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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Agenda01Company Highlights

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Agenda

Pulsatile Release and

Multiparticulates

Possible Applications

Developing Patient Centric

Medicines

Case Studies

Summary & Remarks

Technology Platform


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



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




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Agenda


Multiparticulates



Medicines

Case Studies

Summary & Remarks

Technology Platform


Proven innovative technology platforms

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Pharmaceutical

Technologies

Right drug

Right patient

Right form

Microbiome

Our bacteria influencing our

state of being



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




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Agenda


Multiparticulates



Medicines

Case Studies

Summary & Remarks

Technology Platform


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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2

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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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Agenda


Multiparticulates



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


Challenge

GenericsFast Onset and

Termination

Address

Tolerance

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwj-hNqgueHgAhXisaQKHRgQD3gQjRx6BAgBEAU&url=https://www.flaticon.com/free-icon/colon_954392&psig=AOvVaw2OhBjTxtVPAV3wS5RHuBIQ&ust=1551546975807090

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwj-hNqgueHgAhXisaQKHRgQD3gQjRx6BAgBEAU&url=https://www.flaticon.com/free-icon/colon_954392&psig=AOvVaw2OhBjTxtVPAV3wS5RHuBIQ&ust=1551546975807090


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


• 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


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



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Agenda


Multiparticulates



Medicines

Case Studies

Summary & Remarks

Technology Platform


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


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


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



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Agenda


Multiparticulates



Medicines

Case Studies

Summary & Remarks

Technology Platform


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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120

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%D

rug

Rele

ase

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


Feasibility Prototypes and Expected Outcome

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0 2 4 6 8 10 12 14

%D

rug

R

ele

ase

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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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


- 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

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Time (hour)

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Case 2PK Simulation - Input Parameter


• Sleep Onset

• Sleep Maintenance

• No Residual Effect

Case 2Conceptual Target Profile

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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

ula

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


• 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

100

0 1 2 3 4 5 6

% D

rug

Re

leas

e

Time / Hr



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Agenda


Multiparticulates



Medicines

Case Studies

Summary & Remarks

Technology Platform


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


THANK YOU!

Interested in knowing more about Adare’s technologies?

Please visit us at Boot #15

how-to use oral drug delivery technology innovatively · 1european pharmacopoeia. 9th ed....

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