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Dissolving Microneedles for Transdermal Drug Delivery
Jeong Woo Lee, Jung-Hwan Park, Mark R. Prausnitz
22 Oct 2008
Graduate Student Colloquium 2008
Chemical and Biomolecular EngineeringGeorgia Institute of Technology
Outline
1. Drug Market2. Transdermal Drug Delivery Route3. Dissolving Microneedles4. Conclusion
Biopharmaceuticals Market
Sales ($ billions)
R&D Expense ($ billions)
Nat. Biotech. 23 (1466) 2005
Public Biotech Sales and R&D
Biopharmaceuticals Delivery
Oral Delivery
Injection Delivery
Injection Delivery
Skin
Epidermis (Stratum corneum + Viable epidermis)
Dermis
Hypodermis(Subcutaneous tissue)
High MW and hydrophilic
Small MW and moderately lipophilic
From www.antbits.co.uk
Microneedle Patent by Alza Corp. in 1971 Microfabrication technique
100 mm
Dissolving Microneedle
“Dissolvable microneedles encapsulating biomolecules”
Viable Epidermis
Dermis
Stratum Corneum
Dissolving Microneedle
Advantages Patient compliance Self-administration No sharp and biohazardous waste Solid platform for biopharmaceuticals Controllable delivery
Key Questions
Fabrication Mechanical Strength Drug Delivery Drug Stability
Fabrication (1) 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
Polysaccharide
Fabrication (2)
Centrifugal casting Aqueous drying process External centrifugal force Reliable mass production
Centrifugal Force
Inverse Mold
Solidified Hydrogel
Hydrogel
Fabrication (3)
Matrix Carboxymethyl
Cellulose (CMC) Amylopectin
Drug only BSA
600 µm
A B
C D
A: Master Structure B: CMCC: Amylopectin D: BSA
Key Questions
Fabrication Mechanical Strength Drug Delivery Drug Stability
Mechanical Strength
Metal Surface Pig Skin
(A) Force-Displacement Measurement
(B) Thumb-Push Demonstration
Mechanical Strength (A) Force-DisplacementSudden yield for high aspect ratioYield at lower force for CMC Microneedles
Displacement (mm)
0.0 0.1 0.2 0.3 0.4 0.5
Fo
rce
(N/n
eed
le)
0.0
0.2
0.4
0.6
0.8
1.0
Cone PLA
Displacement (mm)
0.0 0.1 0.2 0.3 0.4 0.5
Fo
rce
(N/n
eed
le)
0.0
0.2
0.4
0.6
0.8
1.0
Cone PLACone CMC
Failure Simulation
Conical (800 µm Length) Pyramidal (600 µm Length) Conical (600 µm Length)
Diameter (µm)
Pcri (N)Base (µm)
Pcri (N) Diameter (µm)
Pcri (N)CMC PLA CMC PLA CMC PLA
50 0.0004 0.0020 50 0.0020 0.0102 50 0.0007 0.0035100 0.0061 0.0307 100 0.0255 0.1271 100 0.0109 0.0546200 0.1021 0.5105 200 0.3639 1.8194 200 0.1815 0.9076300 0.5266 2.6329 300 1.7798 8.8899 300 0.9362 4.6808400 1.6813 8.4064 400 5.5223 27.6113 400 2.9889 14.9447600 8.6032 43.0158 500 13.3433 66.7164 500 7.3438 36.7191800 27.3415 136.7075 600 27.4795 137.3976 600 15.2945 76.4725
Critical Buckling Load (Pcri) Low aspect ratio 16-fold increase Large cross area 2-fold increase
Conical (800 µm Length) Pyramidal (600 µm Length) Conical (600 µm Length)
Diameter (µm)
Pcri (N)Base (µm)
Pcri (N) Diameter (µm)
Pcri (N)CMC PLA CMC PLA CMC PLA
50 50 50100 100 100200 0.1021 0.5105 200 200300 300 1.7798 8.8899 300 0.9362 4.6808400 400 400600 500 500800 600 600
Mechanical Strength (A)
Displacement (mm)
0.0 0.1 0.2 0.3 0.4 0.5
For
ce (
N/n
eedl
e)
