Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs
Introduction
Cilostazol is a synthetic antiplatelet agent with vasodialating effect [1]. This drug is approved for a treatment of ischemic symptoms related to peripheral arterial occlusive diseases in Japan and several other countries as Pletaal® tablet, and for a treatment of intermittent claudication in U.S.A. and U.K. as Pletal® tablet [2], [3], [4], [5]. Recent study proved that cilostazol is also effective for a prevention of recurrence of cerebral infarction [6]. The molecular weight and melting point of cilostazol are 369.47 and 159.4–160.3 °C, respectively. Cilostazol is a neutral molecule having an aqueous solubility of 3 μg/mL at 25 °C [7]. Octanol–water distribution coefficients (logPoct) of the drug ranged from 2.72 (pH 2.0) to 2.76 (pH 11.0) [7]. An apparent permeability of cilostazol through Caco-2 cell monolayer was found to be 1.92 × 10− 5 cm/s [8]. Therefore, according to Biopharmaceutics Classification System (BCS) [9], cilostazol is categorized in Class II (poorly soluble and highly permeable). Fraction dose absorbed of cilostazol from a suspension in 5% ethanol in rats or dogs was found to be 88.0% at 10 mg/kg or 50.7% at 3 mg/kg, respectively, calculated from the recovery of unabsorbed drug in feces [10], [11]. The area under the serum concentration–time curve (AUC) of cilostazol for the 50 mg tablet was found to be significantly less (− 13%) than that for ethanolic solution in humans. A shorter half-life (t1/2z) of cilostazol at the apparent terminal elimination phase after dosing the ethanolic solution (2.5 ± 0.4 h) than that of the tablet (11.0 ± 4.0 h) suggested that the absorption rate constant from the tablet was smaller than the elimination rate constant. These results suggest that the incomplete absorption of cilostazol from the tablet in humans was likely due to the poor dissolution [12].
It is well known that poorly water-soluble drugs often exhibit increased or accelerated absorption when they are administered with food [13]. This positive food effect would be attributed to the enhancement of the dissolution rate in the gastrointestinal (GI) tract caused by many factors such as delayed gastric emptying, increased bile secretion, larger volume of the gastric fluid, increased gastric pH (for acidic drugs) and/or increased splanchnic blood flow. In fact, a standard high fat breakfast increased both the rate (+ 91%) and extent (+ 24%) of cilostazol absorption after an oral administration of the 100 mg tablet [12], suggesting that the oral bioavailability of cilostazol could be enhanced due to the improvement of dissolution by food.
The dissolution rate of a solid drug can be expressed by the Noyes–Whitney equation [14], and it is also well known that the dissolution rate can be proportionally increased by increasing surface area as a consequence of comminution. Mechanical milling is a common technique to enhance dissolution of poorly water-soluble drugs [15]. Impact mills such as a hammer-mill or fluid energy mills such as a jet-mill are generally used for micronization of active ingredient in pharmaceutical industry [16]. In general, the former produces particles having mean diameters greater than 10 μm and the latter provides particles approximately ten times smaller than the hammer-milled particles. However, it is difficult to reduce particle size in sub-micron region using these dry-mills. NanoCrystal® is an enabling technology to produce sub-micron particles by wet-milling [17], [18], [19]. In this technology, materials are grinded with milling beads in water containing steric- and charge-stabilizers to prevent irreversible agglomeration of the resulted sub-micron particles. Anionic surfactants and hydrophilic polymers are used as the charge-stabilizers and the steric-stabilizers, respectively. Significant enhancement of oral bioavailability by this technology was reported for some BCS Class II compounds [17], [19]. Elimination of positive food effect was also reported as an advantage of NanoCrystal® [19].
The active ingredient of the commercial formulations is sized with a hammer-mill, resulting in mean particle diameter greater than 10 μm. Oral bioavailability of cilostazol, therefore, is thought to be improved by extensive particle size reduction with a jet-mill or a media-mill (NanoCrystal®). The purpose of the present study was to investigate the effects of particle size on the dissolution rate as well as the rate and the extent of oral absorption of cilostazol. Food effect on the absorption was also investigated.
Section snippets
Materials
Cilostazol and an internal standard OPC-13012 (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy]-3,4-dihydro-1-ethyl-2(1H)-quinolinone) were synthesized in Otsuka Pharmaceutical Co., Ltd. (Tokushima, Japan). Sodium taurocholate and egg lecithin (biochemistry grade) were obtained from Tokyo Kasei Kogyo Co., Ltd. (Tokyo, Japan) and Kanto Chemical (Tokyo), respectively. All other reagents were analytical grade commercial products.
Particle size reduction of cilostazol
The hammer-milled cilostazol crystal was prepared with Atomizer AIIW5G
Size distribution of milled cilostazol
Particle sizes of the three different types of milled cilostazol were measured and the size distributions are shown in Fig. 1. The median particle diameters of cilostazol in the hammer-milled, the jet-milled and the NanoCrystal® suspensions were found to be 13, 2.4 and 0.22 μm, respectively.
Solubility
Equilibrium solubility values of the jet-milled cilostazol crystal at 37 °C were determined to be 6.26 ± 0.06, 6.35 ± 0.12 and 12.7 ± 0.2 μg/mL in water, FaSSIF and FeSSIF, respectively. The solubility in FeSSIF
Conclusion
In the present study, it was demonstrated that the in vitro dissolution rate of cilostazol from aqueous suspension was improved by milling, which was described by the Noyes–Whitney equation. The bioavailability of cilostazol was increased by the reduction of particle size, but remarkable enhancements with minimum food effect were observed for the NanoCrystal® cilostazol suspension, while moderate enhancement of bioavailability and significant food effect were seen in the absorption for the
Acknowledgement
Dr. Tahei Tomida (Tokushima University) is gratefully acknowledged for help programming the 4th Runge–Kutta calculation on Mathematica 5.0.
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