ivivc in pediatric oips - ipac-rs...ipac-rs, ivivc in pediatric oips, h. wachtel, march 20, 2014 15...

IPAC-RS/UF Orlando Conference 2014 March 20, 2014

IVIVC in Pediatric OIPs

Herbert Wachtel

Declaration of Conflicts of Interest

H. Wachtel is employee of Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

2 IPAC-RS, IVIVC in Pediatric OIPs, H. Wachtel, March 20, 2014

Contents

Success factors for pediatric inhalation: • the inhalation device, • the pharmaceutical formulation • the patient (adherence…)

Impactor measurements acc. to USP/Ph.Eur. vs. replica • flow profiles and electronic lung

Comparison with in vivo deposition data …… literature „validation“

Checking ped. M-T replica using monodisperse particles

– 3 micrometers (and below?) are our target size Applications to device and formulation development

Summary

introduction


4

Motivation : Success factors for pediatric inhalation... (1) The inhalation device

SALE – Devices– SALE – Devices – SALE – Devices– SALE – Devices – Devices– SALE –

IPAC-RS, IVIVC in Pediatric OIPs, H. Wachtel, March 20, 2014

5

Motivation : We are prepared for any challenge ... (2) The pharmaceutical formulation

SALE – Powders for inhalation – SALE – Powders for inhalation – SALE -

toxicologically acceptable force control agents? IPAC-RS, IVIVC in Pediatric OIPs, H. Wachtel, March 20, 2014

6

Motivation : We are prepared for any challenge ... (3) The patient

Attention – Customer approaching – Attention – Customer approaching – Attention

Improper use of devices is common

Design inhaler / accessory for the use with children


Summary of motivation section: - what we want to do:

Make better medicines for children (~>EuPFI, US-PFI) How?

• Demonstrate performance in clinical trials • Establish laboratory tests ( draft: <1602> Spacers and valved holding chambers ) • mix Lab.- Methods and flow profile measurements

-> Handling Studies • low risk • low cost


The aerodynamic diameter is important, but there are additional influencing factors (inhalation, airway dim. …)

H. Wachtel - PCP ad board 2014 8

ICRP-Modell

0.0

0.2

0.4

0.6

0.8

1.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

depo

sitio

n pr

obab

ility

aerodynamic diameter [µm]

alveolarbronchialextrathoracictotal

Source: ICRP66; 1994 International Commission of Radiological Protection + later updates

shift expected for younger

The pharmacopeial aerodynamic fine particle assessment: - lots of work but it is far away from the patient

Apparatus A (EP only) Q = 60 L/min

Apparatus C, 4 Q = 60 L/min (and calcul.)

Appa

ratu

s 2 (U

SP o

nly)

Q

= 6

0 L/

min

(and

cal

cul.)

Apparatus E, 5, 6 (with presep.) Q = 15 – 100 L/min

Apparatus D, 1, 3 (with presep.) Q = 28.3 L/min (preferred)


10

Air flow profiles for testing: important, they co-define the delivered dose, site, …

Compendial testing Duration T (s) = 4 L * 60 (s/min) / Q (L/min)

T flow rate to achieve pressure drop = 4 kPa

alternative testing (averaged ?) flow profile corresponding to flow resistance of device

volume = 4 L

volume = 1.7 L

COPD (fitted avg.)

Example HandiHaler with flow resistance 0.16 Sqrt(mbar)*min/L


11

Performance tests closer to reality: Finlay‘s idealized throat models the patient.

The simplistic USP throat used for release testing is complemented by

more realistic throat models for early development.

~ ~

Alberta throat child‘s throat USP-inlet


Realistic models of children‘s extrathoracic airways for in vitro inhaler testing.

V=0.0398 L V=0.0245 L V=0.0148 L V=0.0112 L

for comparison: adult model V=0.079 L

Age 3-4 yrs Age 2-3 yrs Age 1-2 yrs Age 4-5 yrs


The in vitro patient:

13

Inhalation device

Mixing inlet

Upper airway model

Electronic lung

To pressurized air


Minimalistic set-up for realistic inhaler tests using filters and a lung simulator

e.g. Eklira Genuair

Filter

Throat model

Breathing pattern Lung simulator ASL 5000


Contents

Success factors for pediatric inhalation: • the inhalation device, • the pharmaceutical formulation • the patient

Impactor measurments acc. to USP/Ph.Eur. vs. replica • flow profiles and electronic lung


Checking ped. replica using monodisperse particles

- 3 micrometers (and below?) are our target size Applications to device and formulation development

Summary

introduction


Aerosol deposition studies using our realistic pediatric models are close to published in vivo data (1)!

