneedles (two
months storage), CMC + Lysozyme
Circular Dichroism
10
Untreated
Microneedle
Microneedle after 2 months storage
Heat treated
100
Relative Activity (%)
5
CD (mdeg)
Functional Activity
0
80
60
40
-5
20
-10
0
200
220
240
Wavelength (nm)
260
A
B
C
Lysozyme treatment
D
 Cell population depending on the conc. of hGH
 No activity loss of the encapsulated hGH
hGH (Non-processed) + CMC
hGH Microneedles
hGH Microneedles (after 3 months)
Increase of Cell Population (%)
800
600
400
200
0
1
10
100
hGH Concentration (pg/ml)
1000
 Placebo microneedles and hGH microneedles
 Bolus hGH release in 6 hours
hGH microneedles
hGH concentration in rat serum (ng/ml)
4
Placebo
hGH Microneedles
3
2
1
0
0
5
10
15
Time (Hour)
20
25
 Polysaccharide microneedles dissolved
inside the skin after the insertion, enabling
two different delivery strategies: bolus and
sustained delivery
 CMC dissolving microneedles encapsulated
protein drugs, lysozyme and human growth
hormone, without the loss of drug stability.
 Thesis Committee
Dr. Mark Prausnitz, Dr. Mark Allen, Dr. Yulin Deng,
Dr. Eric Felner, Dr. Lakeshia Taite
 Microneedle Fabrication
Dr. Seong-O Choi
 Cell Group of Drug Delivery Lab
Dr. Robyn Schlicher, Ying Liu, Prerona Chakravarty,
Joshua Hutcheson
 hGH Pharmacokinetics
Dr. Laura O’Farrell, Jae hyung Park
 Funding from NIH