How-to Use Oral Drug Delivery Technology Innovatively · 1European pharmacopoeia. 9th ed....
Transcript of How-to Use Oral Drug Delivery Technology Innovatively · 1European pharmacopoeia. 9th ed....
©2018 Adare Pharmaceuticals
How-to Use Oral Drug Delivery Technology Innovatively
Luigi BoltriDirector, Technology Development
DDF Berlin, March 11-13, 2019
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©2018 Adare Pharmaceuticals
Agenda01Company Highlights
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03
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05
07
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Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals
Agenda01Company Highlights
02
03
04
05
07
06
Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals
Company Overview
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One of only a handful of global, turnkey, high-quality specialty CDMOs
Intellectual property
>300 patents
Global focus and reach
Manufacturing capabilities
Marketed product
experience
Quality track record
Global R&D
Pharmaceutical development
Clinical
Regulatory affairs
©2019 Adare Pharmaceuticals
©2018 Adare Pharmaceuticals
Proven track record Over 40 products with blue-chip partners in more than 100 countries
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Human / Veterinary – Prescription / Over-the-Counter – Adult / Pediatric
©2019 Adare Pharmaceuticals
©2018 Adare Pharmaceuticals
Agenda01Company Highlights
02
03
04
05
07
06
Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals
Proven innovative technology platforms
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Pharmaceutical
Technologies
Right drug
Right patient
Right form
Microbiome
Our bacteria influencing our
state of being
©2019 Adare Pharmaceuticals
©2018 Adare Pharmaceuticals
Pharmaceutical technologiesRight drug, right patient, right form
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To improve taste and provide
alternative dosage formsTo optimize therapeutic
performance
To improve solubility
High dose, immediate release, and/or
customized release
Orally disintegrating tablets (ODTs),
rapidly disintegrating tablets (RDTs),
powder for extemporaneous
suspensions, and sprinkles for ease of
administration and convenience
Effective taste masking
Patient-friendly, ideal for those who
experience difficulty swallowing
regular capsules and tablets
Customized drug release profiles to
optimize efficacy, safety, and dosing
frequency
Drug formulations exhibiting unique
release profiles can be combined in a
single dosage form
Enables the development of viable
formulations of drugs with limited
solubility
Solid solutions, hot-melt extrusion
(HME), and spray-drying capabilities
also available
©2019 Adare Pharmaceuticals
©2018 Adare Pharmaceuticals
Agenda01Company Highlights
02
03
04
05
07
06
Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals
Pulsatile Release
1European pharmacopoeia. 9th ed. Strasbourg
Council of Europe; 2016.
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.
Park, K. (2014). Journal of Controlled Release, 190, 3–8.
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Multiparticulate - 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
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Multiparticulate - 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
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©2018 Adare Pharmaceuticals
Agenda01Company Highlights
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03
04
05
07
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Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals 14
Colonic
Absorption
Site Specific
DeliveryTimed Deliver
Multiple Actives
BID and TID
Mimicking
Chrono-
therapy
Pulsatile Drug Delivery
Possible Applications
Challenge
GenericsFast Onset and
Termination
Address
Tolerance
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Real Case Applications
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Source: https://hznp.azureedge.net/, Vimovo Full
Prescribing Information PDF, Page 28; accessed
03/05/2018.
Swanson, J., Gupta, S., Guinta, D., Flynn, D., Agler, D., Lerner, M.,
Williams, L., Shoulson, I. and Wigal, S. (1999), Acute tolerance to
methylphenidate in the treatment of attention deficit hyperactivity
disorder in children. Clinical Pharmacology & Therapeutics, 66: 295–
305.
Es
om
ep
razo
le c
on
ce
ntr
ati
on
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• Once daily delivery of Cyclobenzaprine ER shows optimal PK profile
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Single-day PK study:
Mean Cyclobenzaprine Concentration Over Time (N=36)
Cyclobenzaprine ER 30mg once dailyCyclobenzaprine IR 10mg 3 x daily
Inert Core
Material
Timed Erosion Polymer
Seal-Coat Polymer
Drug
Substance
Adare’s experience: Cyclobenzaprine
©2018 Adare Pharmaceuticals
Plasma Profiles of InnoPran XL
versus Inderal LA
InnoPran XL is a registered mark of ANI Pharmaceuticals, Inc.
Inderal is a registered mark of ANI Pharmaceuticals, Inc.
