Preliminary Study On The Construction Of A New Type Of Transdermal Penetration Enhancer Based On Amino Acid Ester Ionic Liquids And Its Penetration Enhancement Mechanism

In transdermal drug delivery systems,CPEs can accelerate the penetration of drugs through the skin without causing serious irritation and damage,and penetration enhancers are the most common and convenient way to overcome the barrier properties of the skin.Ionic liquids are molten salts composed of large asymmetric organic cations and anions and are liquid at room temperature.Compounds with specific chemical and physical properties are synthesized by changing the anion/cation combination of ionic liquids or introducing specific functional groups.Studies have shown that imidazole ionic liquids have good transdermal penetration effect on drugs,but still have strong resistance to biodegradation and induced skin irritation,and safety issues restrict their further development in transdermal drug delivery systems And application.It is worth noting that amino acid derivatives have been shown to enhance skin penetration and biodegradability and low irritation.In order to develop safe and effective penetration enhancers,this paper combines the structural designability of ionic liquids with the biodegradability of amino acids and the common penetration promotion activity to design and synthesize new amino acid ionic liquids(AAE-ILs).The transdermal penetration promoting effect and mechanism of ionic liquids have been systematically studied.We first used the lipophilic drug hydrocortisone and the hydrophilic drug 5-fluorouracil as model drugs to investigate the transdermal promotion of 15 amino acid methyl ester hydrochlorides([AAC1]Cls)Osmosis,its activity was evaluated and screened.Among them,three[AAC1]Cls with the best penetration promoting activity were selected.With reference to the structure-activity relationship of amino acid esters and ionic liquids,different length straight carbon chains were selected to modify their ester groups,and the newly obtained AAE-ILs could significantly increase Penetration of the two model drugs.For AAE-ILs,skin tissue was used to investigate its safety,in vitro transdermal penetration experiments were conducted to study the penetration of different drugs,and CLSM was used to analyze the regulatory effect of AAE-ILs on skin barrier function,and then through ATR-FTIR,solid-state NMR,SEM and TEM further study its penetration mechanism.The main research contents and results of this article include:1、Evaluation and screening of the penetration enhancing activity of amino acid methyl ester ionic liquid:The hydrophilic drug 5-fluorouracil and the lipophilic drug HC were used as model drugs.Cumulative permeation Q12h,steady-state flow Flux,diffusion coefficient Pm,and penetration-promoting ratio ER are evaluation indexes.The percutaneous penetration-promoting activities of 15 amino acid ester ionic liquids were investigated.For the hydrophilic drugs 5-FU,[L-Leu C1]Cl,[Gly C1]Cl,[L-Pro C1]Cl and[L-Thr C1]Cl provide a relatively higher penetration promoting effect,and the ER values are 2.74,2.18,2.08 and 2.03.Compared with the commercial penetration enhancer in the experimental group,it has better penetration promotion effect.For the lipophilic drug HC,compared with the control group,only[Gly C1]Cl,[L-Leu C1]Cl penetration enhancing activity is slightly stronger than the control group.Based on this,[L-Leu C1]Cl,[Gly C1]Cl and[L-Pro C1]Cl have been used to promote the penetration of two drugs,and compared with other[AAEC1]Cls The effect is outstanding,and it is better than Azone~?,Tween20,Transcutol~?commercial penetration enhancer.2.Synthesis and characterization of new amino acid ester ionic liquids:refer to the structure-activity relationship of ionic liquids and amino acid ester derivatives.Successfully designed and synthesized 6 kinds of amino acid lipid ionic liquids.Including[L-Leu C8]Cl,[L-Leu C12]Cl,[Gly C8]Cl,[Gly C12]Cl,[L-Pro C8]Cl and[L-Pro C12]Cl.The synthesis reaction starts with glycine,L-leucine,L-proline and saturated linear fatty alcohols with carbon chain lengths of eight and twelve.The first step is esterification,and the second step is acidification.The reaction is easy to purify,easy to obtain pure product,and the yield is almost above 70%.The final product was characterized by NMR and FTIR.And the melting point of all products is below65℃.3、Evaluation of the new amino acid ester ionic liquid’s penetration promotion effect:through the in vitro Franz diffusion cell experiment to further study the transdermal penetration of 6 new ionic liquids and its molecular structure Correlation with penetration promoting activity.By comparing amino acid ester ionic liquids with the same nucleus and anion,the ester chain carbon length is 1,8,12 The influence of the barrier.Six new amino acid ester ionic liquids can promote the transdermal absorption of model drugs 5-FU and HC.It is more obvious when it is used for 5-FU,and the effect on HC is not particularly great.The length of the hydrophobic chain of the ionic liquid has a significant effect on its penetration promoting effect,and the penetration promoting effect of[AAE]Cls on the two model drugs increases with the length of the ester carbon chain.And the penetration promoting activity follows the following rules:[AAEC12]Cl>[AAEC8]Cl>[AAEC1]Cl.The use of six[AAE]Cls on the skin significantly increased the skin’s TEWL value.After removing the test solution,the TEWL value gradually increased to reach the peak within 1 hour,and then gradually decreased.And at the end of the experiment(6 hours after removing the solution),the TEWL of each test group returned to normal levels,which was not statistically different from the negative control group.This indicates that[AAE]Cls’effect on the stratum corneum barrier is reversible.4.Research on the penetration promoting mechanism of the new amino acid ester ionic liquid:when[L-Pro C12]Cl and[L-Leu C12]Cl act on the skin,the CLSM experiment shows that it can significantly increase the penetration depth of fluorescein sodium and Nile Red And strength.ATR-FTIR and solid-state NMR experiments have shown that it can cause the lipid of the stratum corneum to fluidize and change the conformation of the keratin.The SEM and TEM experiments proved that it can make the skin horny layer surface rough and wrinkled,and the lipid layers are separated from each other,which can extract and fluidize the lipids in the stratum corneum,thereby adjusting the skin permeability to promote penetration effect.And it has time and concentration dependence.In short,[AAE]Cls successfully combines the advantages of amino acid esters and IL solvents,mainly through the interaction of lipid fluidization and lipid extraction with intercellular lipid domains and a small part of keratinocytes,thereby playing a role in promoting penetration.5.Safety evaluation of the new amino acid ester ionic liquid:through histopathology experiments and cytotoxicity experiments,it can be seen that[L-Pro C12]C1 and[L-Leu C12]Cl have no irritation to normal skin at different concentrations and different treatment times with good biocompatibility.In this paper,5-FU and HC were used as model drugs to screen new[AAEC1]Cls that can improve skin permeability,and to modify the structure and preliminary study the mechanism of penetration promotion.It is proved that these[AAE]Cls have the characteristics of significantly promoting skin penetration and biodegradability,can be used in transdermal drug delivery systems,and contribute to the further development and utilization of ionic liquids in the pharmaceutical industry to achieve the intended purpose.