Mar 9, 2018 - impact of lipolysis on colloid formation and drug solubilization. Dr HDR Vincent ... Zeta potential. Optical microscopy & cryo-TEM. Tran, T. et al.
WG 3 – First F2F meeting, Leuven, March 9th, 2018
Lipid-based formulations – impact of lipolysis on colloid formation and drug solubilization Dr HDR Vincent Jannin, UNGAP all WG meeting, March 2018
LIPID-BASED FORMULATIONS
Type
Composition
Comments
I
Lipids
Not self-emulsifying, digestion required
II
Lipids + water-insoluble surfactants
Self-emulsifying, high lipid
III
Lipids + surfactants + co-solvents
Self-emulsifying, lower lipid
IV
Water-soluble surfactants + co-solvents Formation of micelles
Koziolek, M. et al. 2018. Pharm Res https://doi.org/10.1007/s11095-017-2289-x
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IN VITRO DISPERSION – COLLOIDS FORMATION
Coacervation at 25°C
No coacervation at 25°C
Polarized Light Microscopy & XRPD Jannin, V. Bruley, C. 2007.
Coacervation at 37°C
Optical microscopy & cryo-TEM
Williams, H. et al. 2013. Pharm. Res. 30(12) 3059–3076
Tran, T. et al. 2016. Int. J. Pharm. 502. 151-160.
No coacervation at 37°C
Visual aspect & Stability Zeta potential
Dynamic Light Scattering & Taylor Dispersion Analysis
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Chamieh, J. et al. 2016. Int. J. Pharm. 513. 262-269
GASTROINTESTINAL TRACT Lipids
Bile (sels biliaires, cholestérol)
Pancreatic juice (HPL, HPLRP2, CEH)
Lipolysis of esterbased excipients eg. Polyoxylglycerides
Preduodenal lipase : Gastric lipase (HGL)
Lipolysis in the small intestine
Absorption of lipolysis Bakala N’Goma, J.C. et al. 2012. Therapeutic Delivery, 3(1) 105-124. byproducts Fernandez, S. et al. 2007. Biochim. Biophys. Acta. 1771. 633-640 Fernandez, S. et al. 2008. Biochim. Biophys. Acta. 1781. 367-375.
5
COMBINED IN VITRO DISPERSION & DIGESTION: pH-STAT • Lipolysis medium, pH 6.5 (fasted duodenal): Tris-maleate CaCl2, 2H2O NaCl NaTDC Phosphatidylcholine Milli-Q water
2 mM 1.4 mM 150 mM 3 mM 0.75 mM qs
• LFCS Consortium protocol:
Enzyme
Formulation
-10
-
5 Dispersion
0
5
1 g formulation in 36 mL lipolysis medium Stirring at 450 rpm Addition of 4 mL of pancreatin solution pH regulation with NaOH 0.2 or 0.6M
15
30
60
Digestion Williams, H. et al. 2012. J. Pharm. Sci. 101. 3360-3380 Williams, H. et al. 2012. Mol. Pharm. 9. 3286-3300
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VARIATIONS: 2-PHASE LIPOLYSIS 1 vessel, diluting
2 vessels, pumping
Fernandez, S. et al. 2009. Pharm. Res. 26. 1901-1910
Tran, T. et al. 2017. PhD thesis. Copenhagen University
Cinnarizine dissolved in the aqueous phase (%)
120
rDGL | pancreatin
100
80
60
40
No enzyme Active enzymes
20
0 0
10
20
30
40
50
60
70
80
90
Time (min)
Rhizopus oryzae
Pancreatin
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INFLUENCE OF DIGESTION ON COLLOIDAL STRUCTURE Synchrotron SAXS
Taylor Dispersion Analysis
Vithani, K. et al. 2017. AAPS Journal 19(3) 754-764
Chamieh, J. et al. 2018. Int. J. Pharm. 537(1-2) 94-101
Cryo-TEM Tran, T. et al. 2017. Eur. J. Pham. Sci. 108 62-70
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INFLUENCE OF DIGESTION ON DRUG ABSORPTION
Dissolution/Permeation system (PL membrane)
Ajine Bibi, H. et al. 2017. Eur. J. Pharm. Biopharm. 117, 300-307.
In situ intestinal perfusion Crum, M.F. et al. 2016. Pharm. Res. 33, 970–982.
Dissolution/Permeation system (Rat intestinal tissue/Ussing Chamber) Kristin, F. et al. 2017. Eur. J. Pharm. Sci. 101, 211-219.
Dissolution/Permeation system (Caco-2) 9 Kataoka, M. et al. 2013. Eur. J. Pharm. Biopharm. 85(3B), 1317-1324.
UNMET NEEDS FOR LIPID-BASED FORMULATIONS
• IVIVC or at least good rank order for many drugs (lack of published data) • Compendial methods to assay the performance of lipid-based formulations • Computational and PBPK modelling
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