adare pharmaceuticals a patient-centric approach to drug...
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©2017 Adare Pharmaceuticals, Inc.
Adare Pharmaceuticals A Patient-Centric Approach to
Drug Formulation
Drug Delivery & Formulation Summit Berlin, March 27-29, 2017
Holger Neecke Director of Business Development
Luigi Boltri Director, Innovation & Technology Liaison
©2017 Adare Pharmaceuticals, Inc. ©2017 Adare Pharmaceuticals, Inc.
Patients and our partners are at the heart of everything we do
©2017 Adare Pharmaceuticals, Inc.
Adare Pharmaceuticals
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We are a global specialty pharmaceutical
company inspired to improve the lives of
patients whose treatment needs are not
fully addressed by current medications.
©2017 Adare Pharmaceuticals, Inc.
Corporate Overview
• Profitable, $150M revenues (2016)
• Product commercialization capabilities
• Unique pharmaceutical technologies
• Global Footprint
• Proven Leadership Team
• Actively seeking acquisitions in select markets
• Supported by TPG Capital
• Pipeline – 8 proprietary development assets – Current focus in CNS and GI
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Vandalia, Ohio, U.S.
Pessano, Milan, Italy
©2017 Adare Pharmaceuticals, Inc.
Global Locations
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Established Commercial Operations in North America and Europe
Multinational Presence To Serve Global Markets
Mont-Saint-Hilaire
Vandalia
San Giuliano
Pessano
Princeton
Houdan
©2017 Adare Pharmaceuticals, Inc. 6
Business Model
Product Portfolio
• Portfolio of 40 products commercialized through partners
• Over 60 launches by our partners since 2009
• Commercialization of selected pipeline products
Pipeline
• Differentiated, high value products
• Develop complex proprietary specialty and generic products addressing the unmet needs of patients
Formulation Development
• Co-develop new formulations in partnership with biotech/ pharma companies
©2017 Adare Pharmaceuticals, Inc.
Product Launches in Major and Emerging Markets
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Since 2009, Over 60 Product Launches in 44 Countries
Over 40 Products incorporating our proprietary technologies have been commercialized around the world
©2017 Adare Pharmaceuticals, Inc.
Proprietary Pipeline
• 6 NDAs and 2 ANDAs – APT-5025 GUDFUA date: March 2017 – APT-5031, a complex generic for CNS due to file with FDA in 2017
• Initial markets target for approval in US and Europe
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ADA-5070
APT-5041
APT-5035
APT-5032
APT-5030
APT-1011
APT-5031
APT-5025
Form Dev POC Ph II Ph III Filing
CNS
CNS
CNS
CNS
CNS
CV
GI
GI
Partnered products not disclosed
Granted Orphan Drug Designation – US, EMA
©2017 Adare Pharmaceuticals, Inc.
Broad Proprietary Technology Portfolio
• Eight distinct oral formulation technologies – Scaled-up and validated
– Commercialized worldwide
– Patent protected
• Applicable to Rx and OTC products ─ therapeutic area agnostic
Create patient-centric formulations: novel products and differentiation for line extensions
DIFFUCAPS, DIFFUTAB, EURAND MINITABS, LIQUITARD, and MICROCAPS are registered trademarks of Adare Pharmaceuticals S.r.l. BIORISE and ORBEXA are trademarks of Adare Pharmaceuticals S.r.l. ADVATAB is a registered trademark of Adare Pharmaceuticals, Inc
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• Taste-masking and ODTs
• Customized Drug Release
Bioavailability enhancement
• AdvaTab®
• Microcaps®
• Liquitard®
• Diffucaps®
• Diffutab®
• MMTS™
• Orbexa™
• Biorise™
• Diffucaps®
©2017 Adare Pharmaceuticals, Inc.
Track Record of Partnering Success
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The above corporate marks are the property of their respective owners.
Over 40 Products Incorporating Our Proprietary Technologies Have Been Commercialized Around the World
©2017 Adare Pharmaceuticals, Inc.
