How-to Use Oral Drug Delivery Technology Innovatively - Luigi Boltri Director, Technology Development - DDF Berlin 2019
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How-to Use Oral Drug Delivery Technology Innovatively Luigi Boltri Director, Technology Development DDF Berlin, March 11-13, 2019 ©2018 Adare Pharmaceuticals 1
Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare Pharmaceuticals
Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare Pharmaceuticals
Company Overview
One of only a handful of global, turnkey, high-quality specialty CDMOs
Global focus Quality track Manufacturing
and reach record capabilities
Pharmaceutical development Marketed
Clinical Global R&D product Intellectual >300 patents
Regulatory affairs experience property
©2018Adare
©2019 AdarePharmaceuticals
Pharmaceuticals 4
Proven track record
Over 40 products with blue-chip partners in more than 100 countries
Human / Veterinary – Prescription / Over-the-Counter – Adult / Pediatric
©2018Adare
©2019 AdarePharmaceuticals
Pharmaceuticals 5
Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare Pharmaceuticals
Proven innovative technology platforms
Pharmaceutical
Microbiome
Technologies
Right drug Our bacteria influencing our
Right patient state of being
Right form
©2018Adare
©2019 AdarePharmaceuticals
Pharmaceuticals 7
Pharmaceutical technologies
Right drug, right patient, right form
To improve taste and provide To optimize therapeutic To improve solubility
alternative dosage forms performance
High dose, immediate release, and/or Customized drug release profiles to Enables the development of viable
customized release optimize efficacy, safety, and dosing formulations of drugs with limited
frequency solubility
Orally disintegrating tablets (ODTs),
rapidly disintegrating tablets (RDTs), Drug formulations exhibiting unique Solid solutions, hot-melt extrusion
powder for extemporaneous release profiles can be combined in a (HME), and spray-drying capabilities
suspensions, and sprinkles for ease of single dosage form also available
administration and convenience
Effective taste masking
Patient-friendly, ideal for those who
experience difficulty swallowing
regular capsules and tablets
©2018Adare
©2019 AdarePharmaceuticals
Pharmaceuticals 8
Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare Pharmaceuticals
Pulsatile Release
Pulsatile release dosage form1
A pulsatile release dosage form is a modified-release dosage form showing
a sequential release of the active substance(s).
Sequential release is achieved by a special formulation design and/or
manufacturing method.
2
1European pharmacopoeia. 9th ed. Strasbourg 2
Park, K. (2014). Journal of Controlled Release, 190, 3–8.
Council of Europe; 2016.
©2018 Adare Pharmaceuticals 10Multiparticulate - Flexibility and Improved Safety
• Dose is divided in multiple units ensuring better distribution on the
mucosa with lower risk of local irritation
• Reproducible pharmacokinetic, being GI transit time less dependent
on gastric emptying
• Minimizes the risk of “dose dumping” for modified release systems,
• Easier titration of a broader range of dosages,
• Possibility to develop multiple strength products using the same
formulation
• Opportunity to facilitate development programs based on dose
proportionality
©2018 Adare Pharmaceuticals 11Multiparticulate - Precise Dosing and Improved Compliance
• Different APIs or same APIs with different dissolution profiles
can be combined in the final dosage form
• Can be combined with a measuring/dispensing device to
facilitate administration and/or adjust the dose based on dosage
directions (weight/age)
• Can be formulated as a direct dose sachet or ODT to further
improve patient compliance, make it easier to swallow, and
support oral administration without need for liquid
• Multiparticulates can be used as a "sprinkle" formulation
©2018 Adare Pharmaceuticals 12Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare PharmaceuticalsPossible Applications
Pulsatile Drug Delivery
Colonic Challenge Fast Onset and Address BID and TID Site Specific Chrono- Timed Deliver
Absorption Generics Termination Tolerance Mimicking Delivery therapy Multiple Actives
©2018 Adare Pharmaceuticals 14Real Case Applications
Esomeprazole concentration
Swanson, J., Gupta, S., Guinta, D., Flynn, D., Agler, D., Lerner, M., Source: https://hznp.azureedge.net/, Vimovo Full
Williams, L., Shoulson, I. and Wigal, S. (1999), Acute tolerance to Prescribing Information PDF, Page 28; accessed
methylphenidate in the treatment of attention deficit hyperactivity 03/05/2018.
disorder in children. Clinical Pharmacology & Therapeutics, 66: 295–
305.
