| Local anesthetics have been widely used in clinical practice,which greatly reduces the pain of patients.However,there are still some problems,such as high toxicity and inconvenient administration of local anesthetics for injection.Transdermal drug delivery system has the advantages of avoiding liver first-pass effect,controlling drug delivery,reducing drug delivery frequency and improving patient compliance.Although the existing transdermal local anesthetics are convenient to use and greatly improve the dependence of patients,they work slowly.Therefore,it is urgent to prepare a transdermal local anesthetic with low toxicity,quick effect and long-acting time.This subject aims to prepare a local anesthetic ethosomes,which is applied to a transdermal drug delivery system to achieve the purposes of low toxicity,fast onset and long-acting time.The contents of this paper mainly include four parts :(l)screening of transdermal local anesthetics;(2)Preparation and characterization of TCH ethosomes;(3)Transdermal effect and safety of TCH ethosomes;(4)Preliminary study on the transdermal mechanism of the ethosomes from the cell level.The main research methods and results adopted are as follows:(1)The ethosomes and aqueous solutions of TCH,lidocaine,tetracaine,propiocaine and their pairwise combinations were prepared,and the local anesthetics with better transdermal effect were screened by the mouse tail swing experiment in warm bath.Preparing TCH ethosomes,aqueous solution and tincture and comparing the onset speed of each group.The results showed that the transdermal effect of TCH was better and the ethosomes group was obviously better than the aqueous solution group and tincture group.(2)Using the encapsulation efficiency as a screening index,the preparation method of TCH alcohol plastids was screened out.Finally,the injection ultrasonic method was selected.On the basis of single factor experiment,the formula of TCH ethosomes was optimized by Central composite design-response Surface methodlogy.The optimal preparation process of TCH ethosomes was as follows: the mass added amount of egg phosphatidylcholines is 172 mg;Cholesterol mass concentration is 3 mg/m L;Ethanol volume fraction is 30%;The predicted encapsulation efficiency is 46.33%.Three batches of TCH ethosomes were prepared according to the above conditions and the results showed that the average encapsulation efficiency was 45.93% and the relative deviation from the predicted encapsulation efficiency was 0.87%.The TCH ethosomes prepared by this method were observed to be spherical and uniform in size by electron microscopy.The average particle size was(80.33±2.24)nm,and the average potential was(-22.6±1.33)m V.The TCH ethosomes were well stable in the sealed and dark environment at 4 ℃ for21 days.(3)TCH ethosomes,tinctures,and aqueous solutions were prepared,and their cumulative permeabilities were examined and compared through Franz diffusion cells;The toxicity and skin irritation of TCH ethosomes to SD rats were examined.The results showed that the transdermal effect of TCH ethosomes was better than that of TCH tincture and TCH aqueous solution group;TCH ethosomes were non-toxic and irritating to the skin.(4)Investigate the toxic effect of ethosomes on HaCaT cells,and then screen out the less toxic ethosomes concentrations;CM-Dli stained the HaCaT cell membrane red,and NBD-PC labeled ethosomes were green.Observe its distribution by using of CLSM.The results showed that the concentration of the selected protoplasts was 2.5%,it was observed by using of CLSM that the protoplasts passed through the keratinocytes through the intercellular space.In summary,The TCH has the best transdermal effect.The TCH ethosomes prepared by the optimal method has uniform size with good stability and good safety at 4 °C,and provides a theoretical basis for the application of TCH in transdermal drug delivery systems. |
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