MICRO-ARRAY PATCHES: DELIVERING HIGH DRUG DOSES TRANSDERMALLY

Professor Ryan F. Donnelly

❖ Intradermal vaccines

❖ Local drug delivery

❖ Systemic administration of potent drugs

❖ Dissolving microneedles

❖ Coated microneedles

❖ Typically small patch sizes

MICRONEEDLE (MICROARRAY) PATCHES

HIGH-LOADING DISSOLVING MICRONEEDLES

T0

T30 s

T5 min

T15 min

600 µm

❖Loading of 50% w/w drug

❖Use biodegradable or low MW polymer

❖Polymer must be good film former and have low Tg

❖Dry slowly to promote physical stability

❖Microneedle and patch design will influence deliverable dose

❖Dissolution characteristics will affect duration of delivery

❖Polymer MW and drug properties will determine whether baseplate delivery is appreciable

❖Manufacture must be carried out in a low bioburden environment as a minimum

Shaved area of rat skin

Occlusive backing

layer

Ibuprofen sodium-

loaded baseplate

Ibuprofen sodium-loaded

microneedle array

Adhesive foam

0

50

100

150

200

250

300

350

400

450

500

0 200 400 600 800 1000 1200 1400 1600

Ibu

pro

fen

so

diu

m (

µg/

ml)

Time (min)

Delivery of clinically-relevant doses of non-potent drugs in vivo

Patch size for 24

hours’ delivery

= 10 cm2

❖Load nanoformulated drugs into aqueous gels

❖Cast into mould

❖Dry and add border adhesive and occlusive backing layer to form microarray patch (MAP)

❖Baseplate should readily detach upon microneedle dissolution in skin

❖Nanoformulated drugs deposited in viable skin layers for sustained release and absorption by rich dermal microcirculation

FORMULATION AND APPLICATION OF LONG-ACTING ANTI-RETROVIRAL MICROARRAY PATCHES

7 day

s

28 d

ays

56 d

ays

0.0

0.5

1.0

1.5

2.0

NS NS

*

RP

V C

on

c (

ng

/mg

tis

su

e)

1 4 7 28 56

-500

0

500

1000

1500

2000

Days post-MAP application

RP

V c

on

cen

trati

on

in

pla

sm

a

(ng

/ml)

1 4 7 28 56

-200

0

200

400

600

800

Days post-IM injection

RP

V c

on

cen

trati

on

in

pla

sm

a

(ng

/ml)

7 day

s

28 d

ays

56 d

ays

0.0

0.5

1.0

1.5

2.0*

NS

NS

RP

V C

on

c (

ng

/mg

tis

su

e)

RILPIVRINE

NANOSUSPENSION

MICROARRAY PATCH

IN VIVO RAT STUDY: RILPIVIRINE

PATCH SIZE FOR 7-DAYS’ HUMAN TREATMENT ≈ 25 - 30 CM2 PLASMA VAGINAL TISSUE

DISSOLVING MICRONEEDLES

❖Self-disabling

❖Delivery of clinically-relevant amounts of small molecule non-potent drugs in vivo

❖Effective in vivo delivery of nanoparticles for sustained systemic delivery (weeks or months)

❖Reasonable patch sizes

❖Deposit 5-10 mg polymer per cm2 in skin

❖Damaged by heat/steam sterilisation

❖Gamma sterilisation alters release profiles and may cause drug degradation or chemical binding to polymer

❖Manufacture in a low bioburden environment

HYDROGEL-FORMING MICRONEEDLES

❖Microneedles contain no drug themselves

❖Drug contained in a separate drug reservoir

❖Microneedles are chemically crosslinked

❖Rapid uptake of skin interstitial fluid

❖Drug diffuses through swollen microneedles

❖Rate of drug delivery determined by crosslink density

❖Reservoir properties can be altered to modulate drug delivery

❖Potential for higher doses and prolonged delivery

DONEPEZIL DELIVERY IN VIVO

Patch size for 24 hours’

delivery = 30 cm2

+

0 4 8 12 16 20 240

50

100

150

200

Time (h)

Ibu

pro

fen

-so

diu

m (

g/m

l)

IBUPROFEN DELIVERY IN VIVO

Patch size for

24 hours’

delivery =

30 cm2

METFORMIN DELIVERY IN VIVO

Patch size for 24 hours’

delivery = 8 cm2

Microneedle delivery Microneedle delivery

I.V. antibiotic administration

• Gut microbiome disruption

• Selection of resistant strains

• Amplification of resistance genes

• Increased susceptibility to infection

• Increase risk of dysbiosisrelated disorders

Gut microbiome exposure

Oral antibiotic administration

Microneedle antibiotic administration

Minimally-invasive, user-friendly system that bypasses the gut microbiome

Microneedles removed from skin intact

OVERCOMING ANTIBIOTIC

RESISTANCE?

+

AMOXICILLIN DELIVERY IN VIVO

Patch size for therapeutic delivery in humans = 30 cm2

Microneedles

Oral delivery

Metronidazole delivery in vivo

Patch size for 48 hours’ delivery = 10 cm2

IN VIVO: FITC-BSA HYDROGEL-FORMING MICRONEEDLES

0

2

4

6

8

10

12

0 4 8 12 16 20 24

Pla

sma

con

ecn

trat

ion

FTI

C-B

SA (

µg/

ml)

Time (h)

No FITC-BSA detected for

passive delivery

MNs in dry state Swollen hydrogel MNs

1

10

100

1000

10000

100000

0 20 40 60 80 100 120 140 160 180

Bev

aciz

um

ab c

on

cen

trat

ion

(n

g/m

l)

Time (hours)

High dose Low dose IV dose

ANTIBODY DELIVERY IN VIVO

HYDROGEL-FORMING MICRONEEDLES❖Self-disabling, but removed intact

❖No polymer deposition in skin

❖Sustainable in vivo delivery of insulin

❖Delivery not limited by what can be loaded into needles themselves

❖Potential for novel applications

❖Sterilisable without affecting properties

❖Selection of drug reservoir can enhance delivery of high-dose small medicines.

❖Differing pharmacokinetic pattern for very large biomolecules: Potential for lymphatic targeting

PATIENT USE

400 m

600 m

900 m

Consent form

Questionnaire

With pressure indicating sensor

film

Press firmly for 30 sec

Red impression

Microneedle patch with pressure indicating

sensor film75%

Microneedle patch

without pressure indicating

sensor film10%

No preference

15%

CONFIRMING CORRECT INSERTION

600 µm

Outcome measures

APPLICATION OF LARGE PATCHES

Before After0.0

0.5

1.0

1.5

TN

F-

levels

pg/m

l

ns

Before After0.0

0.5

1.0

1.5

2.0ns

TN

F

pg

/ml

IN VIVO HUMAN REPEAT APPLICATION STUDY: HYDROGEL-FORMING MICRONEEDLES

CONCLUSION & NEXT STEPS

❖Microneedles have great potential for delivery of high-dose therapeutics

❖Engage with regulators to discuss translation

❖Develop a bridging programme applicable to any drug to be delivered

❖Manufacturing scale-up

❖GMP manufacture

❖Clinical studies

❖Commercialisation and patient benefit

http://www.action.org.uk/