| As a novel transdermal drug delivery tool,microneedles(MNs)has been widely studied in recent years with the advantages of painless,minimally invasive and efficient drug delivery.Microneedles can pierce the human skin,break through the stratum corneum and form self-repairing micropores.When applied to transdermal administration,microneedles can significantly increase the permeability of the drug,and are particularly suitable for transdermal delivery of macromolecular drugs that are difficult to achieve with conventional patches.Microneedles mainly include solid MNs,coated MNs,hollow MNs,dissolving MNs,degradable MNs and hydrogel-forming MNs.Dissolving microneedles are usually prepared from water-soluble carbohydrates or polymers,with good biocompatibility,and can be dissolved or degraded in the skin.Compared with the coated microneedles,the dissolving microneedles has a larger drug loading amount and the dosage is easier to precisely control.Compared with metal or non-degradable materials,dissolving microneedles materials are safer,so their field research has been heating up year by year.The materials for preparing dissolving microneedles are mostly concentrated in hyaluronic acid(HA),carboxymethyl cellulose(CMC),polyvinyl alcohol(PVA),polyvinylpyrrolidone(PVP),dextran,chondroitin sulfate and some composites,there are few studies on the preparation of microneedles using new natural materials.These materials have good film formation,plasticity and biocompatibility.As a natural glucomannan material,bletilla striata polysaccharide(BSP)has the above-mentioned advantages,it also has anti-inflammatory,anti-bacterial,wound repair and other pharmacological activities,and has been widely used in the processing and manufacturing and clinical treatment of various preparations.Therefore,the use of BSP " combination of drug and auxiliary " characteristics for microneedles preparation has great application potential.Aim: For the first time,this study attempted to prepare novel dissolving microneedles(BMNs)using natural glucomannan material,namely,bletilla striata polysaccharide(BSP),and optimized the mold of BMNs;Study material formability,molding conditions,screening and optimization of preparation methods and process parameters;The basic properties of the microneedles after molding were examined,and transdermal drug delivery using such dissolving microneedles as a transdermal delivery vehicle was investigated.Methods: 1.PDMS molds with different edge types and sizes were prepared by laser drilling;The optimum dosage and concentration of bletilla striata polysaccharide solution for the preparation of BMNs was investigated,and the preparation method and process was optimized.2.Infrared analysis(FTIR)and thermogravimetric analysis(TGA-DSC)were carried out for BMNs.The changes of solid characteristics were analyzed.Investigate the basic properties of the molded microneedles,including mechanical properties,skin penetration,self-solubility,skin irritation,and cytotoxicity.3.Rhodamine B(RB)was selected as a model drug to investigate the drug-loading properties of BMNs and to study the interaction between drug loading and mechanical properties;The in vivo release of RB-loaded BMNs was initially explored;and compared the in vitro drug transdermal permeation of the RB-loaded BMNs and RB-loaded patches.Results: 1.Laser drilling of PDMS molds by microscopic examination showed no defects,with strong toughness,can be reused many times;The 2 mm edge size of PDMS mold is preferred;The BMNs is preferably prepared by a centrifugal spin coating method,and the optimal concentration range is 15%-25%(w/v),the centrifugation time is 30-60 min.2.The average height and base width of the prepared BMNs were 781.9±13.1μm and 318.2±12.5μm(n=10),respectively.It has excellent moldability and easily to demold.Texture analysis showed that the mechanical properties of BMNs were 25.44 ± 2.78 N(n = 4).Histological examination confirmed that BMNs had sufficient mechanical properties to penetrate into the skin with a penetration depth of about 170-215 μm.After the microneedles shaft was inserted into the rat skin,it was almost completely dissolved within 1 h.Safety studies have shown that after removal of BMNs,the skin surface is slightly irritated and returns to normal within 24 h.The microneedles matrix had no toxic effects on L-929 cells(mouse fibroblasts).3.Confocal laser scanning microscopy(CLSM)studies found that when rhodamine B(RB)as a model drug was loaded into BMNs,as BMNs penetrated the skin,BSP gradually dissolved and released,then spreading from the insertion site to the periphery.The fluorescence penetration depth reached 180 μm.In addition,through in vitro franz diffusion cell experiments,it was found that BMNs with drug concentrations of 10 wt.% and 5 wt.% provided sustained drug release,and cumulative infiltration at 4 days reached 731.19±75.52 μg and 389.95±51.48 μg,respectively.At the same time,the amount of RB-loaded patch delivery RB was only about 10% and 5.82% of RB-loaded BMNs.Conclusions: 1.The microneedles mold prepared by PDMS material is safe,cheap and durable;the new microneedles prepared by using BSP is strong in formability and stable in formation.The mild manufacturing method makes the drug selection of the new microneedles more diverse.2.The BMNs conforms the basic properties of the microneedles,with good mechanical properties,solubility and safety,and can be applied to transdermal drug research.3.BMNs loading drugs can provide a slow and sustained drug release,enhancing the permeability of the drug and providing more possibilities for transdermal drug delivery studies.In short,BSP as a natural material of " combination of drug and auxiliary" is more secure than synthetic microneedles materials in terms of safety and biocompatibility.BSP is widely proven to have anti-inflammatory,anti-bacterial and other effects to help reduce skin infections after microneedles application.While it is used as a microneedles matrix material,the synergistic application of pharmacological activity is also attractive for subsequent drug-loading studies. |
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