Percutaneous Permeability And Stability Of Formoterol And Its Fumarate Patches

Formoterol(FMT),aβ2 receptor agonist with long-lasting and powerful bronchodilating action,is used to relieve and treat bronchial asthma.Currently,there are tablets and powder inhalers for patients,dosing twice a day.At present,the low rate of asthma control is mainly due to the poor compliance,including the inconvenience of taking the medicine and the misuse of the inhalation device.Therefore,it is important and meaningful to develop a user-friendly,dosage-controllable and treatment-sustainable pharmaceutics for patients’self-managing.The transdermal drug delivery system has the above advantages and can improve the compliance of patients with long-term medication.The purpose of this paper is to investigate the transdermal permeability of formoterol and formoterol fumarate(FFMT),to select appropriate model drugs for the preparation of transdermal patches,and to investe the stability of the patches.First,we investigated the effects of pH and different skin on transdermal permeability of FMT and FFMT and transdermal permeation kinetics by in vitro percutaneous permeation test.The results showed that the permeation of FFMT in rat skin decreased as pH increasing,but there was no significant difference in nude mouse skin;permeation behavior of FMT did not change significantly in both skin models and different pH systerm.The permeation of FFMT and FMT in rats are both higher than that in nude mice.This increase may be due to the presence of hair follicles.What’s more,the penetration of the two drugs in the epidermis was similar,while the degrees of obstruction by the stratum corneum is different.However,they both mainly obstructed by the barrier from the stratum corneum.In summary,nude mouse skin was selected as an in vitro study skin model.Secondly,we selected several kinds of penetration enhancers such as azone(Az),oleic acid(OA),long-chain alcohol and isopropyl myristate(IPM)and investigated their effects by in vitro permeation experiments of nude mice.Then,we examined the permeability of the optimal patch by in vitro human skin permeation test.The results showed that for FFMT patches,the penetration enhancement effect was 15%IPM>10%IPM>no penetration enhancer≈5%IPM≈3%Az>carbitol>OA;which for FFMT patches was 15%IPM>10%IPM>5%Az>no penetration enhancer≈10%dodecanol>10%carbitol.The FMT patch containing 15%IPM had a cumulative permeation of 5.20±0.96?g/cm~2 in isolated human skin for 24 h,which is nearly8 times as the FFMT patch containing 15%IPM(0.70±0.16?g/cm~2),so FMT is selected as a model drug for this study.Then,the time-lag test,it was calculated that the maximum content of FMT in the drug-loaded matrix was 26%and it was evaluated the cumulative permeation and drug utilization rate by the skin permeation test of nude mice.Using the cumulative transmission and drug utilization rate as evaluation indicators and through the in vitro permeation test of nude mouse skin and in combination with the physical appearance of the patch,a patch of FMT 5%and IPM15%was selected as the final formulation for this study.Finally,we investigated the stability of FMT patch including the related substance content,content determination and crystallization by influence factors experiment and accelerated test.The results showed that FMT patch had poor stability at high temperature and affected patch extraction and the release of the patch,while there’s a good stability in high humidity and highlight.Suggesting that the storage conditions of the patch should be in a cool place.