| The pathogenesis of hypertrophic scar is complicated.Therefore,the clinical treatment is difficult;and also the recurrence rate is high.5-fluorouracil(5-FU),an anti-tumor drug,is proved to have effect on hypertrophic scar.However,repeated intralesional injection often cause erythema,pigmentation and poor compliance of patients.Transdermal drug delivery has the advantages of convenient administration,non-invasion,controlled drug release,etc.It is better than oral administration and local injection,as to some diseases.In this paper,we combined electret,a physical penetration enhancer,with chemical enhancer to prepare the 5-FU transdermal patch,for the purpose of better effect on inhibition of scar growth.Our work is divided into the following four parts:1.Screen of patch formulation and influence of electret in patch propertiesThe 5-FU patch was prepared by using Eudragit E100 as pressure sensitive adhesive(PSA),tributyl citrate as plasticizer,water soluble azone as chemical enhancer.Through single factor analysis,it showed that E100,plasticizer and azone had significant influence in adhesive force of the patch.The primary adhesive force,lasting adhesive force and in vitro drug release were taken as indexes to optimize the formulation by orthogonal test.All the skin irritation,formulation stability and skin adhesive ability of the optimal formulation met the requirement of pharmacopoeia.The studies of influence of electret in adhesive force and in vitro drug release of the patch indicated that electret with higher surface potential could promote the natural release of 5-FU from the patch by decreasing the lasting adhesive force of the patch and the distribution of drug in patch.2.The transdermal behavior of chemical enhancer contained electret 5-FU patch through back and scar skin of the ratThe chemical enhancer contained electret 5-FU patches with different surface potential and polarity were applied to the back and scar skin of the rat.The improved Franz diffusion cell and high performance liquid chromatography were used to study the transdermal behavior.The results indicated that(1)Changes of the cumulative permeation amount and skin residual amount of 5-FU respectively through both kinds of skin had the similar pattern.(2)The higher the surface potential of the electret,the more the cumulative permeation amount and skin residual amount.The negative electret had better promotion effect than that of the positive electret with the same surface potential.(3)Although the cumulative permeation amount of normal skin was higher than that of scar skin,the scar skin had more skin residual amount than that of the normal skin.(4)The electret drug patch of higher surface potential increased the skin residual amount of the drug,which provided the foundation for the in vivo study.3.In vivo study of chemical enhancer contained electret 5-FU patchThe wound deep to fascia layer was made in rat.The patches were applied to the wound after the stage of acute inflammation.Four weeks later,the skin was sampled for HE and Masson staining to study the effect of electret on scar growth.The results indicated that(1)The epidermis and dermis in natural healing rat proliferated obviously.The collagen fibers deposited clearly and arranged irregularly,which was in accord with the characteristics of hypertrophic scar.(2)The morphological structure of the wound treated by electret patch was similar as that of natural healing wound,indicating that electret had no obvious effect on inhibition of scar growth.(3)Although the chemical enhancer contained 5-FU patch could inhibit the growth of the scar to some extent,the electret 5-FU patch showed much better effect on inhibition of scar growth than that of the chemical enhancer contained 5-FU patch.(4)The chemical enhancer contained electret 5-FU patch had the best effect on inhibition of scar growth among the patches studied.The higher was the surface potential of the electret,the better was the effect on inhibition of scar growth.The negative electret drug patch had better effect than that of the positive electret drug patch.4.The mechanism of effect of chemical enhancer contained electret 5-FU patch on inhibition of scar growthIn this study,the content of type I collagen,type III collagen,TGF-?1 and HSP47 were evaluated by measuring the mean optical density,to study the mechanism of effect of electret on inhibition of scar growth.The results showed that(1)Normal skin had low expression of type I collagen,type III collagen,TGF-?1 and HSP47;however,type I collagen,type III collagen,TGF-?1 and HSP47 were expressed higher in tissues of hypertrophic scar,indicating successful establishment of scar model.(2)In comparison with the controlled group,electret only decreased the value of mean optical density of type III collagen.(3)Both the chemical enhancer contained 5-FU patch and chemical enhancer contained electret 5-FU patch decreased the expression of type I collagen,type III collagen,TGF-?1 and HSP47 in scar tissue.However,the latter had the stronger inhibition effect.In summary,chemical enhancer contained electret 5-FU patch obviously increased the skin residual amount of 5-FU in in vitro transdermal experiment and decreased the expression of type I collagen,type III collagen,TGF-?1and HSP47 in scar skin in in vivo experiment.Therefore,it had the effect on inhibition of scar growth,and it could provide the thinking and ways for clinical treatment of hypertrophic scar. |
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