| Microneedle can overcome the skin barriers in a minimally invasive way and can effectively promote the transdermal penetration of drug molecules,especially in the transdermal delivery of large-molecule drugs.At the beginning of the 21 st century,it has been gradually demonstrated that microneedles could significantly improve the transdermal delivery of insulin.With the increasing availability of materials,more and more materials have been developed for the preparation of insulin microneedles.Among them,insulin-loaded dissolving microneedles have received widespread attention due to its treatment effect similar to those of injection.By controlling the dissolution of the microneedle matrix material or loading responsive small molecules,rapid or slow release of insulin can be achieved.However,the insulin-loaded dissolving microneedles are still in the experimental research stage and has not been used in clinical practice.There is still a lack of systematic research on the drug stability of insulin-loaded microneedles during storage,application and the biological safety during long-term use.This subject is mainly based on insulin-loaded polyvinyl alcohol(PVA)and hyaluronic acid(HA)microneedles,two commonly used materials in the fabrication of insulin-loaded microneedles,as the research object.Several studies have been explored from the perspectives of storage conditions,biosafety and application,hoping to provide preclinical support for the clinical transformation of insulin-loaded dissoving microneedles.(1)Long-term storage stability of insulin-loaded dissolving microneedlesBased on micromolding method,we prepared four kinds of insulin-loaded dissolving microneedles including insulin-loaded PVA microneedles,insulinloaded sucrose containing PVA microneedles and HA insulin microneedles with molecular weight of 8 k Da and 160 k Da.The drug stability after storage at 4°C,25°C,40°C and 60°C for different periods of time was explored.The results showed that the insulin-loaded on the microneedle had better heat resistance than the insulin solution and significantly delayed the degeneration of insulin,especially at high temperature.For example,insulin-loaded PVA microneedles can be stably stored for 2 months at 40℃ and 1 month at 60℃,respectively.Insulin-loaded HA microneedles with molecular weight of 160 k Da can be stably stored for 3 months at 40℃ and 1 month at 60℃.Additionally,combined of molecular dynamics simulation,it was found that insulin always preferentially binds with water and then diffuses to the matrix material,which not only avoids the change of insulin structure caused by the matrix material,but also enables most insulin to be protected in the matrix material after drying of microneedle.Finally,the storage conditions of different insulin-loaded dissolving microneedles under different conditions were analyzed,and corresponding suggestions were given.(2)Biosafety evaluation of soluble microneedles for long-term useInsulin free PVA microneedles and HA microneedles with molecular weight of 160 k Da were prepared based on micromolding method.The biological safety of long-term use of PVA microneedles and HA microneedles were investigated on the healthy Balb/C mice,respectively.PVA microneedle group was performed for more than 5 months of long-term continuous microneedle application,and the HA microneedle group was conducted for three months.During the experiment,the effects of long-term use of PVA microneedles and HA microneedles on local skin and systemic health in mice were investigated from the surface level to the cellular level.The results showed that neither PVA microneedle nor HA microneedle caused skin infection in mice,nor caused systemic inflammation or toxicity in mice during the experimental period,indicating that PVA and HA have good biosafety in the experimental period.(3)Hypoglycemic behavior of insulin-loaded dissolving microneedlesThe hypoglycemic behavior of insulin-loaded PVA microneedles in type 1diabetic rats was investigated using rapid-acting insulin aspart and ultra-longacting insulin degludec as drug models under different dietary patterns.The effects of administration time,feeding time,amount of food intake and dietary pattern on the hypoglycemic behavior of insulin-loaded PVA microneedles were considered,and the potential of PVA microneedles in the application of fastacting insulin and ultra-long-acting insulin were investigated.The results showed that insulin type did not affect the subcutaneous dissolution behavior of PVA microneedles,and PVA material did not significantly interfere with the onset time and action time of insulin.But,it was noting that the time difference between dosing time and eating time can significantly affect the glycemic effect of soluble microneedles.Similar to insulin injection,insulin aspart loaded PVA microneedle is suitable for mealtime administration and can reduce blood glucose to the lowest value 1-2 h after administration,lasting about 3-4 h.The continuous blood glucose control ability of insulin degludec-loaded PVA microneedle was consistent with that of injection,and sustained blood glucose control in rats for up to 48 h.(4)Preparation and application of dissolving microneedle rollersA kind of dissolving microneedle rollers was designed to solve the limitation of insulin delivery on curved skin with large microneedle patches.The experiment successfully prepared the dissolving microneedle rollers by optimizing the demolding time and the height of the microneedle.STZ-induced type 1 diabetic rats were used to investigate the effect of transdermal administration of insulin-loaded dissolving microneedle rollers.The results showed that in the rolling process of dissolving microneedle roller,the drugloaded tips of microneedles arranged on the rollers could be successfully implanted under the skin to achieve the purpose of lowering blood glucose. |
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