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