(T1230-07-42) Fabrication of PVA Microneedles Using Vacuum Compression Molding for Three-Day Transdermal Delivery of Palonosetron Hydrochloride

Purpose: Transdermal drug delivery via microneedles has emerged as a promising approach to bypass the stratum corneum barrier, while offering patient comfort over invasive routes. However, conventional microneedle (MN) fabrication methods such as micromolding are sometimes limited by prolonged drying times, solvent residues, and batch variability. To address these challenges, this study introduces vacuum compression molding (VCM)—a solvent-free, continuous manufacturing technique—to fabricate polyvinyl alcohol (PVA)-based microneedles. We have evaluated the influence of various PVA grades on microneedle mechanical integrity, drug loading efficiency, drug permeation, and sustained-release profiles. Palonosetron hydrochloride (PAL-HCl), a hydrophilic 5-HT₃ receptor antagonist (MW: 332.85 g/mol), was selected as a model drug, partly due to its low therapeutic dose and clinical relevance in managing chemotherapy-induced nausea and vomiting (CINV). Current oral and intravenous routes pose challenges for dysphagic or needle-averse patients, making transdermal delivery an attractive alternative. Using VCM, we developed PVA microneedles capable of loading PAL-HCl and delivering it over 72 hours, leveraging the polymer’s tunable degradation kinetics for sustained release. This work emphasizes the optimization of VCM parameters, microneedle characterization, and in vitro permeation studies to validate its potential as a patient-friendly, minimally invasive CINV therapy.

Methods: Ten PVA grades— PVA 4-88, Particle-engineered PVA 4-88, Particle-engineered PVA 3-82, PVA 5-88, PVA 8-88, PVA 18-88, PVA 26-88, PVA 40-88, Particle-engineered PVA 40-88, Particle-engineered PVA 5-88 (M1-M10 respectively), were screened for microneedle fabrication feasibility using VCM. Films of PAL-HCl-loaded PVA were prepared by mixing different PVA grades with PAL-HCl in deionized water. The drug-polymer blend was then cast into polydimethylsiloxane (PDMS) molds and preheated at 90°C for 1.5 hours to form a film. This film was transferred to a VCM setup and compressed under vacuum at 260°C for 15 minutes (Figure 1). After cooling, the resulting microneedles were characterized for mechanical uniformity, skin insertion ability via dye-binding studies, and drug content. Initial screening involved testing the ability of PAL-HCl-loaded microneedles to penetrate a three-layer parafilm model. Only grades achieving full penetration were selected for further testing. In vitro permeation studies compared PAL HCL loaded MNs, poke-and-solution formulations (1% w/v PAL-HCl in PBS using blank MNs), and passive controls (1% w/v PAL-HCl in PBS). Vertical Franz diffusion cells with dermatomed human skin (n=4) were used. Microneedles were inserted using gentle thumb pressure for 120 seconds and secured with surgical tape. Receptor samples were collected over 72 hours and analyzed using a validated HPLC method (LOD: 0.1 µg/mL). Concurrently, in-vitro release kinetics were assessed using cellulose dialysis membranes (14 kDa MWCO) to differentiate diffusion-controlled from polymer degradation-driven release mechanisms. Statistical analysis (one-way ANOVA; p< 0.05) was performed to compare cumulative permeation, and flux across formulations.

Results: Among the fabricated microneedles, M1, M2, M4, M5, and M10 (Figure 2) demonstrated successful insertion capabilities, as evidenced by their penetration into three layers of the Parafilm® skin simulant model upon manual application. This indicates that lower viscosity PVA grades can have the potential to effectively pierce the stratum corneum and deliver PAL-HCl transdermally. Histological evaluation and methylene blue staining further confirmed disruption of the stratum corneum and formation of microchannels in the skin upon MN application. However, M2 and M10 could not be inserted into human skin and were therefore excluded from further studies. SEM imaging validated the morphology of the microneedles, revealing well-defined, sharp pyramidal structures that are essential for effective skin penetration. IVPT studies using vertical Franz diffusion cells demonstrated an increase in PAL-HCl delivery across dermatomed human skin for M1, M4, and M5 formulations compared to passive controls. Among the tested formulations, M1 showed the highest cumulative permeation (Q₇₂), achieving 248.42 ± 50.85 µg/cm² over 72 hours, followed by M5 at 39.03 ± 20.2 µg/cm², and M4 at 36.97 ± 5.87 µg/cm². Passive controls showed significantly lower permeation than M1, confirming the enhanced transdermal delivery potential of the drug-loaded MNs. Additionally, M1 exhibited significantly higher delivery than both M4 and M5 (p < 0.05). In comparison, the poke and patch method using blank M1, M4, and M5 followed by PAL-HCl solution application resulted in rapid drug permeation, with values of 248.4 ± 12.6 µg/cm², 135.43 ± 21.45 µg/cm², and 136.21 ± 10.14 µg/cm², respectively, over 72 hours. In contrast, PAL-HCl-loaded microneedles demonstrated sustained drug release, suggesting their suitability for achieving therapeutic plasma levels over an extended period (Figure 3). IVRT studies using cellulose dialysis membranes revealed sustained release profiles of PAL-HCl from all MN batches, with complete drug release observed within 72 hours. This sustained release is attributed to optimized polymer-drug interactions.

Conclusion: The study successfully demonstrated the feasibility of VCM for fabricating drug-loaded microneedles with reproducible mechanical properties and enhanced transdermal delivery capabilities. Among the tested formulations, M1, M4, and M5 achieved sustained PAL-HCl delivery with effective skin permeation and complete drug release within 72 hours, highlighting their promise as a transdermal system for improved CINV management.

References: 1. Kshirsagar SM, Kipping T, Banga AK. Fabrication of Polymeric Microneedles using Novel Vacuum Compression Molding Technique for Transdermal Drug Delivery. Pharm Res. 2022 Dec 1;39(12):3301–15.
2. Kang D, Ge Q, Natabou MA, Xu W, Liu X, Xu B, et al. Bolus delivery of palonosetron through skin by tip-loaded dissolving microneedles with short-duration iontophoresis: A potential strategy to rapidly relieve emesis associated with chemotherapy. Int J Pharm. 2022 Nov 25;628.
3. Wang C, Ye Y, Hochu GM, Sadeghifar H, Gu Z. Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody. Nano Lett. 2016 Apr 13;16(4):2334–40.

Acknowledgements: This project was funded by Merck KGaA, Darmstadt, Germany, Frankfurter Str. 250, 64293 Darmstadt, Germany. MilliporeSigma is the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany. Product designations of Merck KGaA, Darmstadt, Germany, and third parties may appear in this material. Please refer to publicly available resources such as tmdn.org for details of the ownership of trademarks.


Figure 1. Schematic illustration of the methods used in this study


Figure 2. Formulation and characterization of the PAL HCl loaded PVA microneedles


Figure 3. Results from IVPT and IVRT studies (n = 4). (a.) Permeation profile of PAL HCl. (b.) Cumulative amount of PAL HCl delivered across the dermatomed human skin in 72 hours (c.) Release profile of PAL HCl from PVA microneedles (M1, M4 and M5). Statistical differences between the groups were determined using one-way ANOVA with Tukey's Multiple Comparisons test. ** indicates p<0.01; ns indicates no significant difference)