Interventional effect of off-label use of alprostadil lipid microsphere injection in neurosurgical patients: a before-after study

Background As adjuvant drug, alprostadil lipid microsphere injection (Lipo-PGE1) is one of the highest-selling classes of drugs in China in recent years and the off-label use of Lipo-PGE1 is very common. To investigate the situation of the use of alprostadil lipid microsphere injection (Lipo-PGE1) and evaluate the clinical and economic impacts of administrative intervention in reducing inappropriate use of Lipo-PGE1 in neurosurgical patients in a Chinese tertiary hospital. Methods: A self-control study before and after an intervention of patients receiving Lipo-PGE1 was performed in the Department of Neurosurgery of the Affiliated Hospital of Southwest Medical University. Administrative interventions were implemented from January to December 2018, including reducing the volume of procurement of Lipo-PGE1, judging the rationality of medical records, establishing reward and punishment mechanism. The effects of administrative interventions on utilization and expenditure of Lipo-PGE1 were analyzed. Then patients admitted from January to December 2017 and from January to December 2018 were randomized extracted and then served as the pre-intervention and the post-intervention group for appropriateness analysis. Results: Administrative interventions significantly decreased prescribing rate (49.98% vs 22.49%), utilization (22311DDDs vs 8334 DDDs), drug use density (43.52 DDDs/TID vs 15.84 DDDs/TID), total cost (3.58 million CNY vs 1.30 million CNY) and average cost (2025.04 CNY vs 1466.49 CNY) of Lipo-PGE1 for all patients in neurosurgery. After administrative interventions, the rate in the use of no indications for Lipo-PGE1 and in the cases of inappropriate drug dose, frequency, menstruum type, combination and contraindications significantly decreased in cases collected (P < 0.05 or P < 0.001), yet the percentage of cases adhering to all the criteria was zero. Moreover, significant reductions were found in the average usage quantity (P=0.008), mean cost (P<0.001) and mean duration (P < 0.001) of Lipo-PGE1. Conclusion: As adjuvant drug, the off-label use of Lipo-PGE1 is very common in neurosurgery. The results from simple administrative intervention are unsatisfied. Combination of administrative intervention and clinical pharmacist real-time intervention should be introduced.

Preparation, Characterization, and Pharmacokinetic Evaluation of Imperatorin Lipid Microspheres and Their Effect on the Proliferation of MDA-MB-231 Cells

Imperatorin is a chemical compound belonging to the linear furanocoumarins. Imperatorin is attracting considerable attention because of its antitumor, antibacterial, anti-inflammatory, and anticoagulant activities, inhibition of myocardial hypertrophy, and other pharmacological efficacies. However, imperatorin has limited water solubility and has better lipid solubility; thus, we decided to design and synthesize imperatorin lipid microspheres to optimize the preparation conditions. The aim was to develop and formulate imperatorin lipid microspheres through nanoemulsion technology and apply the response surface–central composite design to optimize the imperatorin lipid microsphere formulation. The influence of the amounts of egg lecithin, poloxamer 188, and soybean oil for injection on the total percentage of the oil phase was investigated. The integrated effect of dependent variables, including particle size, polydispersity index, zeta potentials, drug loading, and encapsulation efficiency, was investigated. Data of overall desirabilities were fitted to a second-order polynomial equation, through which three-dimensional response surface graphs were described. Optimum experimental conditions were calculated by Design-Expert 8.06. Results indicated that the optimum preparation conditions were as follows: 1.39 g of egg lecithin, 0.21 g of poloxamer 188, and 10.57% soybean oil for injection. Preparation of imperatorin lipid microspheres according to the optimum experimental conditions resulted in an overall desirability of 0.7286, with the particle size of 168 ± 0.54 nm, polydispersity index (PDI) of 0.138 ± 0.02, zeta potentials of −43.5 ± 0.5 mV, drug loading of 0.833 ± 0.27 mg·mL−1, and encapsulation efficiency of 90 ± 1.27%. The difference between the observed and predicted values of the overall desirability of the optimum formulation was in the range from 2.4% to 4.3%. Subsequently, scanning electron microscopy was used to observe the micromorphology of the imperatorin lipid microspheres, showing round globules of relatively uniform shape and sizes within 200 nm. The effect of imperatorin lipid microspheres on MDA-MB-231 proliferation was investigated by the MTT method. Furthermore, pharmacokinetics in Sprague-Dawley rats was evaluated using orbital bleeding. A sensitive and reliable liquid chromatography with the high-performance liquid chromatography (HPLC) method was established and validated for the quantification of imperatorin in rat plasma samples. The data were calculated by DAS (drug and statistics) Pharmacokinetic Software version 3.3.0 (Version 3.3.0, Shanghai, China). Results demonstrated that imperatorin lipid microspheres can significantly enhance the bioavailability of imperatorin and can significantly inhibit MDA-MB-231 cell proliferation. In conclusion, our results suggested that the response surface–central composite design is suitable for achieving an optimized lipid microsphere formulation. Imperatorin lipid microspheres can improve the bioavailability of imperatorin and better inhibit the proliferation of MDA-MB-231 cells as compared to imperatorin alone.

