(M1230-03-15) Vacuum Compression Molding as a Novel Technique for the Fabrication of Polymeric Microneedles

Purpose: Transdermal delivery, although an attractive route of delivery, faces challenges in the delivery of hydrophilic drugs. Several chemical and physical enhancement techniques are employed to facilitate the delivery of hydrophilic drugs. Amongst them, microneedles are extensively investigated due to their non-invasive, pain-free administration. Polymeric microneedles are more versatile in terms of mechanical strength and modified drug release. Microneedles are traditionally fabricated using the micromolding technique. However, conventional micromolding utilizes solvents and numerous unit operations, making the overall process time-consuming, and expensive with a high batch variation. Vacuum compression molding (VCM) is a solvent-free process that reduces the unit operations and batch-to-batch variation in microneedles, thereby reducing the microneedle fabrication time. VCM has been used for screening carrier suitability in the development of various dosage forms. We investigated the feasibility of VCM for the fabrication of poly (D, L-lactic-co-glycolic acid) (PLGA) microneedles and demonstrated the delivery of a model drug lidocaine in its both base and salt form across dermatomed human skin.

Methods: First, polydimethylsiloxane (PDMS) molds were prepared using metal microneedle as master-structures. The PDMS molds were prepared in a 6-well plate by mixing Sylgard® 186 silicone elastomer base and curing agent (1:10 % w/w). Air bubbles were eliminated using vacuum and the molds were cured at 90°C for 3 h. The metal microneedles were then removed, and the molds were punched to fit into the sample chamber of the VCM tool. Pre-weighed quantity of PLGA (EXPANSORB® DLG 50-5A) was added to the MeltPrep® VCM tool. The VCM tool was covered with lid, vacuum was applied at -15 psi and placed on the heating unit at 130°C for 15 min. Further, the VCM tool was removed from the heating plate and placed on the cooling unit that utilizes compressed air for cooling. Upon cooling for15 min, it was removed from the cooling plate. VCM tool was separated and kept in the freezer at -20°C for 30 min. The VCM tool was opened, and the PLGA microneedles were manually separated from the PDMS mold and stored in desiccators at room temperature. The microneedles were characterized by appearance, mechanical strength, and uniformity. The microchannels created upon application of microneedles was confirmed using dye-binding studies, skin integrity measurement, histology, and confocal laser microscopy. The in vitro permeation of model drug lidocaine as lidocaine base and lidocaine hydrochloride salt was demonstrated in both intact and microporated dermatomed human skin.

Results: PLGA microneedles fabricated with the VCM technique were visualized using scanning electron microscopy (SEM). The SEM images showed pyramidal-shaped microneedles with an average needle length of 444.03±1.15 µm (n=5). The SEM images demonstrate successful microporation of the skin by PLGA microneedles. The microneedles successfully created microchannels on all four layers of Parafilm M® as the entire array of 100 microchannels was visible on all layers indicating mechanical uniformity. Dye binding, histology, and confocal laser microscopy studies confirmed the formation of microchannels in the skin, along with a drop in skin electrical resistance followed by an increase in the transepidermal water loss. In vitro permeation studies (IVPT) showed that lidocaine base was delivered in a significantly higher amount than lidocaine salt across both intact and microporated skin. A significant increase in the receptor delivery of lidocaine salt between the intact (142.19 ± 13.70 µg/cm²) and microporated (270.57 ± 3.73 µg/cm²) skin was observed at 24 h. The receptor delivery of lidocaine base from microporated skin was significantly higher (312.37 ± 10.57 µg/cm²) than intact skin (169.68 ± 24.09 µg/cm²) in the early time period of 8 h. However, there was no significant difference in the receptor delivery of lidocaine base between intact (390.19 ± 15.42 µg/cm²) and microporated skin (420.82 ± 4.76 µg/cm²) at 24 h, indicating skin saturation in the later time period. The lag time decreased significantly for both lidocaine base (2.24 ± 0.17 h to 0.64 ± 0.05 h) and salt (4.76 ± 0.31 h to 1.47 ± 0.21 h) upon microporation, indicating quicker drug delivery. The flux profile also shows a steady increase after microporation in the case of both lidocaine base and salt.

Conclusion: PLGA microneedles were successfully fabricated using a novel vacuum compression molding (VCM) technique. Consistently uniform and strong microneedles were obtained, based on characterization studies. In vitro delivery of lidocaine base and salt across intact and microporated dermatomed human skin was demonstrated with a significant decrease in lag time. Thus, we demonstrated the novel use of vacuum compression molding to fabricate consistently uniform, strong polymer microneedles in a short duration of time, using a solvent-free method.

Acknowledgements: This project was funded by Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.


Fabrication of PLGA microneedles using vacuum compression molding technique


Scanning electron microscopy images of A) intact PLGA microneedles, B) single PLGA microneedle, C) dermatomed human skin microporated with PLGA microneedles, D) single micropore formed by the insertion of the PLGA microneedle


A)Receptor delivery of lidocaine base, B) lidocaine salt across intact and microporated (MN treated) dermatomed human skin after 24 h; C)Total delivery of lidocaine base and salt across intact and microporated skin, D) decrease in a lag time of the delivery of lidocaine base and salt between intact and microporated skin (statistical analysis performed with unpaired t-test with Welch's correction at p=0.05)