To improve the solubility of the drug nifedipine (NI), highly stabilized solid-lipid nanoparticles (SLNs) of nifedipine (NI-SLNs) were prepared by high pressure homogenization using two phospholipids, followed by lyophilization with individual sugar moieties (four monosaccharides and four disaccharides). The mean particle diameter, polydispersity index (PDI), zeta potential, drug loading, and the encapsulation efficiency of the NI-SLN suspension were determined to be 68.5 nm, 0.3, 62.1 mV, 2.7%, and 97.5%, respectively. In comparison with the NI-SLNs, the NI-SLNs lyophilized with trehalose (NI-SLN-Tre) showed a slight increase in the particle size from 68.5 to 107.7 nm, but the PDI decreased from 0.38 to 0.33, and no significant change in zeta potential was observed. Aqueous re-dispersibility study demonstrated that NI-SLNs lyophilized with trehalose had the maximum concentration (14.7 µg/mL) at 5 min, compared with lyophilized SLNs using other sugars; the use of other sugars also resulted in significant changes in the particle size, PDI, and zeta potential. A trehalose concentration of 2.5% w/v and a two-fold dilution of the SLN suspension were found to be the best conditions for lyophilization. Data from lyophilized SLNs using differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, and scanning electron microscopy indicated eventual transformation of NI-SLN-Tre from a crystalline to an amorphous state during the homogenization process. Finally, a stability study was performed with NI-SLN-Tre for up to 6 months at 30°C and 65% relative humidity, with no significant deterioration observed, suggesting that trehalose might be a useful cryoprotectant for NI-SLNs.

Previously, we developed lipid nanoparticles (LNs) containing poorly water-soluble drugs using two types of phospholipids, a neutral phospholipid (hydrogenated soybean phosphatidylcholine) and a negativelycharged phospholipid (dipalmitoylphosphatidylglycerol), with mean particle sizes of less than 100 nm. Here, we studied the effects of alkyl chain length and unsaturation of neutral and negatively-charged phospholipids on the physicochemical properties of LNs. Three neutral phospholipids, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, having different alkyl chain lengths, were compared. The mean particle size of the LNs increased with the alkyl chain length, while the concentration of the drug entrapped in the LNs decreased. The particle size of all of the LNs could be maintained at less than 100 nm for 1 month in cool and dark conditions, with the LNs with longer alkyl chain lipids showing greater stability. In the unsaturated phospholipids, the double bond in the alkyl chain of dioleoylphosphatidylcholine and dierucoylphosphatidylcholine did not affect the physicochemical properties of the LNs. The negatively-charged phospholipids dipalmitoylphosphatidylglycerol and distearoylphosphatidylglycerol were also compared; LNs with longer alkyl chain lipids had larger particle sizes and lower drug concentrations, similar to the results for neutral phospholipids. We concluded that although some changes in physicochemical properties were observed among LNs with different phospholipid alkyl chain lengths, this methodology was general. LNs with suitable physicochemical properties could be prepared irrespective of the type of phospholipids used.Key words lipid nanoparticle; poorly water-soluble drug; phospholipid; alkyl chain Many candidate active pharmaceutical ingredients (APIs) in formulations show poor solubility in water. To enhance the solubility of such poorly water-soluble APIs, the use of nanoparticle formulations with particle sizes less than 100 nm has recently attracted considerable attention in the field of pharmaceutical research.1-3) Recently, we successfully prepared lipid nanoparticles (LNs), which had a mean particle size of approximately 50 nm with a narrow particle size distribution, using wet milling, roll mixing, and high pressure homogenization to form small particles.4) The LNs improved the solubility of nifedipine (NI), a poorly water-soluble drug, and improved its oral absorption of NI when NI-LNs were administrated to rats. 5) NI-LNs showed excellent long-term stability in suspension for approximately 4 months in cool and dark conditions, and freeze-drying techniques combined with sugar as a cryoprotectant allowed the preparation of LNs with a good aqueous re-dispersibility.6,7) NI-LNs lyophilized with trehalose exhibited suitable pharmacokinetic properties and good biocompatibility. 8) Generally, two types of phospholipids, neutral phosphatidylcholine (PC) and negatively-charged phosphatidylglycerol (PG) are used to prepare LNs. PG was added to...

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Nifedipine-solid-lipid nanoparticles lyophilized with trehalose (NI-SLN-Tre) were prepared by the high pressure homogenization of a roll mixture consisting of NI and hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol, and in vivo pharmacokinetic properties and their hemocompatibility were determined and compared with those of a NI-SLN suspension. The resulting pharmacokinetic data demonstrated that although no significant differences were observed between the time of peak concentration (Tmax), peak plasma concentration (C max), and the area under the curve (AUC 0→∞) values of both administrated samples, NI tended to be absorbed to a much greater extent from the lyophilized NI-SLN-Tre suspensions because of the enhanced solvation of NI-SLN in gastrointestinal fluid, derived from formation of hydrogen bonds between the polar head groups of the lipids and the O-H groups of trehalose. Furthermore, the results of a hemolysis assay revealed that the NI-SLN and NI-SLN-Tre suspensions showed good hemocompatibility properties with hemolysis values of less than 5%. Taken together, the results of this study demonstrate that NI-SLN-Tre exhibits suitable pharmacokinetic properties and good biocompatibility.