One global health problem that needs attention is ß-thalassemia major (ß-TM). ß-TM is a genetic disorder that occurs due to protein mutations that can trigger excessive red blood cell counts, resulting in severe anemia with various serious complications such as osteoporosis, hepatitis, neurological disorders, metabolic syndrome, and heart failure until death [1], [2]. In 2020, the World Health Organization (WHO) reported that more than 54 million people from the total world population suffer from ß-TM, which increased to 156.76 million in 2021, causing 50–100 thousand children to die each year [3]. Currently, blood transfusion is the first-line treatment for β-TM patients.

Poor erythropoiesis in β-TM patients can be suppressed because a new supply of red blood cells can be obtained through blood transfusion. However, transfused blood contains iron, most of which cannot be excreted by the body. This leads to iron buildup, a catalyst for forming oxygen species (ROS) that can accumulate in the heart and liver, vital organs. The accumulation of large amounts of ROS can lead to complications and even death [4]. Iron chelators (ICs), one of which is deferiprone (DFP), result in the formation of ROS needed to prevent iron accumulation. The use of DFP was superior because clinical reports have shown that patients who receive DFP orally have high compliance and an efficacy profile of 79–98 % compared to with those who receive parenteral deferoxamine (DFX) at 59–78 %. In addition, the use of deferasirox (DFO) is often associated with adverse effects such as renal abnormalities [5]. The use of DFP also has no restrictions, and DFP can be widely used [6], [7]. Unfortunately, commercially, DFP is only administered orally in tablet and capsule dosage forms. Oral delivery itself has several disadvantages: the drug undergoes first-pass metabolism, which results in decreased bioavailability, a short half-life (2–3 h) causing short systemic exposure resulting in frequent dosing, and side effects related to gastrointestinal problems, agranulocytosis, and neutropenia [6], [8]. Therefore, further development is needed for more effective DFP administration, which can improve the standard of living in patients with ß-TM.

To the best of our knowledge, DFP development has been minimal. Huang et al. (2019) and Rashed et al. (2020) developed DFP in the form of micelles and nanocarriers that can overcome the half-life problem and increase the bioavailability of DFP [8], [9]. However, its oral administration has not been able to regulate the controlled release of DFP, avoid the impact of metabolism in the liver, or cause gastrointestinal side effects [10]. One alternative route of administration to overcome these problems is delivery via the transdermal route [11]. Previously, IC delivery via transdermal patches was developed to overcome gastrointestinal effects [12]. Although the system is promising for more effective DFP delivery, the use of patches has limitations due to the low percentage of DFP permeated into the systemic circulation, which is only approximately 14 %–45 %, and the uncontrolled release of DFP [13]. It allows the release of large amounts of DFP under normal iron levels, resulting in iron deficiency and other side effects. In a clinical trial conducted by Kolnagou et al. (2017), they administered deferiprone to 8 patients with normal iron stores. Four patients had to be discontinued due to iron deficiency [14]. For this reason, a feature that can regulate iron chelation levels is needed to avoid iron deficiency and other side effects. One of the organometallic compounds known to provide iron-responsive (IR) properties that utilize ROS is ferrocene (Fc) [15], [16], [17]. Liu et al. (2016) introduced Fc and IR in IC [18]. Researchers have widely studied Fcs as a polymers in drug development. Fc is an organometallic material that is neutral, nontoxic, good redox activity, and owing to its unique electron abundance, it has the potential to scavenge free radicals [19]. However, the problem is that Fc is limited in physiological stability and has poor degradation issues in the body [16]. Therefore, Fc can be copolymerized with polyethylene glycol-poly(ε-caprolactone) (PEG-PCL-Fc), which has a stealth effect due to its biocompatibility, biodegradability, flexibility and increased responsiveness [16], [20], [21]. This copolymerization would provide controlled iron responsiveness (IR) by releasing DFP under high-iron conditions characterized by reactive oxygen species (ROS), thus preventing iron deficiency and other side effects.

Therefore, this research developed an IR system of DFP in nanoparticle form (NP-IR-DFP). The NP-IR-DFP form was chosen because it can control the release of DFP and increase its retention and half-life, which results in improved bioavailability. To maximize the delivery of NP-IR-DFP, dissolving microneedles (DMNs) was chosen because they can overcome the shortcomings of previously developed transdermal patches by increasing drug permeation into blood vessels, which is approximately 80 % [22]. DMNs can penetrate the stratum corneum (SC), the main barrier to the entry of drug molecules into blood vessels. DMN systems contain biodegradable polymers, which can dissolve with skin interstitial fluid and release the encapsulated drug, and the application leaves no residue on the skin area [23], [24]. Therefore, this research is the first to focus on developing a DFP formula in the form of IR nanoparticles delivered through DMNs (NP-IR-DMNs). The development of this system is expected to increase the effectiveness of DFP as an iron overload therapy and preventive measure against iron deficiency in patients with β-TM while supporting the achievement of a healthy and prosperous life based on the third goal of the Sustainable Development Goals (SDGs).