Environmental Engineering Reference
In-Depth Information
Low solubility in water appears to be an intrinsic property of many drugs. If the
molecular target of a drug is located inside the cell, a drug molecule must have a
certain degree of hydrophobicity in order to cross the cell membrane [
9
]. It has also
been observed that a drug or drug candidate often needs a lipophilic group to show
an affinity toward the target receptor [
10
]. Indeed, the GI tract presents a variety of
hurdles for a drug, from morphological barriers (mucus layer, microvilli, etc.) to
stringent physiological factors (a wide range of pH, enzymatic activities, specific
transport mechanisms, etc.), which all conspire to limit intestinal absorption of
drug. In the case of poorly water-soluble drugs, the dissolution time in the GI
contents may be longer than the transit time to the intended absorptive sites
[
11
]. Therefore, dissolution of drugs is quite often the rate-limiting step which,
ultimately, controls the bioavailability of the drug. This poses a major challenge for
effective delivery of poorly water-soluble therapeutics via the oral route. Intrave-
nous administration of aggregates formed by insoluble drug can cause embolization
of blood vessels resulting in side effects as severe as respiratory system failure
[
12
]. The formation of drug aggregates can also result in high-localized concentra-
tions at the sites of deposition associated with local toxicity and/or lowered
systemic bioavailability. Some leading pharmaceutical companies make efforts to
exclude poorly soluble compounds very early in their screening process regardless
how active these compounds are toward their molecular targets [
10
].
To minimize drug degradation and loss upon administration, prevent harmful or
undesirable side effects, and increase drug bioavailability and the fraction of the
drug accumulated in the pathological zone, various drug delivery and drug targeting
systems are currently being developed or under development. Among drug carriers
one can find soluble polymers, microparticles made of natural and synthetic poly-
mers, liposomes, and micelles. Each of these carrier types offers its own advantages
and shortcomings, and all those carriers can be made slowly degradable, stimuli
reactive (for example, pH or temperature sensitive), and even targeted (for exam-
ple, by conjugating them with specific antibodies against certain characteristic
components of the area of interest). In addition, drug carriers should be long
circulating [
13
] since prolonged circulation allows for maintaining the required
therapeutic level of pharmaceuticals in the blood for extended time intervals. Long-
circulating, high molecular weight drugs or drug-containing microparticulates can
also slowly accumulate in pathological sites with affected and leaky vasculature
(such as tumors, inflammations, and infarcted areas) via the enhanced permeability
and retention effect (EPR) and enhance drug delivery in these areas [
14
]. In
addition, prolonged circulation can help to achieve a better targeting effect for
specific ligand-modified drugs and drug carriers since it increases the total quantity
of targeted drug/carrier passing through the target, and the number of interactions
between targeted drugs and their targets [
15
]. Ideally, pharmaceutical drug carriers
for parenteral administration are expected to be biodegradable, have small particle
size, possess high loading capacity, demonstrate prolonged circulation, and accu-
mulate in required pathological sites in the body [
16
]. The development of drug
carriers meeting all these requirements for poorly soluble pharmaceuticals still
represents a challenge.
