| Diabetes is characterized by chronic hyperglycemia due to metabolism disorders, and has become "the third killer" to human health after cardiovascular disease and cancer hazard. At present, drugs for treatment of diabetes mainly include insulin or other antidiabetic drugs, among which insulin is the widely used. Due to its instability in the presence of gastric acid and digestive enzymes, insulin is commonly given by injection. However, numerous daily injections often lead to pain, bleeding, poor compliance, and some other adverse effects. Therefore, developing a new non-injective route, such as nasal, buccal, pulmonary, rectal and transdermal route for insulin delivery has attracted the interest of researchers. Currently, transdermal delivery of insulin has generated a great deal of interest because it may avoid first-pass liver effect, offer patient compliance and controlled drug release.Since skin represents a natural barrier against exogenous physical, chemical and biological agents, amount and velocity of transdermal delivery of most drugs, especially large molecule drugs are low or limited. However, skin permeability can be increased by chemical enhancers, electric enhancers via iontophoresis, electroporation, electret, etc. The previous studies of our research group indicated that electret can effectively enhance the transdermal delivery of methyl salicylate, lidocaine, meloxicam, cyclosporine A. Therefore, in this research, we used electret as enhancer to study its effect on transdermal delivery of insulin, compared its enhancing effect with chemical enhancer, and studied the synergistic effect of combination use of electret and chemical enhancer. We also studied the enhancing mechanism of electret on insulin transdermal delivery. The research is divided into five sections.1. Polarization effect of electret on insulinThe constant corona charging system was used to prepare the electrets with different polarity and surface potential at ambient temperature. The insulin solution and patch were acted by the electrets, and the variation of potential difference on both sides of the solution and patch with time, as well as variation of d33 coefficient of the solution and patch with time were determined to study the polarization effect of electret on insulin. The results indicated that (1) positive or negative electret could provide stable electrostatic field on both side of the solution and patch. (2) The electrostatic field of electret could induce the polarization of insulin molecule and a saturated polarization state of the insulin molecule was observed after 12 hour action of electret (d33 coefficient tended to constant value). (3) The higher the surface potential of the electret, the larger the extent of polarization of insulin molecule.To further study the influence of electret in insulin molecule structure, we used techniques of H-NMR spectroscopy, FTIR spectroscopy and gel electrophoresis. The results showed that electret had no obvious effect on space structure of insulin, but caused some microstructure changes which could be explained by the polarization of insulin.2. Effect of electret, chemical enhancer and combination use of both on in vitro insulin transdermal deliveryThe transderma behavior of insulin was studied using improved Franz diffusion cell after application of ±500V,±1000V,±1500V electret,3% azone,7.5% propylene glycol, and ±1500V electret plus 3% azone. The drug remaining in stratum corneun (SC) and SC-striped skin were also determined after transdermal permeation experiment. The results showed that (1) although both chemical enhancers could effectively enhance the insulin transdermal delivery,3% azone had better enhancing effect and more drug content in SC and SC-striped skin than those of 7.5% propylene was observed. (2) Negative electret presented better enhancing effect on insulin transdermal delivery. The higher the absolute surface potential of the electret, the better was the transdermal enhancing effect. Although electret had no obvious effect on insulin amount in SC, the remaining amount of insulin in SC-striped skin was obviously increased. (3) The combination use of -1500V electret and 3% azone could effectively increase the transdermal delivery of insulin. The cumulative penetration amount of insulin at 36h for combination use of -1500V electret and 3% azone was 1.4 times,2.12 time and 2.93 times as those of the 3% azone,+1500V electret +3% azone and control group, respectively. Therefore,-1500V electret in combination with 3% azone had synergistic enhancing effect on insulin transdermal delivery.3. Effect of electret on in vitro transdermal delivery of insulin via diabetic rat skinIn this study, we developed the diabetic rat model after streptozotocin (STZ) injection as reported. The transdermal behaviors of negative electret treated and non-treated insulin through diabetic rat skin were investigated. The results indicated that the cumulative penetration amount of insulin at 36 hour for non-electret treated insulin solution, as well as -500V,-1000V and -1500V electret treated insulin solution through the diabetic rat skin was 3.2 times,3.54 times,3.86 times and 4.00 times respectively as those of through the normal rat skin. The higher the absolute surface potential of the electret, the more was increased penetration amount of insulin through diabetic rat skin.4. Effect of electret on microstructure of normal and diabetic rat skinTo understand the enhancing effect of electret on transdermal delivery of insulin through normal and diabetic rat skin, we employed the immunofluorescence and light microscope techniques to study the microstructure of normal and diabetic rat skin after action of electret. The results showed that (1) SC of normal rat skin was thinned, the cell gap increased, and hair follicles enlarged. (2) The SC and dermis of diabetic rat skin was slightly thickened. Electret exhibited repairing effect on diabetic rat skin. (3) The transdermal route of insulin after action of electret mainly was via hair follicles.5. Effect of electret on insulin to control blood sugarThe electret treated and non-electret treated insulin showed almost the same blood sugar controlling effect.+1000V and -1000V electret showed somewhat better effect on insulin to control blood sugar.The electret insulin transdermal delivery system studied in this paper was of good stability and biological safety, ease to use, and no need to use an external power supply and so on. It may be a new preparation for treatment of diabetes. |
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