leonie hattler - tablet in a cup
TRANSCRIPT
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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Dru
g r
ele
ase
[m
g]
Time [min]
Influence of core-diameter on dissolution speed
core 9mm
core 7mm
core 5mm
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caff
ein
e r
ele
ase
[m
g]
time [min]
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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La
g-t
ime
[m
in]
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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La
g-t
ime
[min
]
Specifc amount of PCA [mg/cm2]
Correlation of amount PVA with lag-time
specific amount PVA
Linéaire (specificamount PVA)
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caff
ein
e r
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ase
[m
g]
time [min]
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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caff
ein
e r
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ase
[m
g]
time [min]
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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dru
g r
ele
ase
[%
]
time[min]
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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caff
ein
e r
ele
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[%
]
time [s]
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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