Chapter 1

Drug Delivery:
An Evolving
Concept
 Chapter Objectives

•Recognize the factors impacting drug discovery and

d l
development t iin pharmaceutical
h ti l iindustry.
d t

•Understand the evolution of drug delivery concept.

 Introduction
• The total revenue generated from the global
pharmaceuticals,
h l bbiotechnology,
h l andd llife
f sciences
industry is more than $1.1 trillion in 2011

• The cost of developing

p g a new drugg is considered to
be greater than $800 million.

• Many drug candidates are dropped from the

preliminary screening portfolio because of their
unfavorable physiochemical and biochemical
properties.
properties
 Factors in Drug Development
• Developability or Druggability Criteria

– Pharmaceutical companies try to create a

framework in which the lead molecules proceed
further, often termed as the “

– This framework involves the study of

characteristics, properties, and qualities of the
lead molecules and setting of acceptable ranges
for
o further
u t e progression
p og ess o ofo tthee ca
candidate.
d date.
 Chemical Limitations
• Medicinal chemists lead the early discovery of
bioactive compounds.
• This initial process is carried out by random,
random high
throughput screening of compound libraries, by
rational design,
design or both.
both
• The structure–activity relationship is developed that
allows
ll for
f ffurther
th structural
t t l changes
h and
d ffor
selection.
• The detailed structural analysis at this stage involves
more factors, such as potential stability, solubility,
interaction with metabolic enzymes, and
permeability.
 In VITRO and In VIVO Efficacy
• Initially, in vitro testing is carried out to narrow
down the number of lead molecules.
• Studying the drugs in an in vivo animal model is
essential before introduction into human clinical
trials.
trials
• An in vivo model that has all the biochemical,
cellular,
ll l and d physiological
h i l i l complexities
l iti off h
human
systems can predict the actual efficacy of the drug.
• In vitro and in vivo testing is used is the calculation
of pharmacokinetic parameters that may be critical
to the overall success of a compound.
 Pharmacokinetics and Drug
Metabolism
• Drug metabolism and pharmacokinetics (DMPK)
estimations are a very critical part of the drug
development process
• The main goal of DMPK studies is to predict the
absorption distribution
absorption, distribution, metabolism
metabolism, and excretion
of the drug candidate in humans.
• DMPK studies
t di are carried
i d outt in
i multiple
lti l animal
i l
models
• Allometric scaling and animal pharmacokinetics and
metabolism data are applied to predict human
parameters
 Pharmacokinetics and Drug
Metabolism
• Major pharmacokinetic drug parameters are usually
well correlated with the drug’s efficacy and adverse
effects.
• The overall levels achieved are decided by multiple
factors such as
factors,
– site of administration
– complexity of the dosage form
– Total body clearance
• Usually a compound with low to moderate clearance
is preferred
 Final Formulation Characteristics
• Physiochemical properties with possible effects on
drug delivery and pharmacokinetics include:

– Aqueous solubility especially for orally

administered
d i i t d drugsd
– Crystal state of the drug affecting both solubility
and dissolution rates
– The salt form of the molecule affecting the
solubility, dissolution rate, stability, and overall
bioavailability
 Drug Delivery
• Drug delivery can be defined as the method or
process of administering a pharmaceutical
compound d to
t achieve
hi a therapeutic
th ti effect
ff t in
i
humans or animals.

• This process may involve utilization of several

approaches, formulations, technologies, and
systems to facilitate
f ili drug
d at the
h target site.
i
 Drug Delivery
• The active drug needs to enter the target cells
to exert its therapeutic effect.

Figure 1 1: Fate of a drug in the body.

1-1:
 Drug Delivery
• The initial step of drug delivery is drug
dissolution (Figure 1 1 A)
• One of the major concerns with newly
p drugs
developed g is their p
poor aqueous
q
solubility
• 90% of novel drug development candidates
potentially display poor aqueous solubility
( l bili i iin the
(solubilities h range off 1–10 g/mL)
/ )
 Drug Delivery
• Once a compound is in solution
solution, it may be
delivered throughout the body (Figure 1 1 B)

• The extensive biodistribution may cause

toxicity and unwanted side effects.

• Active targeting
g g strategies,
g , therefore,, direct
the drug to act only at the intended target
site thereby minimizing side effects
site, effects.
 Drug Delivery
• The last step in this process is drug uptake by
cells (Figure 1 1 C)
• This step plays a very crucial role in gene
delivery, which can only be successful when
genes are delivered at the target site and
effectively enter the target cells for
expression.
• For most therapeutics, the ultimate bioactivity
is achieved only after the active molecules are
taken up by cells.
cells