TRANSDERMAL DELIVERY OF IRON

描述（申请人提供）：缺铁是世界上最普遍和最严重的健康问题之一。口服或肠外补铁是为了恢复体内的铁储备。铁从胃肠道的生物利用度是不可预测的，由于其侵入性，肠外途径不允许频繁给药。透皮给药途径是一种无创和患者依从性的给药途径，具有精确给药和减少副作用等优点。然而，口服铁盐不能通过透皮途径给药，因为已知它们会释放游离铁，从而导致氧化应激增加。肠外铁由于其巨大的胶体大小而不能给药。焦磷酸铁（FPP）是唯一的低分子量铁盐，已被证明是安全的肠外给药，由于其高稳定常数。然而，由于它的亲水性，它在皮肤上的渗透性很差。我们假设治疗所需的铁可以通过适当的皮肤渗透增强技术通过透皮途径输送。我们提出了三个具体目标来评估我们的假设。在目的1中，我们建议研究选定的化学渗透促进剂对FPP透皮给药的影响。我们建议研究所选增强剂的浓度及其组合对FPP透皮给药的影响。这一特定目标的成功完成将有助于我们确定可纳入透皮铁治疗系统的最有效的渗透促进剂。初步研究证实了离子透皮给药FPP的可行性。我们坚信，适当的化学渗透增强剂与离子透入的结合将导致以相对较低的电流密度（~0.3 mA/cm2，而不是初步研究中使用的0.5mA/cm2）经皮输送治疗所需的铁量。在目的2中，我们建议研究化学渗透促进剂对FPP离子透皮递送的影响。在Aim 3中，我们建议评估妊娠和非妊娠贫血大鼠模型的透皮铁输送系统。通过测定大鼠血浆中脂质过氧化物来评价FPP的毒性。上述具体目标的成功完成将导致第一个经皮铁输送系统的发展，这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.