| Nindedanib,a triple receptor tyrosine kinase inhibitor that can inhibit and control of tumor growth and proliferation,was the first drug approved by FDA to treat idiopathic pulmonary fibrosis.Because of the poor solubility and uneasy absorption of Nindedanib in the intestinal environment,its bioavailability is only 4.7%.Self-microemulsifying drug delivery system is often used as carrier for insoluble drugs.The system can increase its in vitro release by increasing the solubility of the drug,increase penetration of intestinal epithelial cells by forming a hydration layer that easily passes drug through the hydration layer of the stomach and intestine,and improve bioavailability by increasing drug absorption and absorption rate.This article aims to increase the solubility of Nintedanib by self-microemulsion,which can improve its dissolution rate,oral absorption,utilization and bioavailability.This paper is divided into the following five chapters:Part one: ReviewsThis chapter mainly summarized the research of idiopathic pulmonary fibrosis,Nintedanib,self-microemulsion delivery system.To understand the general conditions of idiopathic pulmonary fibrosis and current treatments,to outline the physicochemical properties,pharmacological mechanisms,and pharmacokinetics of Nintedanib,to explore the technology of self-microemulsion drug delivery system and its application in pharmacy.This chapter laid a theoretical foundation for the preparation of Nintedanib self-microemulsion.Part two: Pre-formulation studiesIn this chapter,ultraviolet spectrophotometry was established as a method for determining the in vitro content of Nintedanib.The maximum absorption wavelength of Nintedanib was found at 391 nm by UV full-wavelength scanning,and there was no interference from the dissolution medium and auxiliary materials.The detection wavelength of Nintedanib was determined to be 391 nm.A standard curve for in vitro determination of Nintedanib was established,and methodological validation was performed on the established method.The results indicated that the in vitro content determination method of Nintedanib was consistent with the methodological requirements.The solubility and oil-water partition coefficient of Nidabine in different media were investigated,the results showed that the solubility value of Nintedanib in p H6.8 PBS,p H7.4 PBS was 11.982 ?g·m L-1and 5.144 ?g·m L-1respectively,and the hydrophilic and lipophilic balance value was 2.4 and 2.85,respectively.The p H walue of human intestinal is similar to the p H6.8 or p H7.4 PBS,suggesting that Nintedanib has a low solubility in the intestinal environment,which results in its low bioavailability.The pre-prescription study laid the foundation for the preparation and research of Nintedanib self-microemulsions.Part three: Preparation and in vitro characterization of Nintedanibself-microemulsionIn this chapter,the pseudo-ternary phase diagram was combined with the emulsification state,emulsification time and particle size to determine the optimal formulation of Nintedanib self-microemulsion.The best prescription was determined that oil phase MCT,surfactant RH 40,cosurfactant Ethylene Glycol,Km 1.5,MCT content 10%,Nintedanib drug loading 10%.The optimum preparation parameters of Nintedanib self-microemulsion was determined that 37 ?,stirring speed 200 r·min-1,and magnetic stirring time 20 min.The optimal formulation of Nintedanib self-microemulsion was a pale yellow transparent liquid.After emulsification,the optimal formulation of Nintedanib self-microemulsion showed a pale yellow transparent liquid.The average particle size of microemulsion was about 23 nm,and the Zeta potential was 25.5 mv.Taking the index of the appearance,particle size and drug content of Nintedanib after emulsification,it was proved that the stability of the optimal Nintedanib self-microemulsion was stable.MTT assay was used to investigate the toxicity of the blank SEMDDS carrier to Caco-2 cells.The results showed that the blank self-microemulsion carrier had better safety.In vitro dissolution experiments showed the release rates of Nintedanib were 91.21%,54.01%,40.64%,9.10% in dissolution media of 0.1 mol?L-1 HCl,water,p H6.8 PBS(0.5% Tween 80),p H7.4 PBS(0.5% Tween 80)for 12 hours.The cumulative release rates of Nintedanib self-microemulsion soft capsules in the corresponding dissolution media were 92.30%,75.02%,65.03%,and 57.90%.It was shown that Nintedanib self-microemulsion could significantly improve the in vitro release of drugs in neutral media.Part four: Study on intestinal absorption of Nintedanib self-microemulsionsIn this chapter,rat intestinal circulation test was used to study the intestinal absorption characteristics and absorption sites of Nintedanib and self-microemulsion formulation,and to explore their absorption mechanism.The absorption of Nintedanib solution group and Nintedanib self-microemulsion group in different intestinal segments was studied.The results showed that Ka value of Nintedanib solution group in duodenum,jejunum,ileum and colon was 0.050±0.011,0.050±0.019,0.045±0.009,VI0.037±0.007 respectively,and the percentage of absorption was 12.841±1.88,13.814±2.00,12.009±1.32,9.560±1.02,respectively.Correspondingly,Ka value of Nintedanib self-microemulsion group in duodenum,jejunum,ileum and colon was0.141±0.016,0.149±0.022,0.130±0.014,0.120±0.013 respectively,and the percentage of absorption was 31.229±1.55,34.401±2.37,29.210±1.85,26.978±2.23 respectively.Nintedanib was absorbed in all intestinal segments,with no significant difference(P>0.05),indicating that Nintedanib was absorbed in the entire intestine.Using Nintedanib solution as control group,absorption of Nintedanib self-microemulsion group in each intestinal segment was significantly higher than that of Nintedanib solution group(P<0.01).The total cumulative absorption of Nintedanib self-microemulsion group in the whole intestine segment was 73.59% higher than that of the control group during 3 hours,indicating that self-microemulsion preparation could improve its absorption rate.The absorptions of Nintedanib self-microemulsion at concentrations of 10 ?g·m L-1,40 ?g·m L-1,and 80 ?g·m L-1 in the jejunum were examined.The Ka value and the cumulative absorption percentage(%)were independent of the drug concentration.There was no significant difference between different concentrations(P>0.05),indicating that the intestinal absorption dose was positively correlated with the concentration of Nintedanib when the drug concentration was in the range from 10 ?g·m L-1 to 80 ?g·m L-1.It was determined that the absorption mechanism of Nintedanib self-microemulsion was passive diffusion.Part five: Pharmacokinetics study of Nintedanib self-microemulsionThis chapter established a method for in vivo analysis of Nintedanib with the high performance liquid chromatography.Methodological validation results showed that the established method was complied with the methodological requirements.After intragastric administration to SD rats,this section examined the changes over time in plasma concentrations of Nintedanib solution and Nintedanib self-microemulsifying groups.The in vivo pharmacokinetic parameters were obtained by non-compartment model fitting.The results of in vivo pharmacokinetic experiments showed tmax of the plasma concentrations of Nintedanib solution group and Nintedanib self-microemulsion group were 3 h and 2 h,respectively.Cmax values of Nintedanib solution group and Nintedanib self-microemulsion group were 2.6505?g·m L-1,6.084 ?g·m L-1,respectively.AUC0-12 values of Nintedanib solution group and Nintedanib self-microemulsion group were 12.706 ?g?h?m L-1,30.473 ?g?h?m L-1,respectively.The average relative bioavailability of Nintedanib self-microemulsiongroup,relativing to Nintedanib solution group was calculated to be 239.83% by the relative bioavailability formula.The above results showed that Nintedanib self-microemulsion could significantly accelerate drug absorption rate,increase the degree of drug absorption,and effectively improve oral bioavailability. |
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