Microneedle Patch Delivery System
Microneedle Patch Delivery System
Microneedle Patch Delivery System
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
<strong>Microneedle</strong> <strong>Patch</strong> <strong>Delivery</strong> <strong>System</strong><br />
Development:<br />
Where Are We Now?<br />
Peter Daddona, PhD<br />
CSO<br />
May 19, 2010<br />
1
Zosano Pharma’s<br />
ZP-<strong>Microneedle</strong> <strong>Patch</strong> Technology<br />
• Most advanced microneedle patch delivery technology<br />
• Technology (formerly MACROFLUX) developed over 8 years<br />
at ALZA Corp (the world’s leading developer of commercial<br />
drug delivery products)<br />
• Spun out as a private company from ALZA/J&J in 2006<br />
• Lead program- ZP-PTH patch (parathyroid hormone 1-34,<br />
teriparatide) for daily treatment of severe osteoporosis<br />
• ZP-PTH product entering Phase 3 clinical development<br />
2
Zosano’s Drug Coated <strong>Microneedle</strong> <strong>Patch</strong>-<br />
A Simple and Effective <strong>Delivery</strong> <strong>System</strong><br />
Drug-coated patch<br />
(size of a US quarter)<br />
50X Magnified<br />
drug-coated<br />
microprojections<br />
Tip-<br />
Drug<br />
Coated<br />
<strong>Patch</strong><br />
Dead Skin<br />
(10-15 µm)<br />
Drug<br />
Epidermis<br />
(50-150 µm)<br />
Dermis<br />
Capillaries<br />
Nerve<br />
endings<br />
3
ZP-Drug Coated <strong>Microneedle</strong>s Deliver<br />
Drug Into the Superficial Skin Layers<br />
ZP-Drug Coated<br />
<strong>Microneedle</strong><br />
<strong>Patch</strong><br />
(190 µm long)<br />
Dead skin (10-15 µm)<br />
Cellular epidermis (50-150 µm)<br />
Dermis (750-1500 µm)<br />
Hypodermic Needle:<br />
28 gauge has outside<br />
diameter = 362 µm.<br />
and length =5000<br />
µm.<br />
General needle<br />
ranges: 26-31 gauge;<br />
length 5mm- 13mm<br />
Subcutaneous fat<br />
4
ZP-<strong>Patch</strong> and Applicator <strong>System</strong>: Developed for<br />
Controlled & Convenient Patient Self-Administration<br />
Drug-coated<br />
Zosano <strong>Patch</strong><br />
<strong>Patch</strong><br />
Applicator<br />
Class 1 Device,<br />
Purpose built<br />
<strong>Patch</strong><br />
Ring<br />
Combination<br />
Drug Product<br />
Zosano<br />
<strong>Patch</strong> in<br />
Applicator:<br />
<strong>Patch</strong><br />
Applied<br />
Press to Apply<br />
<strong>Patch</strong> wear time<br />
30 minutes<br />
5
ZP-Transdermal Drug-Coated <strong>Microneedle</strong><br />
<strong>Delivery</strong> <strong>System</strong>: Value Statement<br />
• Ideal solution for delivery of peptides, proteins and hydrophilic drugs<br />
• Traditional transdermal products best suited for hydrophobic drugs<br />
• Single step therapeutic drug delivery<br />
• High patient acceptance, user friendly, and travel friendly<br />
• Cost effective, alternative to outpatient injection<br />
Additional benefits:<br />
• Ready-to-use drug-coated patch (unit dose) with reusable low cost<br />
applicator<br />
• No product refrigeration required<br />
• Short patch wear time (
ZP-<strong>Microneedle</strong> <strong>Patch</strong> Ring Components<br />
Are All Biocompatible<br />
Adhesive <strong>Patch</strong>- Commercial Grade<br />
<strong>Microneedle</strong> Array- Titanium, Grade 2<br />
Inner Ring –USP Class VI polycarbonate<br />
Outer Ring - USP Class VI polycarbonate and<br />
moldable desiccant<br />
7
ZP-Titanium <strong>Microneedle</strong> Arrays Easily<br />
Manufactured With Different Sizes and Geometries<br />
• Flexible Process :autocad design, photomask and chemical etching<br />
•Advancing to reel to reel system<br />
• Microprojection array design can be optimized for drug<br />
loading by changing geometry of coating area<br />
Designs with<br />
Increased Tip Area<br />
