TRANSDERMAL DELIVERY OF IRON

描述（由申请人提供）：缺铁是世界各地人们最普遍和最严重的健康问题之一。口服或胃肠外铁补充剂的施用是为了恢复体内的铁储存。铁从胃肠道的生物利用度是不可预测的，并且由于其侵入性，胃肠外途径不允许频繁给药。经皮途径是一种非侵入性和患者依从性的药物递送途径，其提供了几个优点，包括精确的剂量递送和减少的副作用。然而，口服给药的铁盐不能通过透皮途径给药，因为已知它们释放游离铁，这反过来导致氧化应激增加。由于其巨大的胶体尺寸，不能施用肠胃外铁形式。焦磷酸铁（FPP）是唯一的低分子量铁盐，已被证明是安全的胃肠外给药，由于其高稳定常数。然而，由于其亲水性，它在皮肤上的渗透性很差。我们假设，治疗所需量的铁可以通过透皮途径使用适当的皮肤渗透增强技术。我们提出了三个具体目标来评估我们的假设。在目的1中，我们建议研究所选的化学渗透促进剂对FPP经皮给药的影响。我们建议研究所选促进剂的浓度及其组合对FPP经皮给药的影响。这一具体目标的成功完成将有助于我们确定最有效的渗透促进剂，可以纳入透皮铁治疗系统。初步研究表明FPP离子导入经皮给药的可行性。我们坚信，适当的化学渗透增强剂与离子电渗疗法的组合将导致在相对较小的电流密度（约0.3 mA/cm 2，而不是初步研究中使用的0.5 mA/cm 2）下经皮递送治疗所需量的铁。目的二：研究化学促渗剂对FPP离子导入经皮给药的影响。在目的3中，我们建议在妊娠和非妊娠贫血大鼠模型中评估经皮铁递送系统。还将通过测量大鼠血浆中的脂质过氧化物来评估FPP的毒性。上述具体目标的成功完成将导致第一个透皮铁输送系统的开发，该系统可能更容易被所有年龄组的患者接受。

DESCRIPTION (provided by applicant): Iron deficiency is one of the most prevalent and serious health issues among people all over the world. The oral or parenteral iron supplements are administered to restore the iron stores in the body. Bioavailability of iron from the gastrointestinal tract is unpredictable and parenteral route do not allow frequent administration due to its invasiveness. Transdermal route is a noninvasive and patient compliant route of drug delivery that offers several advantages including precise dose delivery and reduced side effects. However, orally administered iron salts cannot be administered via transdermal route as they are known to release of free iron which in turn leads to increased oxidative stress. Parenteral iron forms cannot be administered due to their huge colloidal size. Ferric pyrophosphate (FPP) is the only low molecular weight iron salt that has been demonstrated to be safe for parenteral administration due to its high stability constant. However, due its hydrophilic nature it is poorly permeable across the skin. We hypothesize that therapeutically required amounts of iron could be delivered via transdermal route using appropriate skin permeation enhancement techniques. Three specific aims have been proposed to assess our hypothesis. In Aim 1 we propose to study the effect of selected chemical permeation enhancers on the transdermal delivery of FPP. We propose to study the effect of concentration of the selected enhancers and their combinations on the transdermal delivery of FPP. The successful completion of this specific aim will help us to identify the most effective penetration enhancers that could be incorporated in the transdermal iron therapeutic system. The preliminary studies demonstrated the feasibility of iontophoretic transdermal delivery of FPP. We strongly believe that the combination of appropriate chemical permeation enhancer with iontophoresis will result in transdermal delivery of therapeutically required amounts of iron at a relatively less current density (~0.3 mA/cm2 as opposed to 0.5mA/cm2 used in the preliminary studies). In Aim 2, we propose to investigate the effect of chemical permeation enhancers on the iontophoretic transdermal delivery of FPP. In Aim 3, we propose to evaluate the transdermal iron delivery systems in pregnant and non-pregnant anemic rat models. The toxicity of FPP will also be assessed by measuring the lipid peroxides in rat plasma. The successful completion of the above specific aims will result in the development of the first transdermal iron delivery systems which are likely to be more acceptable by patients of all age groups.