(T1330-03-18) Development of a Pulsed Current Iontophoresis System for Transdermal Administration of Palonosetron Hydrochloride: Exploring the Potential for a Shift Toward At-Home Medical Care

Purpose: In the United States, rising healthcare costs and disparities in medical access have accelerated a shift toward home-based care, aiming to reduce medical expenses and improve patients' quality of life (QOL). Iontophoresis (IP) is a technique that delivers drugs transdermal using a weak electric current, enabling rapid onset of drug effects without the need for injections. If IP formulations can be developed to replace injectable drugs, it would allow for drug administration at home, reducing the physical and financial burden of hospital visits and potentially enhancing the QOL of patients undergoing treatments such as cancer chemotherapy. This study investigates the potential of developing a transdermal formulation of palonosetron hydrochloride (palonosetron HCl), a hydrophilic small-molecule serotonin receptor antagonist currently administered via intravenous (I.V.) injection for the treatment of chemotherapy-induced nausea and vomiting (CINV), using constant current IP and pulsed current IP.

Methods: To develop a transdermal formulation of palonosetron HCl using IP, we first estimated the target flux values for skin permeation based on publicly available pharmacokinetic data (Kel = 0.018, Vd = 695 L, Dose = 0.75 mg, Tmax = 0.44 hr) of palonosetron HCl. These values were calculated using the deconvolution method. In this process, a human-to-rat animal scaling factor of 5 was applied to derive the corresponding target values for the rat model. The target flux was calculated assuming an application area of 10 cm² and an application time (i.e., current-on time) of 6 hours. Subsequently, in vitro skin permeation studies were conducted using Franz diffusion cells with both rat skin and human cadaver skin. When IP was performed, Ag-Ag/AgCl electrodes were used under a current density of 0.3 mA/cm². For pulsed current conditions, a rectangular waveform at 10 Hz with a 50/50 duty cycle was applied. The palonosetron HCl solution (1.0 wt%) was prepared in saline. At predetermined time points, receptor fluid samples were collected and analyzed for drug concentration using HPLC-UV. The flux values obtained from the human cadaver skin permeation tests were then used to estimate plasma drug concentrations in humans via the convolution method. Additionally, in vivo IP experiments were performed in rats to compare the skin irritation potential between constant current and pulsed current stimulation.

Results: Based on the deconvolution method and human pharmacokinetic parameters of palonosetron HCl, the target cumulative drug permeation amount in the in vitro skin permeation test was simulated to be approximately 800 µg. This corresponds to a flux of 13.3 µg/cm²/h for human cadaver skin and then by applying a five-fold animal scaling factor, the target drug permeation through rat skin was estimated at 66.5 µg/cm²/h. In the in vitro rat skin permeation tests, the IP system successfully achieved the target flux within 3 hours of initiation. Although the pulsed current IP showed slightly lower permeability compared to the constant current IP, the difference was minimal (Figure 1). Following these permeation studies, in vivo skin irritation tests were conducted in rats, revealing that pulsed current IP caused significantly less irritation (P.I.I. = 0.7) than constant current IP (P.I.I. = 2.0) (Figure 2). Based on these findings, the human cadaver skin permeation tests were performed using pulsed current IP only. In these tests, the target flux was reached within 2 hours of IP initiation (Figure 3). The estimated plasma concentration in humans, calculated using the convolution method, indicated that the drug could reach levels comparable to the maximum concentration achieved by I.V. administration within approximately 3 hours. Furthermore, when assuming the power was turned off after 3 hours and the drug followed the same elimination kinetics as the I.V. injection, The calculated area under the curve (AUC) up to 24 hours was 24.8 ng*h/mL, which was closely comparable to the AUC observed following intravenous administration in humans (25.4 ng*h/mL). (Figure 3).

Conclusion: The results of this study demonstrate that pulsed current IP successfully achieved high transdermal delivery efficiency of palonosetron HCl in excised human skin, with pharmacokinetic profiles estimated via convolution analysis that closely matched those of I.V. administration. Additionally, pulsed current IP significantly reduced skin irritation compared to constant current stimulation, indicating its safety and tolerability. Given that palonosetron HCl is a key therapeutic agent for the prevention and treatment of CINV, the ability to deliver it effectively through the skin suggests that pulsed current IP could serve as a valuable alternative to I.V. administration in oncology settings. This approach holds particular promise for enabling safe and effective at-home drug administration, reducing the burden of hospital visits and potentially improving the QOL for patients undergoing frequent parenteral therapies such as cancer chemotherapy.

Acknowledgements: This study was conducted in collaboration with Tokyo University of Science. We are deeply grateful for their significant contributions, particularly to the rat skin irritation studies included in this work. We would like to extend our sincere appreciation to Professor Saito for his expert guidance and oversight throughout the collaborative research. We also wish to acknowledge Mr. Sakurai, Mr. Okada and Mrs. Takenaka for their dedicated efforts and valuable assistance in the experimental work, which were instrumental to the successful completion of this study.

Figure 1: in vitro rat skin permeation study results (n=3); Flux profile of palonosetron HCl

Figure 2: Rat skin irritation study results; (upper) constant current and (lower) pulsed current

Figure 3: (a) in vitro human cadaver skin permeation study results from 3 different skin donors; Flux profile of palonosetron HCl. (b) Human blood concentration calculated value (area 10cm²) and human I.V. data, (c) Simulated plasma concentration profile based on the assumption that iontophoresis was terminated at 3 hours, with subsequent drug elimination following the same kinetics as the approved I.V. injection product.