4
amount of water, the extruded complex may dry as it cools or
the complex may be placed in an oven to dry.
(f) Dry mixing
Some guest molecules can be complexed by simply adding them to
the cyclodextrin and mixing. This works best with oils or liquid
guest molecules. The amount of mixing time required is variable and depends on the guest. Generally, this method is performed at ambient temperature and is an alternative to the paste
method.
In the following section a detailed guide is given for the preparation of solid-state inclusion complexes of a number of poorly
water- soluble lipophilic drug molecules with 2-hydroxypropyl-βcyclodextrin (2-HP-β-CD). The drug molecules of interest are
irbesartan, losartan, candesartan and candesartan cilexetil, as well
as five bioactive molecules of plant origin, namely caffeic acid, rosmarinic acid, silibinin, curcumin, and quercetin.
Irbesartan (IRB), losartan (LOS), and candesartan (CAN) or
candesartan cilexetil as prodrug (CC) belong to the family of
angiotensin II receptor blockers and are used to treat high blood
pressure, while beyond their ability to lower blood pressure, they
also confer cardiovascular and renal protective effects [14–16].
IRB and LOS belong to class II of the Biopharmaceutics
Classification System, BCS [17, 18], meaning that their poor aqueous solubility is the rate-limiting step for drug absorption. CAN is
classified as a BCS Class IV drug, meaning that it shows both low
solubility and low permeability in vitro. CC is the prodrug form of
the active substance CAN and is classified as a BCS Class II drug
(low solubility) [16]. As a result, enhancement of the aqueous solubility of all three drug molecules can lead to improved oral
bioavailability.
Caffeic acid (CA) is an antioxidant molecule both in vitro and
in vivo [19]. Caffeic acid also shows immunomodulatory and antiinflammatory activities [20, 21]. Chemically, rosmarinic acid (RA)
is a caffeic acid ester of 3-(3,4-dihydroxyphenyl)-lactic acid and
can act as a prodrug for caffeic acid. CA is poorly soluble only in
hot water whereas RA is insoluble in water and soluble only in
organic solvents, not biologically compatible with the human
organism. As a result, the inclusion of both molecules in 2-HP-β-CD
is extremely useful in order to enhance oral bioavailability.
Silibinin (SLB) is the main active component of the flavonoid
mixture silymarin extracted from the plant Silybum marianum
(milk thistle) and is mainly known for its hepatoprotective properties. More specifically, there is some clinical evidence for the use of
SLB as a supportive element in alcoholic and child grade “A” liver
cirrhosis [22]. SLB is one of the most characteristic examples of
poorly water-soluble biomolecules, as its bioavailability is extremely
low when administered orally.
Eirini Christodoulou et al.
amount of water, the extruded complex may dry as it cools or
the complex may be placed in an oven to dry.
(f) Dry mixing
Some guest molecules can be complexed by simply adding them to
the cyclodextrin and mixing. This works best with oils or liquid
guest molecules. The amount of mixing time required is variable and depends on the guest. Generally, this method is performed at ambient temperature and is an alternative to the paste
method.
In the following section a detailed guide is given for the preparation of solid-state inclusion complexes of a number of poorly
water- soluble lipophilic drug molecules with 2-hydroxypropyl-βcyclodextrin (2-HP-β-CD). The drug molecules of interest are
irbesartan, losartan, candesartan and candesartan cilexetil, as well
as five bioactive molecules of plant origin, namely caffeic acid, rosmarinic acid, silibinin, curcumin, and quercetin.
Irbesartan (IRB), losartan (LOS), and candesartan (CAN) or
candesartan cilexetil as prodrug (CC) belong to the family of
angiotensin II receptor blockers and are used to treat high blood
pressure, while beyond their ability to lower blood pressure, they
also confer cardiovascular and renal protective effects [14–16].
IRB and LOS belong to class II of the Biopharmaceutics
Classification System, BCS [17, 18], meaning that their poor aqueous solubility is the rate-limiting step for drug absorption. CAN is
classified as a BCS Class IV drug, meaning that it shows both low
solubility and low permeability in vitro. CC is the prodrug form of
the active substance CAN and is classified as a BCS Class II drug
(low solubility) [16]. As a result, enhancement of the aqueous solubility of all three drug molecules can lead to improved oral
bioavailability.
Caffeic acid (CA) is an antioxidant molecule both in vitro and
in vivo [19]. Caffeic acid also shows immunomodulatory and antiinflammatory activities [20, 21]. Chemically, rosmarinic acid (RA)
is a caffeic acid ester of 3-(3,4-dihydroxyphenyl)-lactic acid and
can act as a prodrug for caffeic acid. CA is poorly soluble only in
hot water whereas RA is insoluble in water and soluble only in
organic solvents, not biologically compatible with the human
organism. As a result, the inclusion of both molecules in 2-HP-β-CD
is extremely useful in order to enhance oral bioavailability.
Silibinin (SLB) is the main active component of the flavonoid
mixture silymarin extracted from the plant Silybum marianum
(milk thistle) and is mainly known for its hepatoprotective properties. More specifically, there is some clinical evidence for the use of
SLB as a supportive element in alcoholic and child grade “A” liver
cirrhosis [22]. SLB is one of the most characteristic examples of
poorly water-soluble biomolecules, as its bioavailability is extremely
low when administered orally.
Eirini Christodoulou et al.