Quality By Design Approach For The Preparation Of Fat-soluble Vitamins Lipid Emulsions

Fat-soluble vitamins lipid emulsion is a parenteral nutrition,which is widely used in clinical.It is a thermodynamically unstable system consisting at least two immiscible phases,so that it will result in physical changes affected by mang factors,such as increasing particle size,aggregation,flocculation,coalescence,and demulsification,and lead to serious adverse reactions.Accordingly,lipid emulsions have been classified as a high-alert medication.The aim of this study was to apply a Quality by Design?QbD?approach to reduce the risk of lipid emulsions,optimization and preparation of fat-soluble vitamins lipid emulsions.Its quality standards,safety and stability were studied at the same time.Chapter ?:Quality by design approach for fat-soluble vitamins lipid emulsionsWith the increasing interest in drug quality management,QbD approach has been widely used in pharmaceutical research and development,generic drug research and declaration,etc.In this chapter,QbD approach was employed to optimize the formulation and process of fat-soluble vitamins lipid emulsions,to improve preparation quality,shorten research time and reduce production cost.Firstly,the quality target product profile?QTPP?of fat-soluble vitamins lipid emulsions was established.According to the properties of lipid emulsion and Fishbone diagram,the critical quality attributes?CQAs?were including drug content,mean particle size,polydispersity index?PDI?,the volume-weighted percentage of fat greater than 5?m?PFAT5?,rheological properties,lysophospholipids and heavy metal contents.The oil phase,emulsifier,stabilizer,homogenization and sterilization process were constituted as the key factors,which can significantly effect on the CQAs.The experimental design of key factors were carried out to optimize the formulation and process of fat-soluble vitamins lipid emulsions,and the control strategy was developed to ensure the quality.Finally,real-time monitoring of the production process,keep and improve the stability of lipid emulsions quality.Chapter ?:Optimization of fat-soluble vitamins lipid emulsions by centralcomposite designAccording to the QbD results above,the microfluidization was used to the preparation of fat-soluble vitamins lipid emulsions.Single-factor experimentals were performed to conduct the key factors.On the composition of lipid emulsion,10%?w/v?of soybean oil and medium chain triglycerides mixture?1:1,w/w?was used as oil phase,Lipoid E-80 was used as an emulsifier,and 0.03%?w/v?sodium oleate was added as a stabilizer.The lipid emulsions were prepared by Mini DeBEE and sterilized at 121^oC for 8 min.According to the results of single-factor experimentals,the content of Lipoid E-80,the pressure and the cycles of homogenization were taken as critical variables,the mean particle size,PDI and PFAT5 value were used as evaluation indexes,to optimized formulation and process of lipid emulsions by Central composite design?CCD?method.The optimized formulation and process were:added 1.2%?w/v?egg lecithin as emulsifier,the homogenization pressure was 10,000 psi for 3 cycles.Chapter ?:Quality control method studies of fat-soluble vitamins lipid emulsionsIn order to improve the quality of fat-soluble vitamins lipid emulsions,current researches were taken to study its quality standards.A simple,efficient and simultaneous determination for the four fat-soluble vitamins was established by comparing the quantitative limit,linear range,detection time and cost with high performance liquid chromatography.The particle size,Zeta potential,PFAT5 value,lysophospholipids content,rheological properties and heavy metal content of fat-soluble vitamins lipid emulsion had been determined.The mean particle size was about 217 nm,PDI was 0.115,Zeta potential was-35 mV,PFAT5<0.05%,lysophospholipids<0.5mg mL^-1,viscosity<21 mPas,heavy metal<0.1 ppm(0.1?g mL^-1),the fat-soluble vitamins lipid emulsion had a good safety and stability,met the quality requirements of lipid emulsions.Chapter ?:Safety studies of fat-soluble vitamins lipid emulsionsIn the safety studies of fat-soluble vitamins lipid emulsions,the in vitro hemolysis assay results shown that the lipid emulsions did not lead to erythrocyte hemolysis and agglomeration within 3 hours,so the lipid emulsions can be used for intravenous.In addition,the solvent stability and equipment compatibility studies taken to investigate the safety of fat-soluble vitamins lipid emulsions.Firstly,a highly sensitive LC-MS/MS method was established for the drug contents during the studies,the mean particle size and PFAT5 value were also determined.The results showed that the lipid emulsions had a good stability and compatibility within 24 hours in Intralipid^?and infusion apparatus.Chapter ?:Stability studies of fat-soluble vitamins lipid emulsionsThe influencing factors test,accelerated test and long-term test were usded to investigate the physical stability of fat-soluble vitamins lipid emulsions.The results showed that the pH and drug content decreased and the particle size increased at 40^oC and 60^oC,while the lipid emulsions were stable at 4,000 lux for 10 days,25±2^oC for 12months and 6±2^oC for 18 months.It indicated that the fat-soluble vitamins lipid emulsions had a good stability.Finally,the stability of fat-soluble vitamins lipid emulsions in different biological media was studied by simulating the changes of particle size and PDI value during the in vitro release.The results showed that glucose and albumin had no effect on the particle size and PDI of lipid emulsions,while the particle size and PDI was increased with the increase of salt content and viscosity.Conclusion:For reduced risks,the microfluidizer processors and CCD method was used to optimize and prepare fat-soluble vitamins lipid emulsions by employing QbD approach.A UPLC method for simultaneous determination of four fat-soluble vitamins was established,the lysophosphatide content,PFAT5 value,rheology and heavy metals contents were acceded to improve the quality standard of lipid emulsions.The stability test,hemolysis assay,solvent stability test,infusion apparatus compatibility test and biological medium stability test were taken to further improve the safety and stability of fat-soluble vitamin lipid emulsions.