A multicomponent microneedle patch for the delivery of meloxicam for veterinary applications

Introduction:: Pain management for livestock has become an important issue for organizations like the American Veterinary Medical Association (AVMA), which is now encouraging the use of pain relief during routine management practices in Cattle (Frida L., Animal. 2018; 8:4-16). However, few pain medications exist commercially that are Food and Drug Administration (FDA)-approved for use in cattle. Meloxicam is a promising NSAID alternative, with a relatively long half-life of 28 h. Currently, meloxicam is FDA-approved and routinely prescribed for pain mitigation in other veterinary species (i.e., dogs and cats) (Dominique V., Animal. 2018; 8:35). Nevertheless, meloxicam delivery to animals is given orally through suspension or tablet form, which is not amenable for livestock administration. This work proposes that a better approach for livestock drug delivery is through the transdermal application with polymeric microneedle patches. Microneedle patches composed of polyvinyl alcohol (PVA), type I collagen (COL), chitosan (CHI), and meloxicam (MEL) were evaluated regarding their physical, chemical, and mechanical properties, and the microneedle insertion abilities in pig's ear cadaver skin for the transdermal delivery of meloxicam as a pain management approach in veterinary applications.

Materials and Methods:: The physical properties of the microneedle patches, including morphology, topography, and distribution were examined before and after ethylene oxide sterilization using Scanning Electron Microscopy (SEM) and a laser microscope 3D & profile measurement. A cross-sectional imaging of the bilayer conformation of the microneedle patch was analyzed and visualized with a laser scanning confocal microscope (LCSM). Fourier transform infrared spectroscopy (FTIR) was used to analyze the chemical composition of microneedle patches with and without drugs before and after the sterilization process. The microneedle patches were tested against the capacity to penetrate the pig’s ear cadaver skin's inner and outer surface at 5 s and 24 h. Finally, mechanical tests were conducted using a tribometer to assess the penetration depth of drug-loaded microneedles into the cadaver skin of a pig's ear at different loads. These tests were also used to determine the deformation behavior of the microneedles compressed against the flat end of a stainless-steel pin (compression tests).

Results, Conclusions, and Discussions:: The microneedle patch consisted of 225 microneedles with 600 μm of height and 300 μm of base uniformly organized on an area of 8 mm × 8 mm. The penetration of the microneedles is through the epidermis and dermis where the microneedle degradation and, consequently, the drug release begins (Fig. 1A-B). The optical cross-section patch side view validated the division and the difference between the two layers of the patch (Fig. 1C). SEM characterization demonstrated the presence of microneedles uniformly organized on the patch surface and preserve their morphological properties after the sterilization process. (Fig. 1D). FTIR characterization confirmed that microneedle patches with and without drug preserve the chemical composition of the PVA, COL, and CHI polymers and meloxicam drug after the sterilization process using ethylene oxide gas (Fig. 1E). In-vitro microneedle insertion study demonstrated that microneedle patches were able to penetrate pig’s ear cadaver skin (Fig. 1F). Full penetration of the microneedles into the skin can be obtained by applying approximately 3 N, and microneedles have the capability of returning to their original shape after compression testing (Fig. 1G).
In summary, this study demonstrates that PVA-COL-CHI-MEL patches presented an organized distribution and homogeneous dimension of microneedles. The morphological properties and chemical composition after the sterilization process were preserved. The resultant microneedle patches were successful in penetrating the surface skin in the pig's cadaver ear. Finally, microneedles have the capability of returning to their original shape after compression testing. This work demonstrated that this system of biodegradable microneedle patches will help to extend the use of FDA-approved meloxicam in the pharmaceutical field and how pain management medication for livestock animals as a suitable way to manage pain in farm animals after routine procedures.

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