Development Research Of Testosterone Undecanoate Capsules Loaded In Nanostructured Lipid Carriers

Objective:In this study,the nanostructured lipid carriers(NLC)drug delivery system were used to prepare NLC nanosuspention loaded the insoluble drug testosterone undecanoate(TU).In order to improve the physical stability,the nanosuspension were further cured,and then filled in capsules.The effect of homemade TU-NLC capsules in vivo bioavailability were measured to market soft capsules as a control drug in beagle dogs.The advantages and feasibility of NLC drug delivery system(DDS)for enhancing the bioavailability of poorly soluble drugs were evaluated.Contents:The prescription screening of TU-NLC nanpsuspension were studied and evaluated through main indexes such as appearance,particle size,polydispersity index and Zeta potential;The process of preparing TU-NLC nanosuspension was optimized through high pressure homogenization machine parameters,which affected the particle sizes,to contain the optimal prescription and technology condition;the vacuum drying technique were used for TU-NLC nanosuspension curing and the determination of cumulative dissolution were measured to confirm the prescription of capsules,and the technological parameters in the production process was optimized at the same time;the physical characterizations of nanosuspension and cured granules in NLC lipid matrix were represented by particle size analyzer,transmission electron microscopy,differential scanning calorimetry and X ray diffraction;the method of the determination of content and dissolution was established and validated;Finally,the TU-NLC capsules and listed soft capsules were carried on pharmacokinetic studies to compare the differences in vivo bioavailability in female beagle dogs.Methods:TU-NLC nanosuspension was prepared by high pressure homogeniza-tion method,single factor test was designed for prescription screening,the process of optimization was studied through the determination of the trend of particle size change;the nanosuspension was cured with a vacuum drying method by adding a protecting agent;the dissolution was carried on for screening and optimizing the capsules;dynamic light scattering and transmission electron microscopy was applied to measure the particle size,Zeta potential and particle morphology;differential scanning calorimetry and X ray diffraction was used to study the crystal characteristics of drug in NLC matrix;the dissolution condition was established and to determinate drug release in vitro,the content of TU was measured by HPLC method;The pharmacokinetics study of self-made TU-NLC capsules and listed soft capsules were conducted in beagle dogs after oral administration?Results:After the single factor experiment,we got the prescription composition of TU-NLC nanosuspension,and the optimum was listed:the solid lipid was melted at 75? with the liquid lipid,subsequently,TU was dissolved in the lipid mixture.Dropping the blend into water solution containing surfactant at the identical temperature with a high-speed stirrer.the obtained crude pre-emulsion was passed through a preheating high pressure homogenizer adopting 2 cycles at 100,300,600,800 bar.the hot o/w naonoemulusion was cooled to room temperature and then the TU-NLC was formed.The obtained TU-NLC nanosusoension performed small particle size,uniform distribution,and stable Zeta potential.the concentration of 80mg/ml suspension had an average diameter of 240.7nm,which was used for the next step of curing;after investigation of the dosage of protective agent and the dissolution curve of different prescription capsules,we obtained the dosage of nano suspension volume to protective agent at a ratio of 1:4(v/w)and prescription of TU-NLC capsules;the dissolution of capsules prepared by different process parameters were determined to obtain the optimal process:the TU-NLC nanosuspension was put into a 60? water bath for one hour,and then cured at 60? using vacuum drying,subsequently,crushed through 20 mesh sieve,mixed with the remaining materials.finally;transmission electron microscopy results showed that TU-NLC nanosuspension ignored the crystal structure and reveaed spherical uniform distribution;the test results of the DSC and X ray diffraction showed that a part of TU-NLC capsule characteristic peaks disappeared or weakened;the dissolution conditions were determined through the screening of dissolution method,speed and medium conditions,and then confirmed the second method(with the settlement basket)described in ChP 2015 as the dissolution method,900ml of 0.25%SDS solution was used as dissolution medium with a rotation speed at 75rpm;the method for the determination of the content and dissolution using HPLC was established,the results of method validation showed that the constructed method could accurately and quickly analyze the quality of TU-NLC capsules;female beagle dogs were used as experimental animals,the Cmax and AUC(0-t)of homemade TU-NLC capsules and commercially available soft capsules were(38.87±17.68)?g/L and 33.83±20.85 ?g/L,(4324.04±2131)?g/min/L and(3090.88±1745.35)?g/min/L,respectively.the paper drawed the conclusion that TU-NLC capsules and listed soft capsules were not equivalent and better than the soft capsules.Conclusion:The concentration of 80mg/ml TU-NLC nano suspension carried an average size of about 240nm,with a negative charge;the nanosuspensionwas cured and then filled into capsules;TU-NLC improved the solubility and bioavailability of drugs,The TU-NLC capsules/soft capsules ratios of Cmax and the AUC values were 1.4-fold and 1.15-fold,respectively,which indicated an important clinical significance.In summary,the preparation technology of NLC drug delivery system was simple and can be used for industrial production.The in vitro dissolution rate and in vivo bioavailability of the TU as a insoluble drug could be effectively improved,which increased the patient's compliance,and indicated broad clinical application prospect.