In silico drug delivery
optimizationPer Larsson
Department of Pharmacy
Uppsala University, Sweden
4th ADD Workshop, Olomouc, 2019
Challenges facing 21st century
pharma R&D
• Decreasing R&D efficiency
– Newer drug candidates display poor “developability”
characteristics, e.g. poor solubility
• Increasing R&D cost
– It is estimated that the majority of costs in new drug
development are now primarily related to costs of
failed projects
• Switch from “blockbuster” to “niche buster”
– Priorities switch to address unmet medical needs
outcomes
Diagnosing the decline in
pharmaceutical R&D efficiency
Scannell et al., Nature Reviews, 2012
The need for new formulation and
drug delivery technology• Patient preference for oral dosage forms
• Over 75% of drugs in development are poorly soluble
• ~30% of medicines licensed since 2010 display a positive food effect
• Need for patient centric dosage forms
• Expediated drug approval and “earlier access” to markets
The problem of insolubility
• Medicinal/computational chemists are largely targeting
high affinity and selectivity
• Solubility can get left by the wayside
• General tendency is that new drugs are becoming more
insoluble
• And formulators are getting crazier….
From Bruce Rehlaender, PharmaDirections, Slideshare
Increasing trend of poorly water
soluble lead compounds
• Increasing number of poorly water soluble drugs in drug
development
Rodriguez-Aller et al., J Drug Delivery Sci Tech, 2015
From Bruce Rehlaender, PharmaDirections, Slideshare
Biopharmaceutical Classification
System (BCS)
Pouton, EJPB, 2006
Thermodynamics of solubility
Bergström and Larsson, Int J Pharmaceutics, 2018
Different strategies for formulating and
delivering poorly water-soluble drugs.
Rodriguez-Aller et al., J Drug Delivery Sci Tech, 2015
How can in silico modeling help?
• Example 1
– Using multivariate statistics and machine learning to
predict drug solubility in formulations
PLS
Visual explanation
• Identify the lines through X and Y space that – together –maximize the covariance between T and U
• Thus, the line through X maximizes explained X variance and the line through Y maximizes explained Y variance
PLS solubility models
Alskär et al., Pharm Res, 2013
SBO Captex355
PLS solubility models in multiple
component systems
Alskär et al., Mol Pharm, 2015
Alskär et al., Mol Pharm, 2015
PLS solubility models in multiple component systems
How can in silico modeling help?
• Example 2
– Using molecular simulation to determine excess
solubility in binary mixtures
Chemical potential
Paluch et al., J Chem Phys, 2015
after some algebra…
Excess/relative solubility
Excess solubility determinations
These compounds are simulated in binary mixtures of water and ethanol at differentmole fractions
Paluch et al., J Chem Phys, 2015
Excess solubility determinations
Paluch et al., J Chem Phys, 2015
Relative solubility
Liu et al., J Chem Theor Comp, 2016
How can in silico modeling help?
• Example 3
– Understanding stability and solubility in amorphous
drug systems
Amorphous formulations
Indapamide
Metolazone
Glibenclamide
Glipizide
Edueng et al., J Cont Release, 2017
Hydroxypropylmethylcellulose(HPMC)
Indapamide
Glibenclamide
MD simulations
Edueng et al., J Cont Release, 2017
Indapamide Glibenclamide
Generalized Amber FF (GAFF)
MD simulations
Edueng et al., J Cont Release, 2017
How can in silico modeling help?
• Example 4
– Using Flory-Huggins theory together with molecular
dynamics simulations.
Docetaxel solubility
Huynh et al., Pharm Res, 2008
Docetaxel
Docetaxel solubility
Huynh et al., Pharm Res, 2008
Compass forcefield, Material Studio
Flory-Huggins
Flory-Huggins interaction parameter
Energy of mixing
Cohesive energy density
Huynh et al., Pharm Res, 2008
Docetaxel solubility
Huynh et al., Pharm Res, 2008
Flory-Huggins theory
Docetaxel solubility
Huynh et al., Pharm Res, 2008
How can in silico modeling help?
• Example 5
– Influence of lipids and bile salts on drug partitioning
Influence of lipids and bile salts on drug
partitioning
DLiPC (1,2-dilinoleoyl-sn-glycero-3-phosphocholine) TCH (taurocholate)
Influence of lipids and bile salts on drug
partitioning
Holmboe, Larsson, Anwar, Bergström, Langmuir, 2016
Influence of lipids and bile salts on
drug partitioning
Holmboe, Larsson, Anwar, Bergström, Langmuir, 2016
Influence of lipids and bile salts on drug
partitioning
Holmboe, Larsson, Anwar, Bergström, Langmuir, 2016
Conclusions
• Understanding solubility is key to modern drug
development
• Solubility can for some systems be reasonably well
predicted using in silico methods
• This is crucial, since it can save a lot of time and effort
for formulation scientists, when a new drug compound is
going to be introduced to the market.