Characterization of on! Nicotine Pouches Part 2: Nicotine

Fadi Aldeek, Nicholas McCutcheon, Cameron Smith, Hannah

Grisevich, Christopher J. Suarez, John H. Miller, Christopher

B. McFarlane, Karl A. Wagner, and Tim L. Danielson.Altria Client Services LLC, Richmond, VA 23219

2020 CORESTA Congress Online

Sciences.altria.com

Characterization of on!® Nicotine Pouches – Part 2: Nicotine Dissolution Release Profiles

2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

INTRODUCTION➢ Oral tobacco products exist in two major categories; traditional smokeless tobacco and modern oral nicotine products.

▪ Evaluate product performance

▪ Guide product design

▪ Product to product performance comparison

▪ Develop in-vivo / in-vitro correlation (IVIVC)

➢ Modern oral nicotine products come in various solid forms including lozenges, gums, dissolving tablets, and nicotine

pouches.

➢ on!® is an oral tobacco-derived nicotine pouch product that does not contain cut, ground, powdered or leaf tobacco.

➢ on!® is currently available with 7 flavors (e.g., Citrus, Wintergreen, Mint, Coffee, Berry, Cinnamon, and Original) and 5

different nicotine strengths (1.5, 2, 3.5, 4, and 8 mg per pouch).

➢ Dissolution testing is a laboratory test method designed to demonstrate how efficiently an active ingredient is extracted out

of a solid oral dosage into solution:

2Altria Client Services | Fadi Aldeek | 2020 CORESTA Online Congress

2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

STUDY OVERVIEW➢ Adopted a robust nicotine release method utilizing the USP-4 flow-through cell apparatus.1

1- J. H. Miller, T. Danielson, Y. B. Pithawalla, A. P. Brown, C. Wilkinson, K. Wagner, and F. Aldeek. Development and validation of dissolution testing for nicotine release from smokeless

tobacco products using flow-through cell apparatus and UPLC-PDA. J. Chromatogr B 2020, 1141, 122012.

3

➢ Evaluated the nicotine release profiles from the 35 varieties of on!® nicotine pouches (7 flavors with 5 nicotine strengths

each).

➢ Performed product-to-product comparison for the 35 varieties of on!® pouches by calculating the difference factor (f1) and

similarity factor (f2) following FDA’s Guidance for Industry.2,3

➢ Compared on!® nicotine pouches to commercially available traditional pouched smokeless tobacco products.

2- Food and Drug Administration, Center for Tobacco Products, Office of Science, Dissolution as a critical comparison of smokeless product performance: SE requirements and

recommendations for the review of dissolution studies. 2016.

3- Food and Drug Administration, Guidance for Industry: Dissolution testing of immediate release solid oral dosage forms. 1997.

Altria Client Services | Fadi Aldeek | 2020 CORESTA Online Congress

2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

DISSOLUTION METHODOLOGY

Fractions CollectorPumpCells Holder

SOTAX CE7 Smart Flow-Through Cell Apparatus (USP-4)-UPLC-PDA

Flow-Through Cell

▪ Flow rate 4.0 mL/min ▪ Temperature 37 °C

https://www.sotax.com/en/usp4_dissolution_testing/

▪ 12 replicates ▪ 9 fractions per replicate

Dir

ecti

on

of A

rtif

icia

l S

aliv

a F

low

Filter Chamber

5 mm Ruby Bead

3 mm Beads1 mm Beads

on!® Pouch

Time (min)

Inte

nsi

ty

Nicotine

UPLC-PDA*

*UPLC-PDA: Ultra-high Performance Liquide Chromatography (UPLC)-Photodiode Array (PDA)


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

CUMULATIVE AND % RELEASE PROFILES

0

500

1000

1500

2000

2500

3000

3500

1 2 3 4 5 6 7 8 9

Ave

rage

d C

on

c. (μ

g/g

)

Fraction number

n =12

0

2000

4000

6000

8000

10000

12000

14000

16000

1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9

Ave

rage

d C

on

c. (μ

g/g

)

Sum of Fractions

n =12

0%

20%

40%

60%

80%

100%

120%

0 10 20 30 40 50 60 70

Pe

rce

nt

Rel

eas

e

Time (min)

n =12

Averaged Nicotine per Fraction (12 replicates) Sum of Averaged Fractions

Cumulative Release Profile% of Total Release Profile

Calculation of nicotine cumulative and % release profiles from 4 mg Mint on!® nicotine pouches (n=12). Error bars represent ± 1 standard deviation.

0

1

2

3

4

0 10 20 30 40 50 60 70

Cu

mu

lati

ve C

on

c. (

mg/

po

uch

)

Time (min)


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTSNicotine Cumulative Release Profiles

Similar observations were seen for Original, Citrus, Berry, Wintergreen, Coffee, and Cinnamon on!® nicotine pouches.