Active Company Description Technology
Macrolide Undisclosed Antibiotic formulated as dry syrup to ensure TM up to 5 days once suspended in water
Microcaps® Diffucaps®
Product Company Description Technology
Pancreatic enzymes in delayed release capsules Reliable delivery through Gastrostomy Tubes MMTSTM
Propranolol HCl in customized release capsules FDA approved for treatment of hypertension Diffucaps®
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Examples of Successful Drug Development
All trademarks are property of their respective owners. The above corporate marks are the property of their respective owners.
©2017 Adare Pharmaceuticals, Inc.
Microcaps® Taste Masking Technology
CASE STUDY Dry Syrup Long Lasting - Taste Masking
©2017 Adare Pharmaceuticals, Inc.
Microcaps® - Complete and Effective Taste-masking
• Microencapsulation by coacervation:
– Uniform coating of a solid particle or liquid droplet with a rigid semi-permeable polymer
• Creates a physical barrier:
– Effective taste masking
– Customized release profile
– Turn liquids into solids
– Combine incompatible APIs
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KCl during micro-encapsulation
with ethycellulose
Final KCl microcapsule
after drying
Polymer Membrane
Drug Particle (crystal, granulate,
or liquid)
Adare is a leader in organic phase coacervation for pharmaceutical products
©2017 Adare Pharmaceuticals, Inc.
Easy to Swallow
• Formulated as a direct dose sachet or ODT (to further improve patient compliance) makes it easy to swallow and support oral administration without need for liquid
• The sachets can be opened and the contents used also as a "sprinkle" formulation
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©2017 Adare Pharmaceuticals, Inc.
Case Study: Antibiotic Dry Syrup Secure Long Lasting Taste Masking for Extemporary Suspension
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DRUG • Antibiotic - Macrolide
NEED • Taste-mask a bitter API • Suitable to secure
Fast release in gastric environment Reduced particle size for pediatric population At least 5 days taste-masking once suspended in
water
SOLUTIONS • Oral powder formulation using Microcaps® taste masking • Commercial presentation: Dry Syrup suitable for
reconstituting a suspension and administering a daily dose of 15/30 mg/kg
©2017 Adare Pharmaceuticals, Inc.
Double Coating: Taste-masking + pH Dependent
Pure API PSD ≈ 100 µm
Primary Coating Microcaps®
Secondary Coating Diffucaps®
20 - 30% (w/w) 10 - 15% (w/w) 55 - 70% (w/w)
Double coating of single particles: original PSD practically preserved
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©2017 Adare Pharmaceuticals, Inc.
Taste Masking Preserved for >10 Days in Suspension
After Suspension Reconstitution
Time Microscope TM evaluation
Start membrane OK tasteless
1 day membrane OK tasteless
4 days membrane OK tasteless
7 days membrane OK tasteless
11 days membrane OK tasteless
15 days secondary coating partially swollen
tasteless
• Taste masking prolonged by appropriate formulation of excipients (suitable buffer)
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©2017 Adare Pharmaceuticals, Inc.
Balance Taste Masking and Narrow Absorption Window
.
Double Coating Prototypes (A and B) vs Reference Product Healthy Volunteers – n=15
S1 S2
Prototype A
Prototype B
Reference
DRT HCl 0.1N ( %)
2’ SD 4’ SD 10’ SD 30’ SD
Prototype A % Released 97 1 98 1 98 1 98 1
• Rapid release at gastric conditions demonstrated in vitro and in vivo • Achieved bioequivalence in pilot clinical study (N=15)
In vitro dissolution
Pilot clinical study (N=15)
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©2017 Adare Pharmaceuticals, Inc.
Antibiotic Dry Syrup - Successful Development
• 10+ days taste masking in extemporary suspension, while maintaining rapid release properties after administration
• Final PSD well below 200 µm to grant suspension homogeneity, minimize sandy effect and improve patient compliance (infants)
• High drug load secured (up to 70%), considering the small PSD (i.e. high surface area) of the starting material
• Bioequivalence proven in pilot clinical study
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©2017 Adare Pharmaceuticals, Inc.
MMTSTM Multi Mini Tablet System CASE STUDY Deliver drugs through Gastrostomy tube
©2017 Adare Pharmaceuticals, Inc.
