title: Development of ligustrazine-loaded lipid emulsion: formulation optimization, characterization and biodistribution.
abstract: 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±2.5 nm, 0.076±0.033, -40.4±5.3 mV 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 0 h to 10 h (AUC(0-10h)) 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 AUC(0-180 min) 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.
authors.affiliation: College of Pharmacy, Yanbian University, Yanji City, Jilin Province 133000, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wei
authors.forename: Nirmal
authors.initials: N
authors.lastname: Marasini
authors.forename: Gao
authors.initials: G
authors.lastname: Li
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.forename: Qizhe
authors.initials: Q
authors.lastname: Quan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D005990:Glycerol / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D054709:Lecithins / Q000737:chemistry; D008297:Male; D019301:Oleic Acid / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D011719:Pyrazines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013024:Soybean Oil / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D004655:Emulsions; D054709:Lecithins; D011719:Pyrazines; D020442:Poloxamer; D019301:Oleic Acid; D013024:Soybean Oil; D005990:Glycerol; C017953:tetramethylpyrazine