(W1230-01-05) Vacuum Compression Molding: A Novel Method to Fabricate Drug-Loaded Microneedles for Three-Day Transdermal Delivery of Palonosetron Hydrochloride

Purpose: Polymeric drug-loaded microneedles are extensively explored as a minimally invasive technique to deliver drugs through the transdermal route. However, traditional fabrication methods like micromolding have drawbacks such as prolonged drying time, organic solvent residues, and low reproducibility. Vacuum compression molding (VCM) is a technique for microneedle fabrication that can overcome these limitations by reducing drying time, eliminating solvent residues, improving reproducibility, and enabling continuous manufacturing with reduced unit operations. Our study is a novel attempt to explore the VCM technique to fabricate drug-loaded polymeric solid microneedles using various grades of polyvinyl alcohol (PVA). Palonosetron hydrochloride (PAL-HCL) is a second-generation serotonin receptor antagonist prescribed for the management of Chemotherapy-induced nausea and vomiting (CINV). However, conventional routes such as intravenous injection or oral tablets may be invasive or impractical for patients with dysphagia. PAL-HCL is a hydrophilic and potent, low-dose molecule, making it a model drug of choice for microneedle-mediated transdermal delivery. Thus, we explored the fabrication, characterization, and in vitro permeation of PAL-HCl-loaded microneedles using the VCM technique as a pain-free, continuous three-day delivery system.

Methods: In this study, various grades of polyvinyl alcohol (PVA) were explored for the feasibility of microneedle formation using VCM, as shown in Figure 1. Grades of PVA that formed microneedles capable of penetrating up to three layers in a parafilm test were further assessed for loading PAL-HCl. To ensure homogenous distribution of PAL-HCL in the microneedles and minimize the time required for melting and compression under high temperatures, films of PAL-HCL-PVA were formulated by mixing various percentages of different PVA grades and PAL-HCl in deionized water, followed by heating at 90°C for 45 minutes to form a homogeneous solution. This drug-polymer blend was then subjected to slide crystallization studies for three days to ensure no crystal formation. The homogenous drug-polymer blend was added to Poly Dimethyl Siloxane molds and heated at 90°C for 1.5 hours to form a film. This film was then transferred to a VCM setup, which was compressed under vacuum at 260°C for 15 minutes. After cooling, the resulting microneedles were characterized for mechanical uniformity, skin insertion ability via dye binding studies, and drug content. Parteck 4-88 PVA with 1% PAL HCl (M1) yielded the most optimized microneedles. PAL-HCl loaded microneedle (M1), and poke and solution (1% w/v PAL-HCl in PBS) using blank M1 were further tested for in vitro permeation in vertical Franz diffusion cells using a dermatomed human skin model (n=4). These formulations were compared to a passive control group (1% w/v PAL-HCl in PBS). Additionally, batch M1 was subjected to in vitro release studies using cellulose dialysis membranes (MWCO 14000 Da) (n=4). Receptor samples were collected at predetermined time points over 72 hours, and both skin and receptor samples were analyzed for PAL-HCl concentrations using a validated HPLC method. Statistical differences between groups were determined using a one-way ANOVA test (p < 0.05).

Results: Formulations M1-M10 were prepared, as shown in Figure 2. M1, M2, M3, and M10 exhibited good mechanical uniformity in the parafilm test and were thus chosen for further evaluation. PAL-HCl was loaded into the microneedles using VCM to form a film. Drug loadings ranging from 1% to 5% were tested for slide crystallization over three days, revealing no crystals in any blend up to 5% PAL-HCl concentration. However, drug loading above 1% did not yield sharp needles. Therefore, a final formulation with 1% drug loading in the film was selected across all grades, indicating the influence of film viscosity on microneedle formation. Notably, M1 (Parteck 4-88), with a drug content of 826.7 ± 0.05 μg per microneedle, demonstrated superior mechanical strength for ex vivo insertion into human skin compared to other PVA grades and thus was used for further studies. The release study of PAL-HCl-loaded M1 revealed that 91.8 ± 3.08% of PAL-HCl was released within the first 12 hours, reaching 100% release by 24 hours. IVPT results showed that passive delivery of PAL-HCl through PBS was observed to be low (29.10 ± 12.6 µg/sq.cm for 72 hours). However, the poke and solution group with blank M1 exhibited rapid permeation of PAL-HCl across human skin (248.4 ± 12.6 µg/sq.cm for 72 hours), while PAL-HCl-loaded microneedles (M1) demonstrated sustained release over three days, achieving a total delivery of 257.56 ± 29.73 µg/sq.cm at the end of 72 hours, reaching the therapeutic target delivery (Figure 3).

Conclusion: In this study, we aimed to develop a novel method for fabricating drug-loaded PVA microneedles using VCM. We screened various grades of PVA to fabricate PAL-HCl-loaded microneedles and successfully fabricated microneedles with the desired skin penetration ability, mechanical uniformity, and appropriate drug loading. The M1microneedle delivered PAL-HCl continuously for three days and achieved the therapeutic target delivery, demonstrating the potential ability to relieve emesis in cancer patients.

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 the 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 MilliporeSigma a Business of Merck KGaA, Frankfurter Strasse 250, 64293, Darmstadt, Germany.


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


Figure 2. Formulation and characterization of the PAL HCl loaded PVA microneedles (a.) Screening of various grades of PVA for formation of microneedles using VCM technique (b.) Formulation of PAL HCl loaded microneedles using VCM (c.) Dye-binding study to test the skin insertion ability of the 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 microneedle (M1). 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)