Percutaneous Enhancement Of Microneedle Arrays For Different Physico-chemical Property Drugs

On the basis of rapid development of Microelectronic Mechanical System and percutaneous enhancement technology, a new technology—Microneedle has been applied in Transdermal Drug Delivery System. Microneedle array has many advantages, including minimal trauma at penetration site because of the small size of the needle, high intensity, precise control of penetration depth, and painless drug delivery. It promotes the cutaneous drug delivery by creating hundreds of microbores in stratum corneum. It has brought great vigor into transdermal drug delivery and it is very meaningful to make futher research, especially in those macromolecules such as polypeptide, protein, vaccine, etc..This paper fabricated the microneedle arrays into different shape with different material,and made research on in vitro transdermal permeation of chemicals and macromolecules. Different experimental influential factors were studied and optimized to gain the optimal transdermal delivery effect. The increasement effect of microneedle arrays were studied for cutaneous hepatitis B DNA vaccine delivery in vitro and in vivo.This paper is devided into four parts as follows:Chapter one: fabrication and evaluation of microneedle arraysTwo kinds of microneedle arrays were fabricated with different material:monocrystal silicon and biodegradable polymer, respectively.silicon microneedles was produced through Deep reactive ion eching (DRIE) technique,which are used largely in this area. For microfabricated polymer microneedle arrays, SU-8 was employed as material, which carryied out bevel tips. This method is comparatively simple, low cost and microneedles are disposable. A needling unit of microneedle arrays for certain pressure and time control was designed and fabricated by ourselves. Different microneedles were evalued with shearing force, and results indicated that microneedle arrays and needling device in this study were qualified for piercing into skin without fracture and residual.Chapter two: enhancement of microneedle arrays on in vitro transdermal drug delivery of chemicals.Four model drugs, indomethacin(IMC), ketoprofen(KTP), methocarbamol(MCM) and ganciclovir(GCV) were chosen and cutaneous deliveried by silicon microneedle arrays,The total flux of the drugs increased to 4.05, 4.77, 6.06, 12.49 times respectively by microneedles insertion for 5 minutes as compared with intact skin.The long microneedles insert, the more increased skin permeability appeared. With the decrease of logP values of drugs, microneedles promoted transdermal delivery more effectively.Chapter three: effect of microneedle arrays on in vitro transdermal drug delivery of macromolecules.Four macromolecules: insulin, lysozyme, ovalbumin and human serum albumen were chosen as model drugs to investigate the microneedle's increasement effect on macromolecules in vitro. The test carried out significant enhancement on the permeability. Influential factors were optimized to get better effect of transdermal drug delivery with orthogonal design method. In optimal condition, the total flux of the four macromolecules had an inverse relationship with molecular weight.Chapter four: immunization effect of hepatitis B DNA vaccine by cutaneous delivery with microneedle arrays.The increasement effect of microneedle arrays were first studied for cutaneous plasmid pVAX1 delivery in vitro. In order to enhance the immune efficacy of DNA vaccination, Flt3L,as an adjuvant was used together. Immunization effects of several immune strategies in C57BL/6 mice were assessed. The level of total antibody was analyzed by ELISA. The vitality of individual mouse in each group was monitored postimmunization. The results showed that microneedle arrays could successfully promote the transdermal transport of plasmid pVAX1. The total permeate flux came up to 25.26% of the whole administration quantity. DNA vaccine with adjuvant Flt3L inoculated by microneedles induced significant stronger humoral and cellular immune responses than other immune strategies. After different immunization, C57BL/6 mice were transplanted CT/26 cells. The vitality of microneedle groups was 40%, twice that of intramuscular injection groups.Our study may provide a strategy for developing an improved immunization against HBV and many other pathogens.