(M1230-05-28) Improved Dissolution and Pharmacokinetic Behaviors of Zerumbone upon Solid Lipid Nanoparticle Approach

Purpose: Zerumbone (ZER), a sesquiterpene isolated from Zengiber zerumbet, has various biological functions, such as anti-microbial, anti-obesity, anti-inflammatory, anti-nociceptive, and anticancer activities. Despite these attractive pharmacological actions, clinical application of ZER could be limited due to (1) low water solubility, and (2) extensive hepatic first-pass metabolism, and both properties could lead to poor oral bioavailability of ZER. Previously, our group developed self-micellizing solid dispersion of ZER (SMSD/ZER) with the aim of improved dissolution behavior and thereby enhanced oral bioavailability. SMSD can be defined as the dispersion of active ingredient surrounded by micelle-forming amphiphilic polymer. Formation of micelles could contribute to high dispersibility of ZER in water, offering improvement in dissolution profile. SMSD/ZER exhibited high dissolution of ZER in water and high oral absorption of ZER after oral administration. In addition to solubilization, avoidance of first-pass metabolism could offer further enhancement of oral bioavailability.  Solid lipid nanoparticle (SLN), nano-sized particles composed of long chain fatty acid-based lipids, was selected as a new dosage option since SLN can increase in the surface area, leading to improved dissolution rate of compounds. SLN would enhance drug absorption via lymphatic pathway, allowing the avoidance of severe first-pass metabolism in the liver. Moreover, SLN could protect encapsulated compounds from severe metabolism in the gastrointestinal tract. Thus, strategic application of SLN approach might be an efficacious option to enhance its biopharmaceutical properties. The purpose of the present study was to develop ZER-loaded SLN (SLN/ZER) for the enhancement of its oral absorption.>

Methods: SLN/ZER was prepared by hot homogenization method using ultrasonicator.  Before ultrasonicating, crystalline ZER, stearic acid, and lecithin were mixed as lipid phase at 70°C, and distilled water was added to lipid phase.  The mixture was emulsified by ultrasonication, and distilled water containing trehalose was added to the solution containing oil in water emulsions.  The solution was freeze-dried, providing SLN/ZER.  Morphology and particle size distribution were evaluated by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively.  The dissolution profile of SLN/ZER was assessed using a dissolution tester.  ZER samples were place in distilled water under constant stirring at 37°C.  Pharmacokinetic behavior of ZER was evaluated after oral administration of SLN/ZER at a dose of 25 mg-ZER/kg to rats, and pharmacokinetic parameters were calculated.

Results: SLN/ZER was prepared by hot homogenization method, and it appeared as a light yellow and dry powder.  According to the TEM images of SLN/ZER, spherical nanoparticles were observed with sizes of ca. 200 nm.  The average particle size was found to be 211 nm with polydispersity index of 0.15, suggesting narrow size distribution.  Encapsulation efficiency of SLN/ZER was calculated to be 69.9%.  Although crystalline ZER showed poor dissolution even after 120 min after sample addition into water, SLN/ZER showed 15.5-fold higher dissolution than crystalline ZER at 120 min.  SLN/ZER exhibited 0.68-fold higher dissolution than SMSD/ZER at 120 min, indicating high solubilizing potency of SMSD approach.  Nanoparticles would contribute to improvement in dissolution behavior.  In rats, crystalline ZER was orally administered at a dose of 50 mg/kg, and SMSD/ZER or SLN/ZER was administered at a dose of 25 mg-ZER/kg.  In rats treated with crystalline ZER, systemic exposure of ZER was negligible.  In contrast, SLN/ZER and SMSD/ZER showed the increase of plasma concentration of ZER with maximum concentration (C_max) of 86.8 and 87.2 ng/mL, respectively.  The improvement in dissolution properties upon SLN or SMSD approach could result in higher level of ZER concentration in plasma.  Mean residence time of SLN/ZER and SMSD/ZER were calculated to be 5.4 and 2.2 h, respectively, suggesting the slower absorption of ZER via lymphatic route in SLN/ZER treated group.  As a result, SLN/ZER exhibited higher oral absorption of ZER compared with SMSD/ZER, as evidenced by area under the curve of plasma concentration vs. time from 0 to 24 h (AUC_{0-24 h}) of 573 (SLN/ZER) and 243 ng.h/mL (SMSD/ZER).  Both improved dissolution and enhanced lymphatic transport could contribute to high oral absorption of ZER.

Conclusion: From these findings, the present investigation illustrated that the potential use of SLN approach for ZER to improve its solubility and pharmacokinetic behavior and thereby enhance the therapeutic potential of ZER.