©2018 Adare Pharmaceuticals 15Adare’s experience: Cyclobenzaprine
• Once daily delivery of Cyclobenzaprine ER shows optimal PK profile
Single-day PK study: Timed Erosion Polymer
Mean Cyclobenzaprine Concentration Over Time (N=36)
Drug
Substance Inert Core
Material
Seal-Coat Polymer
Cyclobenzaprine IR 10mg 3 x daily
Cyclobenzaprine ER 30mg once daily
©2018 Adare Pharmaceuticals 16Adare’s experience: Chronotherapy
Timed Erosion Polymer
Plasma Profiles of InnoPran XL
versus Inderal LA
Drug
Substance Inert Core
Material
Seal-Coat Polymer
InnoPran XL is a registered mark of ANI Pharmaceuticals, Inc. Hastings MH, Reddy AB, Maywood ES. Nature Reviews Neuroscience.
Inderal is a registered mark of ANI Pharmaceuticals, Inc. 4(8):649-61, 2003 Aug.
©2018 Adare Pharmaceuticals 17Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare PharmaceuticalsTraditional approach
• Trial & Error
• Use of dissolution methods developed for quality control
testing
• Extensive use of in vivo testing
• Conservative quality criteria based on history more than
linked to clinical performance
©2018 Adare Pharmaceuticals 19Quality Target Product Profile (QTPP) Prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality Understand PK/PD, develop predictive in vitro tools to tailor, optimize and target the in vivo performance QTPP is the guide to establish the product design strategy and focus the development effort to the therapeutic efficacy QTPPP - Quality Target Patient Product Profile ©2018 Adare Pharmaceuticals 20
QTPPP and De-risking Development… can be complex
3 1
2
2
1IVIVC: Current Perspectives on Models and Practices April 5, 2018 - AAPS Webinar Series
2Pharmaceutical Science and Clinical Pharmacology Advisory Committee, March 15, 2017
3Adapted from Suarez, S – Strategies for developing dissolution tests methods fitted for purpose – AAPS Annual Meeting 2015
©2018 Adare Pharmaceuticals 22Learning Exercise
• Understanding of Clinical Pharmacology and identification of
best candidate
• Listen at the Patient. Care, not only cure.
• One size does not fit all.
• Expert use of powerful, but complex, simulation and
descriptive tools
• Drug is a Physico-Chemical entity, not only biologically
active
• Understand and use the right Formulation Approach
©2018 Adare Pharmaceuticals 22Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare PharmaceuticalsCNS - behavioral disorder Case 1
Need Identification
• Current long acting medications only last up to 8 hours and
patients need control symptoms in the early evening.
• Currently patients need to supplement their long acting
medication with a short acting medication (IR supplement)
• Side-effects of insomnia and appetite suppression are impacting
the quality of life of the patient
Possible Solution
• Product that lasts up to 14 hours
• Optimized PK profile can limit the side-effects of insomnia and
appetite suppression without meaningfully reducing efficacy
©2018 Adare Pharmaceuticals 24Modelling & Simulation Case 1
Target Plasma Profiles for XXX 20 mg Target Dissolution Profiles
120
Prototype 1 (SIM)
7 100
Prototype 1 (SIM) Prototype 2 (SIM)
Plasma Conc (ng/mL)
6
%Drug Release
Prototype 2 (SIM) 80 Prototype 3 (SIM)
5
Prototype 3 (SIM) 60
4
3 40
2
20
1
0
0 0 2 4 6 8 10 12 14
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hour) Time (hour)
Simulation of Ideal PK
Target dissolution profiles
(target plasma profiles)
©2018 Adare Pharmaceuticals 25Formulation Approach Case 1
• Bead combinations each with a distinct release profile
• Optimize peak-to-trough ratios
• Single and combination products
• Ease of dose adjustment
Examples of Customized Release Particles/ Mini-tablets
Polymer
Drug Containing Tablet
Core
Images are not shown actual size.
