Leonie Hattler 15.10.2013

Supervised by Rainer Alles and Dr. Maxim Puchkov

Research Group of Prof. Jörg Huwlyer Department of Pharmaceutical Technology,

University of Basel

Outline Example of a state-of-the-art controlled release market

product

Feasibility trials of the TIC design.

The production of TICs with different release kinetics

Automated production

Constraints of design

Modeling and in-silico optimization of TICs

Conclusion/ Outlook

Concerta (OROS)

de.usermeds.com http://www.medicineonline.com

Disadvantages

Difficult and time consuming formulation work New formulation development necessary for every API Complicated and expensive production with special

equipment needed (3-layer tabletting machine with special turret and tooling due to extra-high tablets, laser-device for the orifice)

Is there an easier possibility?

Hypothesis Produce tablets, that have a constant surface during the release

process, as simple as possible in order to have zero-order kinetic

The knowlegde about intrinsic dissolution will be adapted to a dry coated tablet

Produce a device with the Styl‘One compacting a pure drug core in a non-dissolving, non-swelling , non-porous inert cup

Styl‘One

Single punch research press with dry coating function and possibility to compress up to five –layer tablets

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Influence of core-diameter on dissolution speed

core 9mm

core 7mm

core 5mm

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Dissolution rate of delayed release TICs with 5mm cores , using different amounts of lag-substance

15mg PVA (1)

15mg PVA (2)

15mg PVA (3)

23mg PVA (1)

23mg PVA (2)

23mg PVA (3)

30mg PVA(1)

30mg PVA (2)

30mg PVA (3)

y = 1,7851x - 92,909 R² = 0,9975 0

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Specific amoun of PVA [mg/cm2]

Correlation of amount PVA with lag-time

specific amount PVA

Linéaire (specificamount PVA)

y = 3,356x - 135,24 R² = 0,9886

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Specifc amount of PCA [mg/cm2]

Correlation of amount PVA with lag-time

specific amount PVA

Linéaire (specificamount PVA)

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Dissolution rate of pulsatile release TICs with 5mm cores, using different amounts of lag-substance

15mg PVA (1)

15mg PVA (2)

15mg PVA (3)

23mg PVA (1)

23mg PVA (2)

23mg PVA (3)

30mg PVA (1)

30mg PVA (2)

30mg PVA (3)

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Dissolution profile of 10 TICs (7mm core) automated production

TIC 1

TIC 2

TIC 3

TIC 4

TIC 5

TIC 6

TIC 7

TIC 8

TIC 9

TIC 10

no. TIC speed [mg/min] average speed

[mg/min]

R2 IDR

[mg/min/cm2]

average

[mg/min/cm2]

1 0.9393

0.9533±0.0343

0.9987 2.4410

2.4773±0.0890

2 0.9673 0.9983 2.5138

3 0.9121 0.9962 2.3703

4 0.9163 0.9984 2.3812

5 0.9008 0.9966 2.3410

6 0.9941 0.9981 2.5834

7 0.9941 0.9981 2.5834

8 0.9816 0.9988 2.5509

9 0.9606 0.9988 2.4964

10 0.9663 0.9982 2.5112

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Constraints of the design

Duloxetine hydrochlorid, solubility of 2.74 g/l Duloxetine base , solubility of 0.00296g/l

In silico modeling

The F-CAD software was used for in silico simulations. This software is based on three-dimensional cellular automata and massively parallel computing[1].

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[1]Puchkov M, Tschirky D, Leuenberger H. 3D Cellular Automata in CAD of Pharm. Formulations in “Formulation Tools for Pharm. Dev.” J. Aguilar, ed., Woodhead Publ. 2013.

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optimized end-accelerated TIC

Real end-accelerated TIC

Optimized end-accelerated TIC

Conclusion I The feasibility of drug release modification by tablet

design was proofed.

Zero-order release kinetic was achieved with the TIC design.

Pulsatile release pattern and lag-times were manufactured and correct release sequence was achieved.

Conclusion I The TIC drug delivery device represents a promising

alternative to conventional oral drug delivery systems

The feasibility of drug release modification by TIC design was proofed

TICs with complex release kinetics were developed in relatively short time without formulation development

Zero-order release

Delayed release (pH-independent)

Pulsatile release

Accelerated release

Conclusion II 3D-cellular-automated-based model showed good

agreement with the experimental results and optimization was possible.

Deviations in the duration of the lag-times are due to the behavior of PVA (gel-formation). Therefore PVA is not an optimal substance used as lag-substance.

Outlook The optimization results from the simulation of the

end-accelerated TIC have to be confirmed with further experiments.

Up to now, only two APIs were investigated. Further screening in a wider range of different APIs is required

Further search for lag-substances without gel-formation is required

In the future, different drug substances have to be tested regarding the implementation of the TIC design in polypharmacy.

Thank you for your attention!

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