0.0
0.2
0.4
0.6
0.8
1.0
Pyramid PLAPyramid CMCCone PLACone CMC
(a)
Force-Displacement No sudden yield for low aspect ratio
4:1
2:1
Mechanical Strength (A)
Displacement (mm)
0.0 0.1 0.2 0.3 0.4 0.5
For
ce (
N/n
eedl
e)
0.0
0.2
0.4
0.6
0.8
1.0
PLAAmylopectin80/20 wt% CMC/BSA BSACMC
(b)
Force-Displacement Similar behavior with other material
Mechanical Strength (B)
150 µm
Thumb-Push Reliable insertion (Pig skin) 150-200 µm insertion depth Rapid dissolution of microneedles
Backside Tissue Staining Histology
10 sec
1 min 15 min 60 min
Before
Dissolving Microneedles
Key Questions
Fabrication Mechanical Strength Drug Delivery Drug Stability
Drug Delivery Strategy
If drug is encapsulated in Microneedles Bolus release Backing layer Sustained release
Sustained ReleaseBolus Release
Bolus Delivery (1)
200 µm
stratum corneum
600 µm
Bolus Release Two-step casting Limited dose (a few µg per needle) 1 hour application time
Sustained Release
600 µm
Sustained Release Two-step casting High dose to milligrams Adjustable release kinetics
1 mmAfter 12 h
In vitro Release
Time (Day)
0 1 2 3 4 5 6 7
Cu
mu
lati
ve
am
ou
nt
of
the
rele
ased
dru
g (
mg
)
0.0
0.2
0.4
0.6
0.8
1.0
Carboxymethyl cellulose matrixAmylopectin matrix
Controllable Release Type of matrix material
Time (Day)
Cum
ulati
ve a
mou
nt o
f the
rele
ased
dru
g (m
g) skin
Receptor Chamber
Stir bar
Sampling Port
In vitro Release
Time (hour)
0 1 2 3 4 5 6 7 8 9 10
Cu
mu
lati
ve
amo
un
t o
f th
e re
leas
ed d
rug
( g
)
0
10
20
30
4010 wt% loading30 wt% loading
skin
Receptor Chamber
Stir bar
Sampling Port
Cum
ulati
ve a
mou
nt o
f the
rele
ased
dru
g (µ
g)
Time (Hour)
Controllable Release Loading amount
Key Questions
Fabrication Mechanical Strength Drug Delivery Drug Stability
Drug Stability
Lysozyme Circular Dichroism (Secondary Structure) Functional Activity (Tertiary Structure)
Human Growth Hormone (hGH)Functional Activity (Tertiary structure)Pharmacokinetics (In vivo)
Drug Stability (Lysozyme)
Wavelength (nm)
200 220 240 260
CD
(m
deg
)
-10
-5
0
5
10
UntreatedMicroneedleMicroneedle after 2 months storageHeat treated
Heat Denatured, Negative control, Lysozyme microneedles, Lysozyme Microneedles (two months storage), CMC + Lysozyme
Circular Dichroism
Lysozyme treatment
A B C D
Rel
ativ
e A
ctiv
ity
(%)
0
20
40
60
80
100
Functional Activity
Drug Stability (hGH) Cell population depending on the conc. of hGH No activity loss of the encapsulated hGH
hGH Concentration (pg/ml)
1 10 100 1000
Incr
ease
of
Cel
l P
op
ula
tio
n (
%)
0
200
400
600
800hGH (Non-processed) + CMChGH MicroneedleshGH Microneedles (after 3 months)
hGH Pharmacokinetics Placebo microneedles and hGH microneedles Bolus hGH release in 6 hours
Time (Hour)
0 5 10 15 20 25
hG
H c
on
ce
ntr
ati
on
in
ra
t s
eru
m (
ng
/ml)
0
1
2
3
4
PlacebohGH Microneedles
hGH microneedles
Conclusion
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.
Acknowledgment 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 LabDr. Robyn Schlicher, Ying Liu, Prerona Chakravarty, Joshua Hutcheson
hGH PharmacokineticsDr. Laura O’Farrell, Jae hyung Park
Funding from NIH
Q&A