MICRONEEDLES FORMICRONEEDLES FOR INTRADERMAL VACCINE

DELIVERYDELIVERY

Richard W. COMPANSEmory University School of MedicineEmory University School of Medicine

Influenza Pathogenesis and Immunology Research Center Director

Concept of coated microneedlesConcept of coated microneedles

MicroneedleStratum corneum (10 m) TRANSPORT BARRIER

Drug/vaccine coatingViable

Epidermis p(50-100 m)

Dermis (1-2 mm)

50 m

Concept of coated microneedlesConcept of coated microneedles

MicroneedleStratum corneum (10 m) TRANSPORT BARRIER

Drug/vaccine coatingViable

Epidermis p(50-100 m)

Dermis (1-2 mm)

50 m

Microneedle fabricationMicroneedle fabrication

Material : Stainless steel sheetsMaterial : Stainless steel sheetsCutting tool : Infrared laserD b i El t li hiDe-burring : Electropolishing

(A) SILICON MICRONEEDLES FABRICATED BY REACTIVE ION ETCHING AND (B) METAL MICRONEEDLES FABRICATED BY LASER

ETCHINGETCHING

_____________________________________A B

POTENTIAL ADVANTAGES OFPOTENTIAL ADVANTAGES OF MICRONEEDLE PATCH VACCINES

• Painless• Safe disposalp• Lower vaccine dose• Improved vaccine efficacy p y• Increased stability?• Low costLow cost• Rapid distribution• Possible self-administrationPossible self administration

Dip coatingA B C

Substrate

Coating solution

Capillary rise at micro-length scales C p y se c o e g sc esgB

Cosh

)(

Capillary rise between plates =

h

g = liquid/air interfacial tension = liquid density = contact angle

eg.: Water

B = needle spacing = 1 mm

gB = plate spacing

B = needle spacing = 1 mm

Capillary rise = h = 5 mm

A Incomplete B Contaminated b t t

Microneedl

coating substrate

e

Contaminated substrate

Sub.

Microneedle coatingMicroneedle coating• Coating solution additives:Coating solution additives:

– SURFACTANT – Poloxamer (F-68)• VISCOSITY ENHANCER - Sodium

carboxymethyl cellulose (CMC)

500 mm

Effect of concentration and number of i dlmicroneedles

D i N b f i dl

0.1% 1% 2% 3% 4%0.01%

Drug concentration Number of microneedles

505

2 63

5

gs

1.8

2.6

1 5

2

2.5

3

in B

in c

oatin

gscr

onee

dle) 200 mm

1.92.13

4

min

B in

coa

ting

cron

eedl

e)

200 mm

0.002

0.5

1.0

0.0390

0.5

1

1.5

Mas

s of

vita

mi

( g

/ mic

0

1

2

Mas

s of

vita

m(

g / m

i

00.01% 0.10% 1% 2% 3% 4%

Concentration of vitamin B in coating solution (w/v%)

05 50

Number of microneedles in array

ARRAY OF 50 MICRONEEDLESARRAY OF 50 MICRONEEDLES COATED WITH RIBOFLAVIN

In vitro insertion and releaseIn vitro insertion and release

Rapid release Delivery of small p

Sc

molecule - calcein

200 mm

200 mm

50 needle array50-needle array

1 mm

Efficiency of deliveryEfficiency of delivery after insertion into the skin

Amount deposited inside the skin: 91%

Amount left on the skin surface: 2%Amount left on the skin surface: 2%

Amount left on the microneedle: 7%

MICRONEEDLES COATED WITH PROTEINMICRONEEDLES COATED WITH PROTEIN, DNA, AND MICROSPHERES

SSO G ORAPIDLY DISSOLVING POLYMER MICRONEEDLES

• Improved safety

• Polymerization at low temperaturey p

• Preservation of antigen• Preservation of antigen

• Effective penetration and dissolution

INSERTION CAPABILITIES AND MECHANICAL PROPERTIES OF POLYMER MICRONEEDLES

ARRAY CONTAINING 100 BIODEGRADABLE PLGA POLYMERBIODEGRADABLE PLGA POLYMER

MICRONEEDLES

RAPIDLY DISSOLVING CMCRAPIDLY DISSOLVING CMC MICRONEEDLES BEFORE AND AFTER

INSERTION INTO HUMAN CADAVER SKININSERTION INTO HUMAN CADAVER SKIN

MICRONEEDLES ARE 750 µm TALLµ

SITE OF MICRONEEDLESITE OF MICRONEEDLE PENETRATION AND DEPOSITION IN

HUMAN CADAVER SKINHUMAN CADAVER SKIN

SUMMARY/CONCLUSIONSSUMMARY/CONCLUSIONS

S lid t l i dl b ff ti l t d ith• Solid metal microneedles can be effectively coated with alternative vaccine formulations

• Intradermal delivery of vaccines occurs with high efficiencyefficiency

• Microneedle immunization results in strong humoral as• Microneedle immunization results in strong humoral as well as cellular immune responses

• Antigen containing microneedles can also be constructed using resorbable polymersg p y

SOME CURRENT DIRECTIONSSOME CURRENT DIRECTIONS

• Determine the protective efficacy of immunizationDetermine the protective efficacy of immunization

F l d d i i fl i• Focus on seasonal and pandemic influenza viruses

• Determine the breath of immunity induced by microneedle vaccine deliveryy

• Adjuvants to enhance immune responses to• Adjuvants to enhance immune responses to microneedle delivery

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Emory University Georgia Institute of Technologyy y g gyIoanna Skountzou Mark PrausnitzDimitrios Koutsonanos Harvinder Singh GillChinglai Yang Sean SullivanChinglai Yang Sean SullivanLing Ye Vladimir ZarnitsynSang-Moo KangFu-Shi Quan Karolinska InstituteJaemin Song Jonas Sõderholm

Matti SãllbergMatti Sãllberg

NIAIDNIBIB