PMID- 32593650 OWN - NLM STAT- MEDLINE DCOM- 20210304 LR - 20210304 IS - 1873-3476 (Electronic) IS - 0378-5173 (Linking) VI - 586 DP - 2020 Aug 30 TI - Development and characterisation of novel poly (vinyl alcohol)/poly (vinyl pyrrolidone)-based hydrogel-forming microneedle arrays for enhanced and sustained transdermal delivery of methotrexate. PG - 119580 LID - S0378-5173(20)30564-0 [pii] LID - 10.1016/j.ijpharm.2020.119580 [doi] AB - Methotrexate (MTX) is one of the mainstays of treatment for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) and it is mainly administered either orally or by subcutaneous (SC) injection, which are not so satisfactory. While orally administered MTX is associated with variable bioavailability and causes gastrointestinal side effects, including nausea and vomiting, SC injection is painful and produces high peak blood levels of MTX. Transdermal delivery presents an attractive alternative administration route. However, MTX passive permeation through the skin is hindered by the skin barrier and MTX physicochemical properties. To address these issues, hydrogel-forming microneedle arrays (HFMN) and a patch-like reservoir loaded with MTX (MTX-RV) were developed and combined to form a minimally invasive patch to deliver MTX transdermally in a sustained manner. HFMN were prepared from an aqueous blend of poly (vinyl alcohol) (PVA) and poly (vinyl pyrrolidone) (PVP) which was crosslinked chemically with citric acid (CA) at 130 C. MTX-RV was prepared from hydroxypropyl methylcellulose (HPMC) and glycerol. Both the HFMN and MTX-RV were fully characterised and then combined to form an integrated patch, which was evaluated ex vivo and in preclinical studies. The HFMN demonstrated a satisfactory mechanical strength and insertion capability into excised neonatal porcine skin, as well as moderate swelling properties. The MTX-RV incorporated a high dose of MTX (150.3 +/- 5.3 microg/mg) without precipitation. The integrated patch delivered MTX at a steady-state flux of 506.8 +/- 136.9 microg.cm(2)/h in an ex vivo setup. Furthermore, in preclinical studies performed in Sprague Dawley rats, MTX appeared in blood after 1 h from patch application at a concentration of 7.6 +/- 2.0 nM. MTX blood level increased gradually to reach its peak, C(max) = 35.1 +/- 5.1 nM, at 24 h. Importantly, the HFMN were removed intact from the skin with only mild erythema, despite the cytotoxic nature of MTX. Accordingly, the integrated patch produced in this work represents a promising minimally invasive transdermal drug delivery system that can overcome the skin barrier and deliver MTX in a sustained manner. This may help in minimising or even avoiding the nausea and vomiting, associated with the conventional administration routes. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Tekko, Ismaiel A AU - Tekko IA AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom; Faculty of Pharmacy, Aleppo University, Aleppo, Syria. FAU - Chen, Gaoyun AU - Chen G AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - Dominguez-Robles, Juan AU - Dominguez-Robles J AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - Thakur, Raghu Raj Singh AU - Thakur RRS AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - Hamdan, Iman M N AU - Hamdan IMN AD - Faculty of Pharmacy, Middle East University, Amman 11831, Jordan. FAU - Vora, Lalitkumar AU - Vora L AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - Larraneta, Eneko AU - Larraneta E AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - McElnay, James C AU - McElnay JC AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - McCarthy, Helen O AU - McCarthy HO AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. FAU - Rooney, Madeleine AU - Rooney M AD - Centre for Experimental Medicine (CEM), School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. Electronic address: R.Donnelly@qub.ac.uk. FAU - Donnelly, Ryan F AU - Donnelly RF AD - School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. Electronic address: M.Rooney@qub.ac.uk. LA - eng PT - Journal Article DEP - 20200625 PL - Netherlands TA - Int J Pharm JT - International journal of pharmaceutics JID - 7804127 RN - 0 (Antirheumatic Agents) RN - 0 (Delayed-Action Preparations) RN - 0 (Drug Carriers) RN - 0 (Hydrogels) RN - 9002-89-5 (Polyvinyl Alcohol) RN - FZ989GH94E (Povidone) RN - YL5FZ2Y5U1 (Methotrexate) SB - IM MH - Administration, Cutaneous MH - Animals MH - Antirheumatic Agents/*administration & dosage/pharmacokinetics/toxicity MH - Chemistry, Pharmaceutical MH - Delayed-Action Preparations MH - Drug Carriers/*chemistry MH - *Drug Delivery Systems MH - Female MH - Hydrogels MH - Methotrexate/*administration & dosage/pharmacokinetics/toxicity MH - Needles MH - Polyvinyl Alcohol/chemistry MH - Povidone/chemistry MH - Rats MH - Rats, Sprague-Dawley MH - Skin Absorption MH - Swine MH - Transdermal Patch OTO - NOTNLM OT - Crosslinking OT - Hydrogel-forming microneedles OT - Juvenile idiopathic arthritis OT - Methotrexate OT - Sustained release OT - Transdermal delivery COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/07/01 06:00 MHDA- 2021/03/05 06:00 CRDT- 2020/06/29 06:00 PHST- 2020/05/14 00:00 [received] PHST- 2020/06/20 00:00 [revised] PHST- 2020/06/22 00:00 [accepted] PHST- 2020/07/01 06:00 [pubmed] PHST- 2021/03/05 06:00 [medline] PHST- 2020/06/29 06:00 [entrez] AID - S0378-5173(20)30564-0 [pii] AID - 10.1016/j.ijpharm.2020.119580 [doi] PST - ppublish SO - Int J Pharm. 2020 Aug 30;586:119580. doi: 10.1016/j.ijpharm.2020.119580. Epub 2020 Jun 25.