Lovastatin (LVS) is a well-known compound for lowering plasma cholesterol levels. After oral administration, the inactive
parent lactone is hydrolyzed to the corresponding hydroxyacid form. The hydroxyacid is the principal metabolite and a potent
inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase. This enzyme catalyzes the conversion of hydroxymethylglutarate
to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis (1, 2).
LVS is white crystalline powder that is insoluble in water (0.4 g/mL). At room temperature, the partition coefficient of LVS
in n-octanol/water system is approximately: Ko/w = 1.2 × 104 (3). Low aqueous solubility of LVS leads to inadequate dissolution in gastrointestinal fluids and, hence, poor absorption,
distribution, and targeted organ delivery. The improvement of aqueous solubility in such a case is a valuable goal to improve
Cyclodextrin (CD) is a cyclic (α-1, 4)-linked oligosaccharide made of α-D-gluco-pyranose units (see Figure 1). Hydroxypropyl-β-cyclodextrin
(HPβ-CD) is more water soluble than the parent molecule and has hydroxypropylester groups attached to the hydroxyl groups
in position 2. The molecule has a cone-like configuration with a hydrophilic surface and a lipophilic cavity. In this cavity,
hydrophobic molecules interact with lipophilic molecules without forming any covalent bonds and can produce so-called "inclusion
complexes," which increase the water solubility and stability of the drug substance (4–6). Complexation with CDs has been
reported to enhance the solubility, dissolution rate, and bioavailability of poorly water-soluble drugs. CDs first gained
attention in marketed products as drug delivery technologies that enabled the development of various prostaglandins (7). The
inclusion complex of rofecoxib/HPβ-CD (1:1 molar ratio) was prepared by Baboota et al. using a kneading method with a subsequent improvement in dissolution caused by amorphization (8). Several other drugs such
as ganciclovir, nimesulide, itraconazole, and tolbutamide have been tested for CD inclusion to enhance solubility (9–12).
Figure 1: The structure formula for the β-cyclodextrin molecule.
β-CD has ideal dimensions to complex a range of commonly used drugs. Unfortunately, it has the limitation of a high affinity
for cholesterol, which may lead to crystallization of a poorly water-soluble β-CD–cholesterol complex in the kidney. This
complex could cause nephrotoxicity. HPβ-CD, a chemical derivative of β-CD, similarly improves the aqueous solubility of many
drugs, but it is more hydrophilic than β-CD, forms a less-stable complex with cholesterol, and, therefore, is less toxic (13).