Development of a Drug Dose-Adjustable Transdermal Microneedle System

Abstract

In the first wave of COVID-19 pandemic, it was seen that overcrowded hospitals and lack of personnels increased the risk of mortality. Dexamethasone is a corticosteroid recommended by the World Health Organization (WHO) for use in severe COVID-19 patients. Microneedle technology allows patients to take drugs painlessly with high bioavailability directly into the skin. Therefore, with the developments in this technology, this system which allows self administered without the need for any specialist will come forward in the future. Dosing systems ensure that the drug remains at the therapeutic level for a long time without side effects. Micropumps, which are defined as small devices capable of delivering the drug to the patient at a certain rate, have the ability to provide long-term therapeutic effects by adjusting the dosing on demand. When microneedle systems are combined with micropumps, more reliable, effective and hospital/expert-independent drug dosing/management can be achieved compared to traditional drug administration strategies.

Within the scope of this thesis, a micropump-assisted microneedle system with a drug reservoir, capable of dosing in the presence of a magnetic field, has been developed for the use of COVID-19 patients. Accordingly, the hollow polymeric microneedle array was produced from poly-L-lactic acid (PLLA) by solvent casting method in a single step within a suitable mold. The length, width and tip diameter (OD) of the microneedles were calculated as 1.4 ± 0.2, 0.9 ± 0.1 and 0.20 ± 0.03 mm, respectively and this system consists of 6 microneedles in a circular geometry and spaced at 1.8 mm intervals. As a result of the mechanical analysis, the failure force of the microneedles was found to be 2.9 ± 0.4 N per needle and the decrease in their length was 58 ± 4%. Subsequently, to test the skin penetration abilities of the microneedles, in vitro studies were carried out with the skin model created from Parafilm®. In the Parafilm® test, 8 Parafilm® layers were folded on top of each other to create an artificial skin with a thickness of approximately 1 mm and it was determined to what extent the microneedles fixed to the mechanical analyzer could pierce the Parafilm® layers. It has been observed that the microneedles can effectively pierce the Parafilm® up to the 7th layer (~ 900 µm). Considering all these results, it has been shown that the microneedle array, which is capable of penetrating the skin painlessly with its length and mechanical properties, is suitable for the "poke and flow" approach for transdermal or intradermal applications.

The liquid drug reservoir was 3D printed from acrylonitrile-butadiene-styrene (ABS) with a diameter of 28 mm, a height of 8 mm, and a diameter of the filling port of 2 mm. It has been observed that the drug solution can be easily fillled into the reservoir with a hypodermic needle (21 gauge) and the fluid can be drained through the same opening. No leakage was observed in the reservoir.

Iron oxide (Fe3O4) particles were produced by co-precipitation to be used in the production of the magnetic membrane. Then, Fe3O4 particles and PDMS were mixed with a homogenizer at certain ratios (10, 20 and 30%, wFe3O4/wmembrane, %) by mass, and then coated on a glass substrate surface by dynamic spin coating method and cured at 90ºC for 3 hours. The saturation magnetization of the iron oxide particles was found to be 62.5 emu/g. The saturation magnetization of the thin magnetic membranes were measured as 5.5, 10.7 and 15.3 emu/g, respectively. The thickness of the magnetic membranes varies between 0.74 and 0.44 mm. The deflection of the membranes at applied voltages (10, 20 and 30 V) was analyzed. The resulting deflection values varied from 0.165 ± 0.014 to 1.1358 ± 0.1 mm. The amount of deflection are maximum at Fe3O4 ratio of 20% and minimum at 10% by mass.

Two different assembly processes were performed for the fabrication of the micropump-assisted microneedle array. The microneedle array and the reservoir were attached together by solvent bonding using dichloromethane, while the magnetic membrane was joined to the reservoir by the partial curing method. When the entire system was assembled, the total weight was measured as 4.6 g. Afterwards, the reservoir was filled with approximately 1.3 mL of dexamethasone solution and the dosing performance of the developed system at different voltages (30, 40, 50 and 60 V) was analyzed. The aqueous solution of dexamethasone 21-phosphate (0.2 mg/mL) was used as stock drug solution. For this, different voltage values (30, 40, 50 and 60 V) were applied to the system, but pumping did not occur because the deflection of the magnetic membrane alone was not sufficient. Afterwards, it was observed that the pumping was achieved by placing a cylindrical neodymium magnet of 10x1.5 mm size on the magnetic membrane. Accordingly, liquid pumping capacities ranging from 43 ± 17 to 115 ± 8 μL/s were achieved when each voltage between 30 - 60 V (10 V increment) was applied to the system alone, and between 32 ± 12 and 142 ± 45 μL/s were achieved when the system was operated in stages between 30 - 60 V (10 V increment, 2 s on, 2 s off). The system is capable of delivering a total of 52 μg dexamethasone in 16 seconds. It has also been shown that the system are capable of dosing in different volumes and perform multiple dosings according to the applied voltage values over time.

The micropump-assisted microneedle array produced in this study, may come forward as a 'proof of concept' system that patients can apply it directly on their own, adjust the drug dose, and make repeated dosing at a certain time interval. In addition, this developed system can be used successfully for other dosing applications where necessary besides dexamethasone.