A lyophilized etoposide submicron emulsion with a high drug loading for intravenous injection: preparation, evaluation, and pharmacokinetics in rats.
OBJECTIVE
To develop a submicron emulsion for etoposide with a high drug loading capacity using a drug-phospholipid complex combined with drug freeze-drying techniques.


METHODS
An etoposide-phospholipid complex (EPC) was prepared and its structure was confirmed by X-ray diffraction and differential scanning calorimetry analysis. A freeze-drying technique was used to produce lyophilized etoposide emulsions (LEPE), and LEPE was investigated with regard to their appearance, particle size, and zeta potential. The pharmacokinetic study in vivo was determined by the UPLC/MS/MS system.


RESULTS
It showed that EPC significantly improved the liposolubility of etoposide, indicating a high drug loading intravenous emulsion could be easily prepared by EPC. Moreover, the obtained loading of etoposide in the submicron emulsion was 3.0 mg/mL, which was three times higher than that of the previous liquid emulsions. The optimum cryoprotectant was trehalose (15%) in freeze-drying test. The median diameter, polydispersity index, and zeta potential of the optimum formulation of LEPE were 226.1 ± 5.1 nm, 0.107 ± 0.011, and -36.20 ± 1.13 mV, respectively. In addition, these parameters had no significant change during 6 months storage at 4 ± 2°C. The main pharmacokinetic parameters exhibited no significant differences between LEPE and etoposide commercial solution except for area under the concentration-time curve and clearance.


CONCLUSIONS
The stable etoposide emulsion with a high drug loading was successfully prepared, indicating the amount of excipients such as the oil phase and emulsifiers significantly decreased following administration of the same dose of drug, effectively reducing the metabolism by patients while increasing their compliance. Therefore, LEPE has a great potential for clinical applications.
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, PR China.
Hao
H
Chen
Shuai
S
Shi
Mingming
M
Zhao
Ling
L
Zhang
Haibing
H
He
Xing
X
Tang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D004655:Emulsions; D005047:Etoposide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D005612:Freeze Drying; D007275:Injections, Intravenous; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013678:Technology, Pharmaceutical; D014961:X-Ray Diffraction
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D004655:Emulsions; D010743:Phospholipids; D005047:Etoposide