(M1530-07-41) Preparation and Characterization of Hydrogel Microneedles Using Gantrez®S-97 and Hyaluronic Acid

Purpose: Microneedles have gained significant attention in recent years as an innovative technology to enhance transdermal drug delivery. These micron-sized needles penetrate the skin without reaching the dermis, causing minimal pain and offering a more user-friendly alternative to hypodermic needles. Hydrogel microneedles, in particular, have gained attention due to their distinct advantages, including long-term delivery, biocompatibility, and the absence of residue within the skin after application. They create a pathway through the skin, allowing the drug to be released from microneedles and their biocompatible polymers enable them to remain on the skin for extended periods without causing discomfort to the patient. This study aims to optimize hydrogel microneedle formulations with drug reservoirs to enhance their efficiency in transdermal drug delivery. We fabricated hydrogel swelling microneedles using a micro-molding technique with varying concentrations of Gantrez® S-97 and hyaluronic acid to deliver metoclopramide HCl. Gantrez® S-97 is highly biocompatible, soluble in aqueous medium, and can crosslink with hyaluronic acid at 80°C to form hydrogels. Additionally, polyvinyl pyrrolidone (PVP), a synthetic, nonionic, water-soluble, biocompatible polymer, was added to the formulation to enhance stability, improve film-forming properties, and provide controlled drug release. Metoclopramide HCl, a dopamine receptor antagonist, is primarily used as an antiemetic for chemotherapy-induced nausea and vomiting, as well as for gastrointestinal reflux disorders. Due to its low and variable oral bioavailability, metoclopramide HCl is an ideal candidate for transdermal delivery. It was chosen as the model drug for this study due to its high water solubility and high skin penetration properties.

Methods: In-vitro permeation studies (IVPT) were conducted to compare formulations with varying concentrations of Gantrez®S-97 and hyaluronic acid. The IVPT was performed on dermatomed porcine ear skin using vertical Franz-diffusion cells. Phosphate-buffered saline (PBS) was used as the receptor solution, and hydrogel microneedles with a hydrophilic patch serving as their drug reservoir were placed in the donor chamber. Samples of 0.3 ml were withdrawn at pre-determined time points over 24 hours and analyzed using validated high-performance liquid chromatography (HPLC) to quantify drug permeation into the receptor chamber. Four distinct reservoir patches were evaluated (Table 1): two hydrophobic patches and two hydrophilic patches. The hydrophobic patches were formulated with Eudragit RS, Eudragit L100, dimethyl sulfoxide (DMSO), polyethylene glycol (PEG), and ethanol. The hydrophilic patches comprised different polymer combinations. One hydrophilic patch contained sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl methylcellulose (HPMC), PEG, ethanol, and water, while the other consisted of HPMC, polyvinylpyrrolidone (PVP), sorbitan monooleate (Span 80), PEG, methanol, and water. The hydrogel microneedle formulations tested included 20% w/v and 30% w/v of Gantrez®S-97, 5% w/v hyaluronic acid, and 1% w/v PVP. Additionally, three different concentrations of hyaluronic acid (2% w/v, 5% w/v, and 8% w/v) were evaluated to identify the optimal formulation for delivery.

Results: A comparison of various drug reservoir patches using an IVPT showed that the reservoir formulation, composed of CMC-Na, HPMC, PEG, methanol, and water (Patch C) reservoir patch had the highest delivery of 0.176±0.028 mg/cm². The drug content within all four formulations was measured to be 675.5 µg/cm². An IVPT conducted with hydrogel microneedles combined with a reservoir, loaded with a total of 34.85 ± 2.89 mg of metoclopramide HCl, demonstrated enhanced drug delivery with an optimized formulation. The microneedle formulation with 30% Gantrez® S-97 delivered more drug (2.89 ± 0.71 mg/cm²) compared to the 20% Gantrez® formulation (1.44 ± 0.46 mg/cm², while both formulations maintained the same concentrations of hyaluronic acid (5%) and PVP (1%). Further enhancement was observed when the hyaluronic acid concentration was adjusted to 2% in the 30% Gantrez® formulation, leading to a drug delivery of 3.03 ± 0.72 mg/cm². These findings indicate that the hydrogel microneedle can achieve up to an 18-fold increase in drug delivery efficiency compared to the reservoir patch alone.

Conclusion: In conclusion, this study demonstrated the potential of hydrogel microneedles as an effective platform for transdermal delivery of metoclopramide. The results indicate that both the microneedle formulation and the reservoir patch composition significantly impact drug permeation. Notably, a higher concentration of Gantrez® S-97, along with a hydrophilic reservoir patch containing CMC-Na, HPMC, PEG, ethanol, and water, led to improved drug delivery. These findings provide a foundation for further optimization of hydrogel microneedle systems for the transdermal administration of metoclopramide and other drugs that face challenges with oral delivery.

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Hou, X., Li, J., Hong, Y., Ruan, H., Long, M., Feng, N., & Zhang, Y. (2023). Advances and Prospects for Hydrogel-Forming Microneedles in Transdermal Drug Delivery. Biomedicines, 11(8), 2119.
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Table 1 Formulation for reservoir patches

Comparison between cumulative release of metoclopramide in various reservoir patches

Comparison between cumulative release of metoclopramide with a. 20% w/v and 30% w/v Gantrez®S-97 microneedles; b. 2% w/v, 5% w/v and 8% w/v Hyaluronic acid with 30% Gantrez®S-97 microneedles.