Effect of Alkyl Chain Length and Unsaturation of the Phospholipid on the Physicochemical Properties of Lipid Nanoparticles

Abstract

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...

Combination of Roll Grinding and High-Pressure Homogenization Can Prepare Stable Bicelles for Drug Delivery

“…NI-LNs made with DMPC had substantially smaller mean particle size and bigger PDI relative to other the particles (Table 8). Previously, it was reported that the size distribution had bimodal peaks, and that NI crystal precipitated one month after preparation [48]; thus, NI-LNs using DMPC had different properties from the other particles. Longer alkyl chain lengths result in higher phase transition temperatures and stronger van der Waals interactions.…”

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