©2018 Adare Pharmaceuticals 26Feasibility Prototypes and Expected Outcome Case 1
Actual Dissolution Data Calculated Plasma Profile
120 Prototype 1 (CALC)
7
100 Prototype 2 (CALC)
6
Plasma Conc (ng/mL)
%Drug Release
80 Prototype 3 (CALC)
5
60 4
Prototype 1 (ACT) 3
40
Prototype 2 (ACT) 2
20
Prototype 3 (ACT) 1
0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hour) Time (hour)
Actual dissolution profiles Calculated plasma profles
©2018 Adare Pharmaceuticals 27CNS - Sleep Disorder Case 2
Need Identification
Medication for insomnia that provides rapid sleep induction,
improved sleep maintenance and limited residual (next day) effects
Possible Solution
− Rapid sleep induction an initial pulse to help you get to sleep
(IR)
− Improved sleep maintenance through the entire night an
additional pulse/s to prevent middle-of-the night awakening
(DR)
− Limited, generally tolerable residual (next day) effects rapid
elimination preserves superior side effect profile from next day
sedation
©2018 Adare Pharmaceuticals 28PK Simulation - Input Parameter Case 2
3
- A model is as good as the parameter that
are fed to it
2.5
- As more data is collected the modelling
Plasma Conc (ng/mL)
will become more powerful
2
1.5
1
0.5
0
0 2 4 6 8 10Time12
(hour)14 16 18 20 22 24
©2018 Adare Pharmaceuticals 29Conceptual Target Profile Case 2 • Sleep Onset • Sleep Maintenance • No Residual Effect ©2018 Adare Pharmaceuticals 30
Conceptual Target Profile - Simulated Case 2
Modelling utilized to establish target profiles meeting objectives
Potential profiles of interest identified:
- Prototype A: Capsule containing X mg IR + X mg DR with a 3hr lag
- Prototype B: Capsule containing X mg IR + X mg DR with a 2 hr lag + X mg DR with a 4 hr Lag
20
Simulated plasma concentration (ng/ml)
18
16
14
IR+ER1+ER2,
3-Pulse Prototype
12 IR + DR1 + DR2 lag time
10mg+5mg+7.5mg,
2.5 hours and 4 hours
10
IR+ER, 10mg
2-Pulse + 10mg,lag
Prototype
8
time
IR +3DR
hours
6
4
2
0
0 2 4 6 8 10 12
Time (hour)
©2018 Adare Pharmaceuticals 31Triple Pulse Protoype Case 2
100
75
% Drug Release
50
25
0
0 1 2 3 4 5 6
Time / Hr
• Combining the different components (IR and DR) into a capsule for
administration results in a prototype with a unique release profile that can be
added to the PK Model to simulate the expected plasma level
©2018 Adare Pharmaceuticals 33Company Highlights 01
Agenda
Technology Platform 02
Pulsatile Release and
Multiparticulates 03
Possible Applications 04
Developing Patient Centric
Medicines 05
Case Studies 06
Summary & Remarks 07 Agenda
©2018 Adare PharmaceuticalsSummary and Remarks
Capabilities and processes for Need
01 Need Identification Scouting and identification of Product
Opportunities
Deep understanding of Clinical
02 Clinical Pharmacology Pharmacology, Efficacy, Safety
Access to specialized and enabling
03 Enabling Technologies formulation technologies
Dedicated expertise and tools for
Patient Centric 04 Modelling and Simulation M&S
Medicines at
Adare 05 BioPharmaceutics
Deep knowledge in Material Sciences
and BioPharmaceutics
Integrated capabilities for Clinical
06 ClinDev - ClinOps Development and Operations
IP and Regulatory functions fully integrated
07 IP and Regulatory in QTPPP definition and development
Control and understanding of the
08 Development Chain entire Development Chain
©2018 Adare Pharmaceuticals 35THANK YOU!
Interested in knowing more about Adare’s technologies?
Please visit us at Boot #15
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