Study On The Dissolving Microneedle As Neurotoxin Transdermal Drug Delivery System For Anti-Rheumatoid Arthritis

Objective The aim of our study is to achieve the transdermal delivery of neurotoxin(NT)and the treatment of rheumatoid arthritis(RA)in rats by preparing NT loaded dissolving microneedle(DMN-NT).Methods DMN-NT was prepared by a two-step centrifugation method.The ratio of CS and PVP k30,the water content of the matrix solution,the backing layer material,and the drying method were optimized by the indexes of formability and mechanical strength of the microneedle and flexibility of the backing layer.The drug content was determined by HPLC,and the morphological characteristics were observed under an optical microscope and a scanning electron microscope.The drug loading position was observed under a fluorescence inverted microscope.And the stability and penetration ability of DMN-NT to the skin were also examined.Franz diffusion cell was used to investigate its in vitro skin permeation characteristics,and its security was investigated by penetration depth,in vivo dissolution,in vivo diffusion and recovery,and long-term administration experiments.Bovine type II collagen was used to induce a rat RA model.Toe volume,pain index,inflammatory factors IL-1β,TNF-α and pathological changes of ankle joints were used as indicators to evaluate its therapeutic effect on RA.Results Through the single-factor exploration,we confirmed that the optimal prescription technique for DMN-NT preparation was a 1:1 ratio of CS and PVP k30,a 5:4 ratio of matrix material and water,CMC as the backing layer material,and normal temperature and pressure drying.The DMN-NT has a pyramidal shape with a smooth surface and a length of approximately 500 μm,that could penetrate the excised skin of rat effectively.The drug content of per petch is 15.4 ± 0.5 μg.The drug is located in the upper part of the needle.DMN-NT has good stability in 3 months.The results of in vitro skin permeation assay showed that the cumulative penetration of NT in DMN-NT could reach 95.8% in 4 h,while NT solution barely penetrated the skin,which proved that it had a good promoting effect on NT transdermal delivery.A series of security test results demonstrated that the depth of skin penetration of DMN-NT was approximately 70 μm;all the needles structure were dissolved completely after 10 min;the channels on the stratum corneum were closed after 6 h;the adverse skin reactions were slight after 15 days of administration.The pharmacodynamics experimental results showed that DMN-NT can significantly reduce the toe swelling of RA rats,significantly reduce the serum TNF-α and IL-1β levels,and reduce the ankle joint injury.Conclusion In this study,DMN-NT was successfully prepared and transdermal delivery of NT was achieved with a good therapeutic effect on rat RA.