MMTSTM Multi Mini Tablet System
Eurand Minitabs®
2.0 mm
Microtablets
1.5 mm
Ultra Microtablets
1.2 mm
Ultra Microtablets
1.0 mm
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• Combining tablet and multiparticulate dosage form – High drug loading capacity – Titration of a broad dosage range – Wide range of customized release profiles in a single capsule
• Improving ease of administration for patients with swallowing difficulties – Broad range of MMTS tablet sizes – Flexible dose delivery (capsules, sachet, sprinkles)
• Commercially proven: successfully developed Zenpep (Allergan) – treatment of pancreatic enzyme insufficiency due to
cystic fibrosis
©2017 Adare Pharmaceuticals, Inc.
DRUG • ZENPEP® FDA-approved pancreatic enzyme product (PEP) for exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) and other conditions
NEED • PEPs are administered through feeding tubes when oral administration is not feasible or convenient
• Current clinical practice is based on clinical experience and anecdotal evidence and very few published data are available to support medication administration through G-tubes.
• Pancreatic enzymes (i.e. Lipase, Protease and Amylase) are very sensitive and they could be inactivated if exposed to gastric environment
SOLUTION • PEP in the form of Eurand Minitabs® and Microtabs • Suitable for being administered through G-Tube without clogging
and being damaged • Uniform gastro-protective coating non impacted by contact with
nutritional fluid and the clinical practice
Case Study: Gastrostomy tube (G-tube) Reliably and Effectively delivery of drugs
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ZENPEP is a registered trademark of Allergan. EURAND MINITABS® is a registered trademark of Adare Pharmaceuticals S.r.l.
©2017 Adare Pharmaceuticals, Inc.
Purpose of the study
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• Identification of a reliable and easy to handle method of administering Pancreatic Enzyme Replacement Therapy using G-tubes
• Investigation of delivery of Zenpep and Ultresa, obtained with MMTSTM technology
• Different typology of nutritional fluids, syringes and G-tubes were investigated
©2017 Adare Pharmaceuticals, Inc.
Use of Pancreatic Enzyme Supplements
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Ultresa Minitablets Zenpep Microtablets
2000 µm
1500 µm
Product Type of beads Syringe tip/ volume (ml)
G-tube type External
diameter (Fr)
Zenpep Microtablets
Catheter tip/35 ml
Mic Bolus
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Minitablets 20
Ultresa Minitablets 20
Creon Pellets
(extruded beads) Slip tip/20 ml 18
©2017 Adare Pharmaceuticals, Inc.
Coating Integrity
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• Visual inspection of the G-tubes after pancreatic enzymes administration demonstrated that G-tube patency was unaffected and beads were deliverable without sticking and tube clogging
• Enteric coating of the beads remained intact after the passage
through G-tube since no appreciable difference between untreated and administered beads was found in terms of dissolution performances
©2017 Adare Pharmaceuticals, Inc.
Future Trends: Ultra Microtablets
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Slip tip syringe Catheter tip
• As a result of the smaller size, Ultra Microtablets placebo (1.2 mm and 1.0 mm) are deliverable by slip tip syringes
• Mic-Key G-Tubes with 16Fr diameter revealed suitable to allow the passage of both size of beads (1.2 mm and 1.0 mm)
Product (size of beads) Syringe tip/volume (ml) G-tube type External diameter (Fr)
Ultra Microtablets (1.2 mm) Slip tip/10 and 20 ml Mic-Key 16
Ultra Microtablets (1.0 mm) Slip tip/10 and 20 ml Mic-Key 16
©2017 Adare Pharmaceuticals, Inc.
DIFFUCAPS® Customized Release Technology ̵ Timed Pulsatile Release
CASE STUDY Innopran XL® - Chronotherapy Release
©2017 Adare Pharmaceuticals, Inc.
Diffucaps® - Optimize Therapeutic Performance
• Drug core layered with one or more rate-controlling polymer blends • Multiparticulate system
– Sophisticated control of drug delivery – Single drugs and drug combinations
Timed Pulsatile Release Timed Sustained Release
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©2017 Adare Pharmaceuticals, Inc.
