| Solid microneedles(MNs)for skin pretreatment have attracted considerable attention in recent years due to their ability to increase skin permeability.There are several approved cosmetic products using microneedles in the market including Dermaroller,silicon MNs,etc.However,a safer MN which is made of biodegradable polymers hasn’t been commercialized.Solid polymer MNs still need the support of theoretical data to realize the prospect of mass production and clinical application.In this paper,polylactic acid(PLA)MNs with different dimensions were prepared using the molding method.The effects of solid polymer MNs on enhancing transdermal drug permeation both in vitro and in vivio and the safety in human were systemically investigated.Also a mass preparation method of solid polymer MNs was proposed and the corresponding MN applicator was designed for the skin pretreatment of solid polymer MNs.The main contents of this paper are as follows:1.The mechanical and stability properties of the microneedles and the effects of MN dimensions,drug concentration,the viscosity of drug formulation and the administration time of drug on the skin on the drug permeation into the pretreated skin were systemically investigated.Multiple applications test demonstrated MNs with the height of 600 μm possessed good mechanical stability performance.800-μm depth microneedle and microneedle with the density of 256 MNs/cm2 were most conductive to enhance the drug permeation.In addition,the increasing of drug concentration could increase the permeation amount of drug,but not affected on drug permeation rate.With the increase of drug viscosity,the drug permeation amount was decreased.To prolong the administration time of drug on the skin at 1 h,the drug permeation amount achieved a stable value and essentially unchanged after 1h.Finally,the permeation effect induced by the MNs was demonstrated by insulin delivery in vivo.In conclusion,the biodegradable polymer solid microneedles can painlessly pierce the stratum corneum and accelerate the absorption of drug and active ingredients.2.The first time the effect of polymer solid MN height and density,drug molecular weight and drug diffusion time on the drug permeability distribution was systemically investigated in vivo by in vivo imaging system.MN with a height of 800 μm was most conductive to enhance the vertical distribution of drug permeation into the skin.While 11×11 MN arrays was most beneficial to promote the horizontal distribution of drug permeation into the skin.In addition,the increasing of drug molecular weight could reduce the drug permeability distribution and Fluorescein isothiocyanate(FITC,MW 389.38 Da)most likely to penetrate into the skin after MNs pretreatment.With the increase of drug diffusion time,the drug distribution in the subcutaneous gradually weakened until the drug was absorbed by the subcutaneous tissue at 8 h.These results suggest that the polymer MNs can penetrate the stratum corneum of the skin for enhancing drug delivery,especially small molecule drugs.3.The safety of solid polymer MNs in human was evaluated from the aspects of pain and irritation,i.e.the effects of mironeedle dimensions on pain and skin irritation were studied.For the forehead,MNs with a height of 400 μm,a density of 100 MNs/cm2,and an array size of 10×10 MN arrays induced less pain and skin irritation.For the forearm,MNs with a height of 400 and 600 μm,a density of 49 and 100 MNs/cm2,and an array size of 10×10 MN arrays generated less pain and skin irritation.For the abdomen,MNs with a height of 400,600 and 800 μm,a density of 49 and 100 MNs/cm2,and an array size of 5×5,10×10 and 10×20 MN arrays induced less pain and skin irritation.In conclusion,optimizing the dimensions of solid polymer MNs rationally based on the MNs application site was conductive for improving the safety of MNs and the patient compliance.4.The apparatus for mass production of MNs and microneedle applicator were designed by using the soft of UG 6.0 and CAD. |
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