Dissolving Microneedles Loaded With Atorvastatin Calcuim Micelles In Hyperlipidemic Disease

Hyperlipidemia is characterized primarily by abnormal blood lipids and is a major risk factor for the development of coronary heart disease,atherosclerosis,and other diseases.Atorvastatin calcium(AC)is currently one of the most commonly used drugs in clinical therapy for hyperlipidemia and has a remarkable lipid-lowering effect.However,AC is poorly soluble in water,and oral administration has issues with hepatic first-pass effect,poor drug absorption,and low bioavailability,making it difficult to achieve expected therapeutic effects.Although the micelle drug carrier presentation can increase the water solubility of AC,the micelle drug carrier is still administered orally.As a result,it is critical to develop a novel delivery strategy in order to achieve effective hyperlipidemia therapy.A new non-invasive,high-efficiency drug delivery technology based on microneedle transdermal delivery has recently gained widespread attention.Microneedle(MN)is a needle array with micron-sized needles that can effectively penetrate the stratum corneum to form micron-sized pores and deliver drugs to the epidermis or superficial dermis,where they are absorbed by subcutaneous capillaries into the body circulation and reach the lesion site.The advantages of microneedle drug delivery include minimal invasiveness,painlessness,convenience,and high drug utilization.This research aims to prepare AC micelles with m PEG-PLA and m PEGPLA-PEG block copolymers to improve the solubility and stability of AC,as well as the bioavailability and therapeutic efficacy of AC combined with microneedle delivery.The following are the main research contents of this study:(1)The drug loading capacity of AC micelles prepared from m PEGPLA and m PEG-PLA-PEG block copolymers with varying molecular weights was investigated using various preparation formulations,and the AC micelles with the highest drug loading capacity(AC encapsulated by m PEG2k-PLA2 k and AC encapsulated by m PEG5k-PLA5k-PEG5k)were chosen for microneedle delivery.Furthermore,to provide theoretical support for the selection of AC micelles,dissipative particle dynamics simulations were used to investigate the structural stability of AC micelles prepared from m PEG-PLA and m PEG-PLA-PEG block copolymers.(2)MN 1(AC encapsulated by m PEG2k-PLA2k)and MN 2(AC encapsulated by m PEG5k-PLA5k-PEG5k)dissolving microneedles loaded with AC micelles were prepared using the micro-mode filling method.As seen under the optical microscope,the tips of the microneedles were intact and the drug was uniformly distributed;mechanical properties characterization and animal skin model experiment demonstrated that the prepared microneedles had good mechanical properties and met the requirements for penetration;needle holes healing process,skin tissue section,cytotoxicity test,and hemolysis test demonstrated that the prepared microneedles had good biosafety.(3)To evaluate the ability of dissolving microneedles loaded with AC micelles to regulate lipids in the blood,a hyperlipidemic rat model was created.Microneedle delivery of AC micelles can considerably reduce TG,TC,and LDL-C while increasing HDL-C in hyperlipidemic rats.The effect of microneedle therapy is far superior to that of oral therapy.