Evaluation Of Inhalation Administration Of Salvianolic Acid In The Lungs

Objective:Salvianolic acids as the model drug,the alkaline solution regulated the pH of the drug solution,the phosphatidylcholine modified the drug particles,and the wet ball milling was used to prepare and screen out the drug micropowder of salvianolic acids with narrow particle size distribution,better fluidity and higher lung deposition rate.Penn-Century endotracheal intubation technique was used to target the delivery of drug micropowder to the lungs of rats.The delivery effect and lung distribution of drug micropowder were observed by living imaging technique.Combined with the stimulation experiment,pharmacokinetics and lung tissue distribution of salvianolic acids inhalation,to analyze the feasibility of pulmonary inhalation of salvianolic acids.In order to provide the material basis for the follow-up study of salvianolic acids drypowder for inhalation and to provide new ideas and methods for the clinical treatmentof salvianolic acids.Methods:50 mg·mL-1 L-arginine and 1 moL·L-1 NaOH solution were used to adjust the pH of salvianolic acids to 5.0.Salvianolic acid(no adjust pH),salvianolic acids-arginine and salvianolic acids-NaOH 3 kinds of freeze-dried powder were obtained.Every kind of freeze-dried powder added 0.5%,1%and 2%of the phosphatidylcholine to modify drug particles.The quality of micropowder was evaluated in 6 aspects:micromorphology,particle size distribution,fluidity,wettability and in vitro deposition rate.The effect of lecithin on the micromeritics properties of salvianolic acids was evaluated.And determined the optimum dosage of lecithin.Using indocyanine green as a fluorescent substance,Penn-Century endotracheal intubation technique was used to target the delivery of drug micropowder to the lungs of rats.Observed the delivery effect and pulmonary distribution of 3 kinds of drugs micropowder by living imaging technique.Screened out the best delivery way.Total protein concentration,the concentration of interleukin-8,the activity of lactate dehydrogenase and the pathological structure of lung tissue in the alveolar lavage fluid(B ALF)were used to screen out the drug micropowder with the smallest lung irritation.Compared with the way of tail vein injection,study the pharmacokinetic and lung tissue distribution of salvianolic acids micropowder for inhalation.Evaluated the feasibility of salvianolic acids for inhalation.Results:The results of the quality evaluation of the drug micropowder showed that the addition of arginine and lecithin could improve the micromeritics properties of salvianolic acids micropowder.The greater proportion of the lecithin,the better micromeritics properties of salvianolic acids micropowder.The addition of 2%lecithin could meet the requirements of the 2015 edition of "People's Republic of China Pharmacopoeia".At the same time,screened out Sal-Arg-2%micropowder owning the finest properties.Its particle size was less than 5 ?m,D50 was 1.153?m,the rest angle was 25.66°±1.24,and the hygroscopic weight gain after 10h and 30h were 7.42%±0.05 and 11.02%±0.04,the delivery rate was 72.99%,the percentage of fine particles was 13.53%,and MMAD was 4.57 ?m.With indocyanine green as a fluorescent substance,Sal-ICG-2%,Sal-NaOH-ICG-2%and Sal-Arg-ICG-2%powder were prepared by the best preparation process of drug freeze-dried powder and 2%quantity of lecithin.Penn-century tracheal intubation was administered,screening out the best way of drug delivery was pushing the 1mL air each time with 3 times.Under this way,3 kinds of powder can be delivered to the lungs successfully and evenly distributed in the lungs.The results of lung irritation showed that the irritation of 3 micropowders of Sal-2%,Sal-Arg-2%and Sal-NaOH-2%were:Sal-2%drug micropowder>Sal-NaOH-2%drug micropowder>Sal-Arg-2%drug micropowder.The rats with minimal irritation in Sal-Arg-2%powder group had better mental state and stable weight gain during administration.The total protein concentration was 0.14±0.04 mg·mL-1,the concentration of interleukin-8(IL-8)was 1.95±0.39 pg·mL-1,and the activity of lactate dehydrogenase(LDH)was 129.99 ± 40.19 U-g-1 in BALF.The above indexes were not significantly different from those of the normal control group.The lung appearance showed that the lung tissue of the rats in the Sal-Arg-2%group were red,smooth and full with no bleeding points,and no typical pathological changes were observed.The results of HE stained lung slices showed that the lung tissue structure of rats in Sal-Arg-2%group were similar to that of the normal control group.The lung tissue structure was clear,the alveolar wall was thinner,and the no inflammatory cells in the alveoli were soaked and exudated.Therefore,we screened out the Sal-Arg-2%drug micropowder for the study of "Pharmacokinetics and distribution of lung tissue in salvianolic acids micropowder inhalation".The absolute bioavailability of pulmonary drug delivery was 74.91%and the bioavailability was high.The drug concentration in lung tissue is much higher than that in the caudal vein group.Pulmonary drug delivery after 60 min of lung tissue concentration of salvianolic acid B was 406.41 ± 50.07 mg·L-1,It suggested that the inhalation of salvianolic acids in the lung is feasible for the treatment of lung disease.Conclusions:Salvianolic acids as a model drug and added 2%lecithin,according to the best preparation process,prepared the salvianolic acids micropowder with the fine quality requirements.The drug micropowder could be successfully delivered to the lungs and distributed evenly in the lungs in the way of "pushing the 1mL air each time with 3 times".The lung irritation results showed that the Sal-Arg-2%drug micropowder was least irritant.The absolute bioavailability of pulmonary drug delivery was 74.91%and the bioavailability was high.The drug concentration in lung tissue is much higher than that in the caudal vein group.It suggested that the inhalation of salvianolic acids in the lung is feasible for the treatment of lung disease.