| Psoriasis is an autoimmune inflammatory skin disease mediated by T cells,which is characterized by inflammation of the skin,epidermal hyperplasia,hyper-keratosis.angiogenesis and abnormal keratosis.Currently,glucocorticoids and retinoic acid drugs play an important role in the treatment of Psoriasis.Betamethasone(BT)is a glucocorticoid with anti-proliferation and anti-inflammatory effects,which can definitely alleviate the symptoms of psoriasis,but it can cause local telangiectasia,skin atrophy and other adverse reactions when long-term use.Transretinoic acid,a first-generation retinoic acid,is commonly used as an adjuvant treatment for psoriasis,but its strong irritation also limits its clinical application.Studies have shown that glucocorticoids can reduce TRA irritation when combinated with TRA because of its anti-inflammatory effects.TRA could regulate the abnormal differentiation of keratinocytes and inhibit ornithine decarboxylase activity,and reverse the adverse effects of glucocorticoid-induced telangiectasia and skin atrophy,but does not affect its anti-inflammatory ability,and does not affect its anti-inflammatory ability.BT conbined with TRA could enhance the therapeutic effect,rapidly controlled inflammatory infiltration and its resulting hypertrophy,and regulated for epidermal keratinzation,avoided the capillaries expansion and skin atrophy and reduced the dependence of skin on hormone drugs.However,conventional transdermal drug delivery system has low transdermal efficiency,great toxic and side effects.Therefore,in this study,TRA and BT co-loaded flexible nano-liposomes(TRA-BT-FNL)were prepared,and a gel containing the flexible nano-liposomes was prepared on this basis,in order to improve the drug skin retention,improve the efficacy of drugs,and reduce the toxic and side effects.In this study,lecithin(S-100)was used as lipid material,and tween 80 was used as surfactant to prepare TRA-BT-FNL by thin film dispersion method.Meanwhile,TRA-FNL,BT-FNL,Free-TRA-BT,Free-TRA and Free-BT were used as controls.The results showed that TRA-BT-FNL had a distinct phospholipid bilayer structure under tem with uniform size,particle size was about 70 nm,the encapsulation efficiency of TRA was 98.74%,and BT was 99.14%,the total drug loading was about 4%;TRA could be released continuously for 48 h,while BT could be released continuously for 24 h.The transdermal rate of TRA in TRA-BT-FNL was 5.24 times as high as that in Free-TRA-BT solution,and the skin retention was 3.56 times than that of Free-TRA-BT for 24 h;the transdermal rate of BT in TRA-BT-FNL was 1.48 times than that of Free-TRA-BT,and the skin retention was 5.09 times than that of Free-TRA-BT for 24 h;TRA-BT-FNL has good percutaneous permeability and time-dependent tolerance.TRA-BT-FNL gel was prepared with carbomer 940,glycerin and distilled water as gel matrix.The results showed that TRA-BT-FNL gel had the ability of skin retention,good coating property and sustained release.TRA can be sustained for 48 h and BT can be released for 12 h.TRA was encapsulated with flexible nano-liposomes,and its skin irritation to rats was significantly reduced.The transdermal rate and skin retention of TRA and BT in TRA-BT-FNL gel were significantly higher than that in free drug solution gel.The percutaneous penetration of flexible nano-liposome gel was significantly stronger than that of free drug solution gel at 12 h in vivo;TRA is significantly less irritating to rats after being encapsulated with flexible nano-liposomes.The co-loaded flexible nano-liposome gel has better percutaneous penetration ability,the stability of TRA and BT is higher than that in free drug gel.The transdermal rate can be increased respectively by 4.41 times and 1.17 times,and the skin retention of 24 h can be respectively increased by 4.40 times and 2.56 times.HaCaT cells were used as model to investigate the cytotoxicity of blank liposomes and drug-loaded flexible nano-liposomes.Flexible nanoliposomes labeled with octadecyl-isothiocyanate fluorescein(ODA-FITC)were used as model drugs To investigate the uptake behavior.The results showed that it had no significant effect on cells growth in the concentration range of 2.5-1000 μg/mL,and the uptake ability of HaCaT cells on flexible liposomes are at time-dependent.In order to observe the effect of TRA-BT-FNL gel,A BALB/c mouse psoriasis model was induced by IMQ At the time,TRA-FNL gel and BT-FNL gel.,Free-TRA-BT gel,Free-TRA gel and Free-BT gel as a control.The results showed that the TRA-BT-FNL gel group had the least effect on the body weight of BALB/c mouse psoriasis model.Spleen enlargement of psoriasis mice was almost completely inhibited.The score of Psoriasis area and severity index(PASI)were better than other treatment groups.The results of HE staining and immunohistochemical showed that the skin in the intervention group of tra-bt-fnl gel was close to normal skin,with no obvious echinodermatosis and no obvious thickening,and the expression of CD3 in the skin tissue was down-regulated,which was better than other control groups.Compared with single TRA or BT flexible liposome gel group and free drug gel group,TRA-BT-F-NL gel group can significantly reduce the expression of TNF-α,IL-6 and other inflammatory factors.To sum up,the TRA-BT-FNL gel can significantly increase the skin retention of drugs and synergistic effects of drugs through flexible nano-liposomes,and this could significantly improve the efficacy of drugs and reduce the toxicity of drugs,which is expected to be a new formulation for the treatment of psoriasis. |
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