Formulation Flexibility to Target a Tailored PK
profiling
Multiparticulate System and Timed Pulsatile Release
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60
80
100
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% D
rug
Re
leas
ed
time (hrs)
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20
40
60
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Time (Hrs)
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% M
PH
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Time (Hrs)
MPH Release from Sugar Spheres Coated with Eudragit RS PO: Eudragit L 100: Eudragit S 100
(0.9:0.8:0.3)
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0 2 4 6 8 10 12 14Time (Hrs)
Sharper pulse with longer lag Longer lag with slow release rate Shorter lag time
Prototype 1
Prototype 2
Prototype 3
©2017 Adare Pharmaceuticals, Inc.
Case Study: Innopran XL®
How to ensure drug release when needed most
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DRUG • Propanolol hydrochloride is a beta-blocker indicated for the treatment of hypertension, to lower blood pressure
NEED • Develop a once-daily, modified release dosage form releasing in the early mooring hours when the patient is usually at greatest risk of high systolic blood pressure
SOLUTION • Innopran XL® customized release beads delivering drug at early morning hours
• Commercial presentation: hard gelatin capsules filled with Diffucaps® XL beads for 80 mg and 120 mg strengths
InnoPran XL® is a registered trademark of ANI Pharmaceuticals, Inc. Diffucaps® is a registered trademark of Adare Pharmaceuticals S.r.l.
©2017 Adare Pharmaceuticals, Inc.
Cardiovascular events - Circadian Clock Dependent
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Hastings MH, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nature Reviews Neuroscience. 4(8):649-61, 2003 Aug.
Chronotherapeutic Propanolol to synchronize drug administration/ delivery with circadian rhythms in order to optimize efficacy
and/or minimize side effects
©2017 Adare Pharmaceuticals, Inc.
Propranolol CRR - A Tailored Approach
• The objective of chronotherapy for hypertension is to deliver more drug during early morning post-awakening when blood pressure is high and less drug during the middle of the sleep cycle when BP is low
• Traditional sustained release agents (e.g. Inderal® LA), which deliver a near-constant drug concentration, do not meet the needs for chronotherapy in hypertension
• InnoPran XL® (Propranolol CRR) has been designed, based on extensive modeling, to provide tailored chronotherapy in hypertension to complement the circadian pattern, thus reducing vulnerability to morning cardiovascular events
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InnoPran XL® is a registered trademark of ANI Pharmaceuticals, Inc. Inderal® LA is a registered trademark of ANI Pharmaceuticals, Inc.
©2017 Adare Pharmaceuticals, Inc.
Rational formulation design: modeling
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Simulated Steady State Plasma Levels of Propranolol HClFollowing Administration of One CRR (IR / TSR) Capsule Every 24 Hours
8:00 10:00 12:00 2:00 4:00 6:00 8:00 10:00 12:00 2:00 4:00 6:00PM AM PM
Time (hrs)
0
5
10
15
20
25
30
35
40
45
50
ng/m
l
Propranolol 34.pr4
20 mg IR / 60 mg TSR
20 mg IR / 100 mg TSR
20 mg IR / 140 mg TSR
Figure 5.0.6 Simulated steady state profiles after oral administration of 1 TPR cps every 24h
©2017 Adare Pharmaceuticals, Inc.
In vivo results: Chronotherapy with InnoPran XL®
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Plasma Profiles of InnoPran XL® versus Inderal® LA
InnoPran XL® is a registered trademark of ANI Pharmaceuticals, Inc. Inderal® LA is a registered trademark of ANI Pharmaceuticals, Inc.
Inert Core Material
Timed Erosion Polymer
Seal-Coat Polymer
Drug Substance
InnoPran XL®
Inderal® LA
©2017 Adare Pharmaceuticals, Inc.
With a Broad Range of Oral Formulation Technologies…
• Overcome complex formulation challenges • Differentiate commercialized products and products in
development – Improve patient convenience – Address specific patient populations – Optimize release profiles for new therapeutic uses
• Add valuable IP
….We Can Help Transform
Your Products
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©2017 Adare Pharmaceuticals, Inc. ©2017 Adare Pharmaceuticals, Inc.
Meet us at Booth #14
To learn more, please contact:
Holger.Neecke@adarepharma.com Luigi.Boltri@adarepharma.com
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