Inert Core
Material
Timed Erosion Polymer
Seal-Coat Polymer
Drug
Substance
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Hastings MH, Reddy AB, Maywood ES. Nature Reviews Neuroscience.
4(8):649-61, 2003 Aug.
Adare’s experience: Chronotherapy
©2018 Adare Pharmaceuticals
Agenda01Company Highlights
02
03
04
05
07
06
Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals 19
Traditional 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
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Quality 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
QTPPP and De-risking Development… can be complex
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3Adapted from Suarez, S – Strategies for developing dissolution tests methods fitted for purpose – AAPS Annual Meeting 2015
2Pharmaceutical Science and Clinical Pharmacology Advisory Committee, March 15, 2017
1IVIVC: Current Perspectives on Models and Practices April 5, 2018 - AAPS Webinar Series
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Learning Exercise
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• 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
Agenda01Company Highlights
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03
04
05
07
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Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals
CNS - 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
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Modelling & Simulation
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Pla
sm
a C
on
c (
ng
/mL
)
Time (hour)
Target Plasma Profiles for XXX 20 mg
Prototype 1 (SIM)
Prototype 2 (SIM)
Prototype 3 (SIM)
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80
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%D
rug
Rele
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Time (hour)
Target Dissolution Profiles
Prototype 1 (SIM)
Prototype 2 (SIM)
Prototype 3 (SIM)
Case 1
Simulation of Ideal PK
(target plasma profiles) Target dissolution profiles
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• 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
Images are not shown actual size.
Drug Containing Tablet
Core
Formulation Approach Case 1
©2018 Adare Pharmaceuticals
Feasibility Prototypes and Expected Outcome
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%D
rug
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Time (hour)
Actual Dissolution Data
Prototype 1 (ACT)
Prototype 2 (ACT)
Prototype 3 (ACT)
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0 2 4 6 8 10 12 14 16 18 20 22 24P
lasm
a C
on
c (
ng
/mL
)Time (hour)
Calculated Plasma Profile
Prototype 1 (CALC)
Prototype 2 (CALC)
Prototype 3 (CALC)
Case 1
Actual dissolution profiles Calculated plasma profles
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©2018 Adare Pharmaceuticals 28
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
CNS - Sleep Disorder
©2018 Adare Pharmaceuticals
- A model is as good as the parameter that
are fed to it
- As more data is collected the modelling
will become more powerful
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Pla
sm
a C
on
c (
ng
/mL
)
Time (hour)
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Case 2PK Simulation - Input Parameter
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• Sleep Onset
• Sleep Maintenance
• No Residual Effect
Case 2Conceptual Target Profile
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©2018 Adare Pharmaceuticals 31
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
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IR+ER, 10mg + 10mg,lagtime 3 hours
Time (hour)
IR+ER1+ER2,10mg+5mg+7.5mg, lag time2.5 hours and 4 hours
Sim
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ted
pla
sma
con
cen
trat
ion
(n
g/m
l)
3-Pulse Prototype
IR + DR1 + DR2
2-Pulse Prototype
IR + DR
Conceptual Target Profile - Simulated Case 2
©2018 Adare Pharmaceuticals 33
• 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
Triple Pulse Protoype Case 2
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75
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% D
rug
Re
leas
e
Time / Hr
©2018 Adare Pharmaceuticals
Agenda01Company Highlights
02
03
04
05
07
06
Agenda
Pulsatile Release and
Multiparticulates
Possible Applications
Developing Patient Centric
Medicines
Case Studies
Summary & Remarks
Technology Platform
©2018 Adare Pharmaceuticals 35
Summary and Remarks
Capabilities and processes for Need
Scouting and identification of Product
Opportunities
Deep understanding of Clinical
Pharmacology, Efficacy, Safety
Access to specialized and enabling
formulation technologies
Dedicated expertise and tools for
M&S
Deep knowledge in Material Sciences
and BioPharmaceutics
IP and Regulatory functions fully integrated
in QTPPP definition and development
Control and understanding of the
entire Development Chain
Need Identification01
Clinical Pharmacology02
Enabling Technologies03
Modelling and Simulation04
BioPharmaceutics05
IP and Regulatory07
Development Chain08
Patient Centric
Medicines at
Adare
Integrated capabilities for Clinical
Development and OperationsClinDev - ClinOps06
©2018 Adare Pharmaceuticals
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