Preparation Of Dual-Drug-Loaded Microneedles And Preliminary Study On Skin Photoaging Resistance

Skin photoaging is a disease caused by long-term exposure to sunlight,which causes hyperpigmentation,skin drooping,and wrinkles.The majority of medicines used to treat skin photoaging are currently available in traditional formulations like creams and gels.The medications are difficult to efficiently delivered into the body due to the barrier effect of the stratum corneum.Using dissolving microneedles(DMNs)can allow medications to be delivered locally or systemically through micro-sized pore channels.Glabridin(GLA)and Ascorbic acid 2-glucoside(AA-2G)have strong antioxidant and anti-inflammatory properties,as well as the ability to resist skin aging,which are widely used in cosmetics.The purpose of this study was to design and prepare dual-drug-loaded DMNs,with the insoluble GLA and the water-soluble AA-2G both loaded in the DMNs.The main findings are as follows:The UV and HPLC analysis procedures for GLA and AA-2G were established.The solubility and oil-water partition coefficient(Log P)of GLA and AA-2G in various medium were measured.And 30% PEG400-PBS(v/v,p H7.4)was chosen as the receiving medium for the sink condition of in vitro release experiment.The Log P of GLA in water and PBS was 3.061±0.108,3.058±0.158,the Log P of AA-2G in water and PBS was-1.065±0.054,-1.439±0.205.The GLA/HP-β-CD inclusion complex was prepared by the solution stirring-freeze-drying method,and the formulation process was optimized by orthogonal experiment.The effects of cyclodextrin inclusion on the biological activity of GLA were investigated.The optimal formulation was the molar ratio(GLA: HP-β-CD)=1:1,the stirring temperature was 40°C,the stirring time was 2h.An encapsulation rate of 61.21%,clathrate yield of 98.18%,and drug loading of 13.28% was obtained from the optimal formulation.The cyclodextrin inclusion had no significant effect on the in vitro antioxidant and tyrosinase inhibitory activities of GLA.The FT-IR,SEM,X-RD,and DSC were used to identify the inclusion complex,demonstrating the formation of the GLA/HP-β-CD inclusion complex.The appearance and drug release properties of the inclusion complex-loaded DMNs were studied.The inclusion complex-loaded DMNs could considerably sustain drug release,compared to those without inclusion complex(P<0.01).Also,a higher initial penetration rate and cumulative penetration amount were obtained.Further,the time lag was shorter(P<0.05).The in vivo skin pharmacokinetics showed that,compared to the GLA DMNs,the GLA inclusion complex DMNs could achieve a higher skin retention more rapidly after administration,and the duration was longer.The hygroscopicity,needle-forming and pierce ability of the GLA/HP-β-CD inclusion complex DMNs was evaluated.And the formulation of flexible DMNs was optimized using sodium fluorescein as the model drug.A 20% PVP K90 ethanol solution as the backing solution and a 30μL 2.5% PVP K30 solution as the needle tip solution was the optimized formulation.The in vitro transdermal experiments showed that AA-2G in the dual-drug-loaded DMNs could quickly enter the body and be released completely in a short time,while GLA could achieve a more sustained release.The stability of GLA/HP-β-CD inclusion complex DMNs,AA-2G DMNs,and dual-drug-loaded DMNs were studied.The results showed that DMNs could be stored at room temperature for two months.The pharmacodynamics of the GLA inclusion complex/AA-2G dualdrug-loaded DMNs were studied.Using guinea pig skin photoaging caused by recurrent UVB irradiation as a pharmacological model,the efficacy of the dual-drug-loaded DMNs was assessed on three levels: skin macroscopic score,skin elasticity,histological examination.The GLA inclusion complex/AA-2G dual-drug-loaded DMNs was found to significantly diminish stratum corneum thickness and skin relaxation induced by skin aging.Blank DMNs and dual-drug-loaded DMNs were tested for skin irritation,and it demonstrated that the skin irritation caused by both types of DMNs be recovered after 24 hours.Overall,the GLA inclusion complex/AA-2G loaded DMNs developed in this study allows both drugs to enter the body quickly and improve their bioavailability.At the same time,it shows a dual-phase drug release mode in which two drugs were release at different speeds.It’s potential in deliver two drugs with DMNs.