Preparation, Characterization and Pharmacokinetics Evaluation of Imperatorin Lipid Microsphere and Its Effect on Proliferation of MDA-MB-231

Imperatorin is a chemical compound belong to Linear furan coumarins. Imperatorin is attracting considerable attention because of its anti-tumor, antibacterial, anti-inflammatory, anticoagulant and inhibition of myocardial hypetrophy and other pharmacological efficacy. However, imperatorin has limited water solubility and preferable lipid solubility, we decided to design and synthesize imperatorin lipid microsphere, to optimize preparation conditions. The aim was to develop and formulate imperatorin lipid microsphere through nano emulsion technology and apply the response surface-central composite design to optimize the imperatorin lipid microsphere formulation. Influence of content of amount of egg lecithin(A), amount of poloxamer188(B), soybean oil for injection accounted for the total percentage of oil phase(C) were investigated. Integrated effect of dependent variables including particle size(Y1), polydispersity index(Y2), Zeta potentials(Y3), drug loading(Y4), encapsulation efficiency(Y5). Data of overall desirabiities were fitted to a second-order polynomial equation, through which three dimensional response surface graphs were described. Optimum experimental conditions were calculated by Design-Expert 8.06. Results indicated that the optimum preparation conditions were as follows: egg lecithin amount 1.39 g, poloxamer188 amount 0.21 g, soybean oil for injection amount 10.57%. Preparation of imperatorin lipid microsphere according to the optimum experimental conditions resulted in an overall desirability of 0.7286, while the particele size (168&plusmn;0.54) nm, polydispersity index (PDI) (0.138&plusmn;0.02), Zeta potentials (&minus;43.5&plusmn;0.5) mV, drug loading (0.833&plusmn;0.27) mg&middot;mL&minus;1, encapsulation efficiency (90&plusmn;1.27)%. The difference between observed and predicted values of the overall desirability of the optimum formulation was in range from 2.4% to 4.3%. Subsequently, using the Scanning electron microscopy to observe the micromorphology of imperatorin lipid microsphere, the result shows that round globular of relatively uniform and sizes within 200nm.The proliferation study of imperatorin lipid microsphere on MDA-MB-231 was investigated by MTT method. Furthermore, pharmacokinetics in Sprague Dawley rats were evaluated using orbital bleeding. A sensitive and reliable liquid chromatography with High Performance Liquid Chromatography (HPLC) method was established and validated for the quantification of imperatorin in rat plasma samples. The data were calculated by DAS (Drug and statistics) pharmacokinetic software version3.2.6 (China). Results demonstrated that imperatorin lipid microsphere can significantly enhance the bioavailability of imperatorin and can significantly inhibit MDA-MB-231 cell proliferating. In conclusion, our results suggersted that the response surface-central composite design is suitable for the optimized lipid microspere formulation. Imperatorin Lipid microsphere can improve the bioavailability of imperatorin and inhibit the proliferation of MDA-MB-231 than that of imperatorin.