Development of ligustrazine-loaded lipid emulsion: Formulation optimization, characterization and biodistribution

• Published in: International journal of pharmaceutics 2012-11, Vol.437 (1-2), p.203-212
• Main Authors: Wei, Lijun, Marasini, Nirmal, Li, Gao, Yong, Chul Soon, Kim, Jong Oh, Quan, Qizhe
• Format: Article
• Language: English
• Subjects: Animals; bioavailability; biological half-life; Cells, Cultured; Characterization; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Stability; drugs; Emulsions; Erythrocytes - drug effects; Erythrocytes - pathology; glycerol; Glycerol - chemistry; Hemolysis - drug effects; intravenous injection; Lecithins - chemistry; Ligustrazine; Lipid emulsion; Male; oleic acid; Oleic Acid - chemistry; Oriental traditional medicine; particle size; patient compliance; Pharmacokinetics; Poloxamer - chemistry; Pyrazines - administration & dosage; Pyrazines - chemistry; Pyrazines - pharmacokinetics; Rabbits; Rats; Rats, Sprague-Dawley; soybean oil; Soybean Oil - chemistry; temperature; therapeutics; Tissue Distribution; zeta potential
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2012.08.027

Ligustrazine is a traditional Chinese medicine used to treat various cardiovascular and neurovascular complications. However, this compound exhibits rapid first-pass metabolism, a short biological half-life, low stability and potential vascular irritation that restrict its use for long-term therapy. The use of a lipid emulsion as a carrier for intravenous administration of ligustrazine might provide sustained and prolonged release, thereby reducing the frequency of administration and improving patient compliance. The main purpose of our study was to develop a highly stable and sterile optimal formulation of a ligustrazine lipid emulsion (LLE) and to evaluate its pharmacokinetic behavior and tissue distribution in rats. The final optimal formulation consisted of soybean oil (12.0%), oleic acid (0.6%), lecithin (1.0%), poloxamer 188 (0.6%) and glycerol (2.25%). The average particle size, polydispersity index (PDI), zeta-potential and pH of the final product were 215.0±2.5nm, 0.076±0.033, −40.4±5.3mV and 7.25±0.05, respectively. The LLE was stable for at least three months at room temperature. In vitro drug release studies of the LLE suggested a sustained release profile, which was further confirmed by in vivo pharmacokinetic studies in rats. The area under the drug concentration–time curve from 0h to 10h (AUC0–10h) for LLE was increased by 1.6-fold compared with that of the commercially available ligustrazine injection (LI), suggesting enhanced bioavailability from the lipid-based emulsion. Furthermore, a tissue distribution study showed significant improvement in the distribution pattern of ligustrazine with a higher AUC0–180min observed in all tissues for LLE than for LI. In conclusion, LLE, with excellent stability, improved pharmacokinetics and tissue distribution, demonstrates great potential for the delivery of ligustrazine for clinical applications.