Cumulative release profiles of nicotine from Mint on!® nicotine pouches (n=12) across all nicotine strengths. Error bars represent ± 1 standard deviation.

0

2

4

6

8

10

0 10 20 30 40 50 60 70

Nic

oti

ne

Co

nc.

(m

g/p

ou

ch)

Time (min)

1.5 mg 2 mg 3.5 mg 4 mg 8 mg

Mint n = 12


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTS


% of total release profiles of nicotine from Mint on!® nicotine pouches (n=12) across all nicotine strengths. Error bars represent ± 1 standard deviation.

0%

20%

40%

60%

80%

100%

120%

0 10 20 30 40 50 60 70

Pe

rcen

t R

ele

ase

Time (min)

1.5 mg 2 mg 3.5 mg 4 mg 8 mg

% of Total Release Profiles of Nicotine

Mint n = 12


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTS

f1 values up to 15 (0-15) and f2 values of 50 or greater (50-100) demonstrate similarity or equivalence between

two products.

➢ Determine nicotine release profiles for two products (12 replicates per product)

➢ Use mean dissolution values from both curves at each time point to calculate difference factor (f1) and similarity factor (f2)

*Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms, FDA Center for Drug Evaluation and Research (CDER),1997.

Approach based on FDA guidance from CDER*

Dissolution Profiles Comparison


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTS

Mint on!®

Compared Products f1 f2 Equivalency

4 mg vs 1.5 mg 0.8 97.4 Yes

4 mg vs 2 mg 3.9 79.0 Yes

4 mg vs 3.5 mg 5.9 71.5 Yes

4 mg vs 8 mg 7.4 67.1 Yes

on!® nicotine pouches exhibit equivalent nicotine release profiles across all flavor variants and nicotine strengths.

Product to Product Comparison using f1 and f2


f1 and f2 values for compared on!® nicotine pouches across all nicotine strengths for each flavor. The on!® 4 mg pouches for each flavor were used as

the reference products for all comparisons.


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTSNicotine Cumulative Release Profiles

Cumulative release profiles of nicotine from 3.5 mg Wintergreen flavored on!® nicotine pouches, Wintergreen Skoal® Bandits, and Wintergreen Skoal® pouches (n=12). Error bars represent ± 1 standard deviation.

0

2

4

6

8

10

12

14

16

18

0 10 20 30 40 50 60 70

Nic

oti

ne

Co

nc.

(m

g/p

ou

ch)

Time (min)

Skoal Bandits Skoal Pouches on! Pouches

n = 12


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTS

% of Total Release Profiles of Nicotine

% of total release profiles of nicotine from 3.5 mg Wintergreen flavored on!® nicotine pouches, Wintergreen Skoal® Bandits, and Wintergreen Skoal® pouches (n=12). Error bars represent ± 1 standard deviation.

0%

20%

40%

60%

80%

100%

120%

0 10 20 30 40 50 60 70

Pe

rce

nt

Re

lea

se

Time (min)

Skoal Bandits Skoal Pouches on! Pouches

n = 12


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

RESULTS

Compared Products f1 f2 Equivalency

on!® Wintergreen vs Skoal® Bandits 8.1 61.0 Yes

on!® Wintergreen vs Skoal® pouches 21.1 46.0 No

3.5 mg Wintergreen on!® was found to be equivalent to Skoal® Bandits and different from Skoal® pouches (Wintergreen flavored traditional pouched moist smokeless tobacco product).

Product to Product Comparison using f1 and f2

f1 and f2 values for compared 3.5 mg Wintergreen on!® nicotine pouches to Wintergreen flavored Skoal® Bandits and Skoal® pouches.


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

SUMMARY

➢ Following FDA guidance, we applied a robust USP-4 dissolution method to determine the nicotine

release profiles for a variety of on!® nicotine pouches.

➢ Demonstrated a dose dependent response for the cumulative nicotine release profiles for all nicotine

strengths.

➢ Nicotine release rate for each flavor variant is equivalent based on % of total nicotine release profiles

and f1 and f2 criteria.

➢ The nicotine release rate for 3.5 mg Wintergreen on!® nicotine pouches was found to be equivalent to

Skoal® Bandits but faster than Skoal® pouches (Wintergreen flavored traditional pouched moist smokeless tobacco product).


2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

THANK YOU


Visit our Altria Science website to access this presentation and learn more about our scientific work.

Sciences.Altria.com or scan the QR Code below.

Questions? Email us! [email protected]

2020

_ST

15_A

ldee

k.pd

fC

ongr

ess2

020

- D

ocum

ent n

ot p

eer-

revi

ewed

by

CO

RE

ST

A

Documents

Characterization of on! Nicotine Pouches Part 2: Nicotine