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.