Delivering methotrexate transdermally employing novel PVA-based hydrogel-forming microneedles for treatment of Juvenile Idiopathic Arthritis: In-vitro studies

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Abstract

Background: Methotrexate (MTX) has a long history of use in the treatment of juvenile idiopathic arthritis (JIA) and the required once-weekly dose ranges between 3- 30 mg depending on child`s age and body area. This drug has shown to be clinically effective with a very good long term safety, but its oral and subcutaneous delivery associated with severe side effects 1. Therefore, its transdermal delivery presents an attractive alternative delivery route and highly desirable. In a previous in-vitro study 2, hydrogel forming microneedles (HF-MNs) have shown to be effective in enhancing the transdermal delivery of MTX significantly. However, the MN forming materials formed a rate-limiting step for MTX permeation through the MNs so that only 13% of the applied dose (7.2 mg applied on a patch size of 0.30 cm2) has been delivered over 24 hours. Therefore, a relatively big patch size (around 10 cm2) is needed to deliver the required highest dose of MTX for JIA patients. Aims: The objective of this study was to design and develop novel HF-MNs from biocompatible and biodegradable polymer which was poly vinyl alcohol (PVA), which would allow the MTX to pass through skin without limitation and deliver the required MTX doses more efficiently in order to be used in treatment of JIA. Methods: Novel HF-MNs arrays were fabricated by a casting method using silicone moulds employing PVA blended with other biocompatible materials. The fabricated MN arrays were characterised for their mechanical strength, swelling properties, penetration depth. Polymeric MTX- containing reservoir wafers were also prepared and characterised. Both the MTX-containing reservoir wafer and HF-MNs were combined together to form a patch where their capability to deliver MTX transdermally was evaluated in-vitro using dermatomed piglet skin. Results: The HF-MNs arrays composed of 11 x11 MNs of conical shape measuring (729.5 ±11.2 um) in height and 300 um in width at the baseplate were fabricated. These MNs were strong enough to pierce and penetrate through the excised porcine skin in-vitro without breaking or bending by applying a relatively small compression force (20 N/MN array), and then, they swell upon contact with water without dissolving to form microconduits allowing MTX from the reservoir wafer to to by-pass the stratum corneum. Interestingly, These MNs were then removed intact from the skin. The fabricated MNs were able to deliver Transdermally MTX more efficiently from the same size patch size of (0.30 cm2) (> 60% of the loaded doses was delivered) Conclusions: The fabricated PVA-based HF-MNs were strong enough to pierce the excised porcine skin in-vitro and then, they swell without dissolving and deliver variable doses of MTX through the excised porcine skin more efficiently in comparison with the previous HF-MNs, and then removed intact without leaving any measurable residues. These HF-MNs could be used as a platform to deliver clinically relevant doses of MTX transdermally to treat JIA patient. However, further studies, to evaluate their efficiency and safety in-vivo, are still required. Acknowledgement: This project is kindly funded by ARUK. References: 1. ReGiannini et al., 1992, Methotrexate inresistant juvenile rheumatoid arthritis: results of the U.S.A.- U.S.S.R. double-blind, placebocontrolled trial. N Engl J Med., 326:1043 1049. 2. Tekko, et al., 2016, Hydrogel Forming Microneedles a Promising Minimally Invasive Tool to Deliver Clinically Relevant Doses of Methotrexate to Treat Paediatric Rheumatoid Arthritis, The 23rd PReS Congress, Genoa, Italy, 28/09/2016 - 01/10/2016.
Original languageEnglish
DOIs
Publication statusPublished - 29 Nov 2016
EventBSPAR Annual Conference 2016 - Midland Hotel, Manchester, United Kingdom
Duration: 29 Dec 201630 Dec 2016
http://www.bsparmanchester2016.co.uk

Conference

ConferenceBSPAR Annual Conference 2016
Abbreviated titleBSPAR Annual Conference 2016
CountryUnited Kingdom
CityManchester
Period29/12/201630/12/2016
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