Link to scintigraphic deposition data of Wildhaber et al. (1999) in six 2 year-old children using the same pressurized Metered Dose Inhaler (albuterol) and valved holding chamber (AeroChamberPlus with facemask).

16

Age 2-3 yrs

0

20

40

60

80

100

Lung deposition Actuator VHC

% d

rug

depo

sitio

n re

late

d to

the l

abel

clai

m

In vivo (Wildhaber et al.*) In vitro (our model)

* J.H. Wildhaber et al. (1999), The Journal of Pediatrics, Vol. 135, No. 1, pp 28-33


Aerosol deposition studies using our realistic pediatric models are close to published in vivo data (2)!

17

0

20

40

60

80

100

Lung deposition Face Face mask%

of d

rug

depo

sitio

n re

late

d to

the

labe

l cla

im

in vitro in vivo *

* Erzinger et al. (2007), Journal of Aerosol Medicine, Vol. 20, S1, S78-84

0

20

40

60

80

100

Lungdeposition

Face Face mask

% o

f dru

g de

posi

tion

rela

ted

to th

e la

bel c

laim

in vitro in vivo *

2-3 yrs old

1-2 yrs old

Link to scintigraphik deposition data of Erzinger et al. (2007) in children aged 1-3 yrs using a pMDI (albuterol) and a valved holding chamber.


don‘t forget the nose!

Aerosol deposition studies using realistic pediatric models are close to published in vivo data .

0

20

40

60

80

100

Lungdeposition

Face Face mask

% o

f dru

g de

posi

tion

rela

ted

to th

e la

bel c

laim

in vitro - oral inhalationin vitro - nasal inhalationin vivo

Link to scintigraphic deposition data of Erzinger et al. (2007)* in children aged 1-3 yrs using a pMDI (albuterol) and a valved holding chamber.

* Erzinger et al. (2007), Journal of Aerosol Medicine, Vol. 20, S1, S78-84

*

1-2 yrs old Oral inhalation:

Nasal inhalation:


Summary of the experimental part (1)

The set up has been shown and compared to: a) pharmacopeial procedures (dose tubes, impactors) b) literature -> ( ~ Validation?) limitation: ethic considerations in children our way forward: refer to existing deposition studies clear gap: Best practice in adults: see e.g. study by Bo Olsson et al. J Aerosol Med and Pulm. Drug Delivery 26 (0), 2013, 1–15 - Validation of a General In Vitro Approach … Recommendation: Please consider recording inhalation flow profiles when planning your next pivotal pediatric study.


Contents






Summary

introduction


Where do our <<inhaled>> particles go?

methylene blue Inner coating: Brij + glycerol + water


Checking pediatric replica using monodisperse particles

Vibrating Orifice

Generator

manifold &

Aerosizer

particles

SEM image of methylene blue particle


Example: In-vitro performance with methylene blue

0%

20%

40%

60%

80%

100%

15 L/min 30 L/min 60 L/min

Dose

to L

ung

[%]

1-2 yrs mouth

3µm5µm7µm

0%

20%

40%

60%

80%

100%


Dose

to L

ung

[%]

1-2 yrs nose

3µm

5µm

7µm

Relevant, as children < 18 months will inhale through their nose

n.b.: typical mouth, typical nose, not from the same subject!


Example: In-vitro performance with methylene blue

Partly relevant, older children will inhale through their mouth

0%

20%

40%

60%

80%

100%


Dose

to L

ung

[%]

4-5 yrs mouth

3µm5µm7µm

0%

20%

40%

60%

80%

100%


Dose

to L

ung

[%]

4-5 yrs nose

3µm5µm7µm

n.b.: typical mouth, typical nose, not from the same subject!