<strong>Microneedle</strong> Array Design<br />
ZP-PTH<br />
40 µg<br />
Higher Dose Products<br />
Up to 3mg<br />
8
Automated Drug Coating Process:<br />
Allows Adjustable and Uniform Dose Loading<br />
• Multiple Dips Increases Coated Amount per microneedle –<br />
• Automated process taken from the printing industry<br />
Microprojection <strong>Patch</strong><br />
Microprojection <strong>Patch</strong><br />
Coated<br />
Microprojection<br />
Liquid Drug Formulation<br />
Liquid Drug<br />
Formulation<br />
Rotating Drum<br />
1 coat 3 coats 5 coats<br />
Ref: Ameri,M. et al.,<br />
Pharm Res. 27,303,2009<br />
5 µg PTH<br />
30 µg PTH<br />
60 µg PTH<br />
9
ZP-<strong>Patch</strong> Dose Can Also Be Controlled By<br />
Size Of Drug-Coated <strong>Microneedle</strong> Array Area<br />
• Increase Coated Array Area/<strong>Patch</strong><br />
• Method used in all transdermal products- Increase drug coated<br />
area and increase dose.<br />
• No formulation or coating process change<br />
1cm 2 10<br />
2cm 2<br />
3cm 2
ZP- <strong>Patch</strong> Packaging Designed to Maintain<br />
Product Stability at Ambient Temperature<br />
• Heat-sealed foil pouch or<br />
cup provides moisture and<br />
oxygen barrier for product<br />
stability<br />
• Nitrogen purge<br />
• Desiccant<br />
Foil Pouch Package<br />
Cup Package<br />
11
Lead Phase 3 Program: ZP-PTH <strong>Microneedle</strong> <strong>Patch</strong><br />
for Treatment of Severe Osteoporosis<br />
• Treatment of severe osteoporosis is growing market<br />
• Parathyroid hormone, PTH (1-34), Forteo® is the only US<br />
approved anabolic agent (bone building) for severe<br />
osteoporosis<br />
• Forteo® requires a once daily injection and requires product<br />
refrigeration.<br />
• Daily, short PTH plasma pulse is critical to the anabolic<br />
mechanism of action<br />
• ZP-PTH patch being developed to provide a:<br />
• Rapid pulse PK profile to drive the PTH anabolic effect<br />
• Patient-friend patch dosage (no injection, RT storage)<br />
12
Lead Product ZP-PTH <strong>Microneedle</strong> <strong>Patch</strong><br />
Developed With Excellent Storage Stability<br />
PTH patch shows better stability than Forteo at 25°C and even at 2-8°C;<br />
>24 months RT shelf-life can be expected<br />
Phase 2 Zosano PTH 40 µg vs. Forteo<br />
100<br />
PTH %Purity<br />
95<br />
90<br />
85<br />
Forteo RT<br />
ZP-PTH<br />
2yr RT<br />
Stable<br />
Forteo (2-8 o C)<br />
80<br />
0 5 10 15 20 25 30 35<br />
Storage Time (Months)<br />
Ref: Ameri, M., et al. Pharm Res, 26, 2454, 2009<br />
13
Phase 1: ZP-PTH <strong>Patch</strong> Delivers A Shorter<br />
PTH Plasma Pulse Than Forteo ® SC Injection<br />
PTH 1-34 (pg/mL) +/- SE<br />
125<br />
100<br />
75<br />
50<br />
25<br />
ZP PTH 30 µg Thigh<br />
ZP PTH 30 µg Upper Arm<br />
ZP PTH 30 µg Abdomen<br />
FORTEO Inj 20µg Thigh<br />
30 min patch wear time<br />
T max =3 X faster<br />
t ½ =2 X shorter<br />
0<br />
0 0.08 0.17 0.25 0.5 1 2 3 4 8<br />
Time (h)<br />
Ref: Daddona, P., et al., Pharm Res, (in press), 2010<br />
14
PTH 1-34 (pg/mL)( +/- SE)<br />
Phase 1: ZP-PTH <strong>Delivery</strong> Is<br />
Rapid and Complete In 30 minutes<br />
300<br />
200<br />
100<br />
0<br />
<strong>Patch</strong> delivery is complete within 30min<br />
<strong>Patch</strong> applied to abdomen<br />
ZP PTH 40 µg 0.5 h<br />
ZP PTH 40 µg 2 h<br />
0 0.08 0.17 0.25 0.50 0.75 1 2 3 4<br />
Time (h)
Study Design<br />
Phase 2: ZP–PTH<br />
Dose Response Study<br />
• 6 month multi-national study in165 post menopausal women with<br />
established osteoporosis<br />
• Daily dose, patient self administered<br />
• ZP-PTH patch at 3 doses (20 µg, 30 µg and 40 µg)<br />
• ZP-Placebo patch as control<br />
• Forteo ® injection product (20 µg) as active comparator<br />
