(M1230-01-04) Week-Long Transdermal Delivery of an Anxiolytic Drug Using Tip-Loaded PVA Microneedles

Purpose: Anxiety is a psychological disorder characterized by motor tension, autonomic hyperactivity, apprehensive expectation, and vigilance and scanning tendencies. Anxiety disorder affects nearly 300 million people worldwide. Various medications such as selective serotonin reuptake inhibitor, benzodiazepines, norepinephrine reuptake inhibitor, and anxiolytic agents are approved for the management of anxiety. Buspirone hydrochloride (BSP, MW 422 g/mol, logP 1.66) is an anxiolytic medication, approved in the form of oral tablets with varying strengths up to 30 mg. The oral bioavailability of buspirone hydrochloride is extremely low (4%); the drug undergoes extensive first-pass metabolism upon oral administration. Moreover, the half-life of the drug is only 2-3 hours. Hence, there is a need for exploration of alternative routes of administration for BSP. The transdermal route of administration can offer the advantages of high bioavailability, reduced dosing frequency, high patient compliance, and better adherence to treatment regimen. In this project, we investigated week-long transdermal delivery of BSP using tip-loaded polyvinyl alcohol (PVA) microneedles. The fabrication of microneedles was optimized for four different types of PVA. These were compared using various characterization techniques, as well as in vitro release and permeation testing.

Methods: Micro-molding technique with in-house prepared molds was used to fabricate the PVA microneedles. To make polydimethylsiloxane molds, silicone elastomer, and curing agent were mixed in a 9:1 ratio, and poured onto a metal master structure, followed by vacuum drying (Vacufuge, Eppendorf, 15 mins) and oven drying (overnight) at 60°C. Four types of microneedles were fabricated, each with a different grade of PVA (4-88, 8-88, 18-88, and 26-88) to make up the needle tips. For drug-loaded needle tips, BSP was dissolved in the 20% w/w PVA and 10% w/w maltose solution to obtain a 10% w/w BSP-polymer solution. Further, 100 mg of this solution was weighed into the MN molds, centrifuged at 4000 rpm for 15 mins, and dried overnight at 60°C. Hence, drug loading per microneedle array was 10 mg. For the baseplate, 200 mg of 20% w/w PVA solution of a higher molecular weight grade PVA (40-88) was added stepwise, centrifuged at 4000 rpm for 30 mins and dried at 60°C for 2 days. The fabricated, drug-loaded microneedles were characterized using Parafilm-insertion testing, histology, and confocal microscopy. HPLC method for the quantitative analysis of BSP was developed and validated. In vitro release testing (IVRT) was performed using vertical Franz diffusion cells across cellulose acetate membrane (cutoff molecular weight of 14 kDa) over 7 days. Further, in vitro permeation testing (IVPT) studies were performed across dermatomed human skin. Two passive (control) groups were used for IVPT, where 100 µL of 10 mg/mL BSP in phosphate-buffered saline was applied to intact skin and skin treated with metal microneedles (Dr. Pen Ultima™). Samples were taken at predetermined timepoints up to 7 days and analyzed using the validated RP-HPLC method.

Results: From parafilm insertion testing, it was seen that all four microneedle arrays penetrated the Parafilm® uniformly up to 3 layers, confirming insertion capability and mechanical uniformity. From histological evaluation, it was observed that the stained, untreated skin section showed an intact and well-structured stratum corneum, epidermis, and dermis, whereas the microneedle-treated skin sections depict a broken stratum corneum with the microchannels extending into the epidermis. Using confocal microscopy, the penetration depth was found to remain consistent across all four types of microneedles and was found to be approximately 200 µm. As per the in vitro release testing study, the rate and extent of BSP release were inversely proportional to the molecular weight of PVA. Hence, the highest release was observed from the PVA microneedles consisting of the lowest molecular weight of PVA 4-88 (55.07%), followed by 8-88 (43.59%), 18-88 (26.27%), and the lowest release was observed from the 26-88 (18.17%) grade microneedles. In vitro permeation testing studies showed that both the control groups showed a drop in permeation after 2 days. All four tip-loaded PVA microneedles showed sustained transdermal delivery over 7 days, crossing the daily as well as weekly therapeutic target. The transdermal delivery from the tip-loaded microneedles was inversely proportional to the molecular weight of PVA present in the needle tips, in the order: 4-88 (4705 µg/sq.cm), 8-88 (3051.93 µg/sq.cm), 18-88 (1818.94 µg/sq.cm), and 26-88 (874.47 µg/sq.cm). Overall, the difference in release and transdermal delivery can be attributed to the differences in solubility of the PVA grades. The lower molecular weight PVAs have higher solubility, which can be directly correlated to the faster release and delivery of BSP.

Conclusion: Tip-loaded microneedles using four different grades of PVA were successfully fabricated. Sustained release and transdermal delivery profiles were observed over 7 days from fabricated microneedles and were correlated to the molecular weights of PVA used in the needle tips. Overall, the feasibility of sustained transdermal delivery of an anxiolytic drug across dermatomed human skin using polymeric microneedles was established.


Figure 1 Characterization studies I) Histological evaluation a) untreated skin, b) 4-88, c) 8-88, d) 18-88, e) 26-88; II) Parafilm testing upto 3 layers A) 4-88, B) 8-88, C) 18-88, D) 26-88; Confocal microscopy a) 4-88, b) 8-88, c) 18-88, and d) 26-88


Figure 2 Results of in vitro release testing across cellulose acetate membrane over 7 days


Figure 3 In vitro permeation testing across dermatomed human skin A) Permeation profile and B) Transdermal permeation over 7 days delivery period (Statistical analysis using ANOVA p<0.05)