Contents






Summary

introduction


Application to dry powder inhalers: Easyhaler - Novolizer & idealized child model (4-5 years)

constant flow flow profile

DD throat DTL DD throat DTL

DD throat DTL DD throat DTL

0 20 40 60

drug

mas

s (%

ND

)

80 100

0 20 40 60

drug

mas

s (%

ND

)

80 100

0 20 40 60

drug

mas

s (%

ND

)

80 100

0

20

40

60

drug

mas

s (%

ND

)

80

flow = 28, 41, 60 L/min

flow = 45, 60, 75 L/min

PIF = 9 L/min

PIF = 24, 42, 51 L/min

Easyhaler

Novolizer

albuterol sulfate lactose blend


Formulation development: Test with lactose (34µm or 19µm) blend containing albuterol sulfate

Lactose blend 1 blend 2 34µm 19µm

A. Below, thesis Univ. Düsseldorf (2013)

0 20

40

60

0

20

40

60

DTL

(% D

D)

DTL

(% D

D)

Easyhaler: • no influence of carrier size • no throat effect

Testing @ 4 kPa

Novolizer: • cyclone+impact+ carrier size • throat effect

tube-like

cyclone

Easyhaler

Novolizer


Formulation dependence: Soft pellets do not work everywhere

Am

ount

of d

rug

[% D

D]

Throat

DTL

<5 µm

A. Below, thesis Univ. Düsseldorf (2013)

Alberta Throat Const. Flow 4 kPa 4 L

60 µm


29

Different types of spacers / valved holding chambers lead to different throat deposition and dose to lung.

0

20

40

60

80

100

Respimat Funhaler Vortex AerochamberPlus

% o

f lab

el c

laim

Mouthpiece Respimat Spacer Throat DTL

DTL33%

DTL22%

DTL33%

ThroatThroat

DTL51%

Throat

RH=50%

Results using throat model and flow profiles a)single breath Respimat and b)5 breaths with spacers of a 5 year-old child.

Can Pediatric Throat Models and Air Flow Profiles Improve Our Dose Finding Stratety? Herbert Wachtel, Deborah Bickmann, Jorg Breitkreutz, Peter Langguth RDD 2010, Vol 1 (2010): pp 195-204


Focus on the patient: Very young children (below 5 years)

The young child‘s different „hardware“requires adaptation!

0 5 10 15 20-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

air f

low

rate

(L/s

)

time (s)

0.0

0.5

1.0

1.5

2.0

1/f

T_pu

lse

Tin

release

VA

Delta

Delta

2

VCin

PIFA

inhaled volume (L)

below 5 years

flow resistance


Handling study investigating children below 5 years: stepwise approach

What is checked?

With help by caregiver

Child alone

Valved holding chamber with help by caregiver

below 5 years


In-vitro results using typical flow profiles of children -- valved holding chamber with face mask --


years years years years r.h.

effect of rel. humidity

32

Dose prediction knowing the inhalation profile (and the inhaler/spacer+mask combination)

Typical patient data:

Resulting dosing prediction:

Weight (kg) Two puffs (µg) µg/kg

10 2 x 0.13 0.026

13.1 2 x 0.39 0.060

16.5 2 x 0.46 0.056

22.4 2 x 0.96 0.086

70 (adult) 2 x 1.6 0.046

Existing theory can be applied In-vitro calibration data


Summary & Conclusion

Deposition studies in vitro require: – Throat models – Inhalation flow profiles

and a common level of acceptance / standardization. -> CSA Z264 1-02 (Spacers + … ) There is an urgent need for these tools in order to enable studies representing children of all age groups and even sub-groups immediately when devices / formulations are created. The in vitro studies contribute to a better understanding of device–patient interaction and help e.g. to extend the range of applications a device might face by simplifying tests with accessories, e.g. spacers.


Many thanks to …

- D. Bickmann, A.-M. Ciciliani A. Jung, M. Metzger, R. Winkler: Boehringer Ingelheim - Professor Dr. Jörg Breitkreutz, A. Below: Heinrich Heine-University, Düsseldorf - Professor Dr. Peter Langguth: Johannes Guttenberg University, Mainz

35

Herbert Wachtel Boehringer Ingelheim Pharma GmbH & Co. KG

Respiratory Drug Delivery Binger Str. 173

55216 Ingelheim am Rhein

+49 (0) 6132 – 7798552 [email protected]


ivivc in pediatric oips - ipac-rs...ipac-rs, ivivc in pediatric oips, h. wachtel, march 20, 2014 15...

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