• Measured PTH anabolic effect -increase in bone mineral density<br />
• Lumbar Spine and Total Hip<br />
• Safety Assessments- systemic and topical<br />
Ref: Cosman, F., et al. J.Clin. Endocrin Metab, 95,151,2010<br />
16
Phase 2: ZP-PTH Provides Rapid Pulse<br />
and Dose Proportional <strong>Delivery</strong><br />
PK Over Time<br />
Mean AUC by Dose<br />
PTH Concentration (pg/ml)<br />
0 20 40 60 80 100 120<br />
0 1 2 3 4<br />
Hours<br />
• <strong>Patch</strong> delivers faster Tmax, higher Cmax, shorter half life than Forteo injection<br />
• Excellent dose proportional delivery<br />
• High drug bioavailability at 40%<br />
AUC (pg hr/ml)<br />
50 100 150 200 250<br />
Forteo ZP-20 ZP-30 ZP-40<br />
17
Phase 2: ZP-PTH <strong>Patch</strong> Is Similar To Forteo ® in<br />
Increasing Lumbar Spine Bone Density<br />
% Change from Baseline (Mean+/-SEM)<br />
6<br />
5<br />
4<br />
3<br />
2<br />
1<br />
0<br />
-1<br />
Placebo<br />
-0.33<br />
ZP-30<br />
ZP-20<br />
ZP-40<br />
4.97<br />
Forteo<br />
3.55<br />
3.47<br />
2.96<br />
All active treatments vs Placebo p=
Phase 2: ZP-PTH Produced An Early and<br />
Significant Increase in Total HIP Bone<br />
1.5<br />
Density Over Forteo ®<br />
1.331<br />
*<br />
ZP-40<br />
Total Hip BMD (%)<br />
1<br />
0.5<br />
0<br />
-0.5<br />
Placebo<br />
ZP-20<br />
0.138<br />
ZP-30<br />
0.553<br />
Forteo<br />
0.094<br />
*vs ZP-Placebo 95% CI = 0.595 – 2.755<br />
* vs Forteo 95% CI = 0.077 – 2.386<br />
-0.634<br />
-1<br />
ZP-Placebo ZP-PTH 20 ZP-PTH 30 ZP-PTH 40 Forteo<br />
19
ZP-PTH Phase 2 Outcomes<br />
• ZP-PTH system performance validated with consistent<br />
dose delivery response; variability similar or better<br />
than SC injection<br />
• Efficacy (increased bone mineral density) is similar to<br />
Forteo at Lumbar Spine but improved at Hip<br />
• <strong>System</strong>ic safety profile no different than commercial<br />
product<br />
• Topical effects minimal;<br />
• No skin infections<br />
• No anti PTH antibody formation<br />
• Study Validates Technology Platform<br />
20
Regulatory Implications For ZP-PTH<br />
Drug Device Combo Product<br />
• Single NDA can cover both the ZP-PTH transdermal patch<br />
and the purpose designed applicator<br />
• Based on Primary Mode of Action (PTH absorbed<br />
systemically to provide anabolic bone building), jurisdiction<br />
for NDA review by CDER with consult by CDRH (Device)<br />
reviewers<br />
• Compliance with Drug GMPS’s for the manufacture of the<br />
ZP-PTH <strong>Patch</strong><br />
• Compliance with Device Quality <strong>System</strong> Regulations (21<br />
CFR Part 820) for the applicator and Critical Device<br />
Elements of the ZP-PTH <strong>System</strong> (i.e. microneedle array)<br />
21
Regulatory Implications For ZP-PTH<br />
Drug Device Combo Product<br />
• NDA filing to follow 505 (b) (2) regulatory pathway<br />
• Relies on previous finding of safety and efficacy of<br />
marketed reference product<br />
• Required to show non-inferiority to Forteo for bone<br />
mineral density response<br />
• Do not need to match PK profile<br />
• Do not need a bone fracture reduction study<br />
• A single 12-month Phase 3 trial with 6-month safety<br />
extension is sufficient for registration for<br />
postmenopausal women with severe osteoporosis<br />
22
Summary<br />
• ZP- Transdermal microneedle patch technology is a<br />
novel combination product<br />
• Drug-coated microneedle patch and applicator system<br />
• First transdermal microneedle patch product to<br />
reach Phase 3<br />
• Clinically validated in Phase 2<br />
• FDA confirmed Phase 3 product specifications and<br />
505(b)(2) regulatory pathway<br />
• Advancing ZP- PTH to Phase 3 clinical testing<br />
23