title: Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery.
abstract: In this study, dissolving microneedles (MNs) were used to enhance ocular drug delivery of macromolecules. MNs were fabricated using polyvinylpyrrolidone (PVP) polymer of various molecular weights (MWs) containing three model molecules of increasing MW, namely fluorescein sodium and fluorescein isothiocyanate-dextrans (with MW of 70 k and 150 k Da). Arrays (3 × 3) of PVP MNs with conical shape measuring about 800 μm in height with a 300 μm base diameter, containing the model drugs, were fabricated and characterized for their fracture forces, insertion forces (in the sclera and cornea), depth of penetration (using OCT and confocal imaging), dissolution time and in vitro permeation. The average drug content of the MNs (only in MN shafts) ranged from 0.96 to 9.91 μg, and the average moisture content was below 11 %. High MW PVP produced MNs that can withstand higher forces with minimal reduction in needle height. PVP MNs showed rapid dissolution that ranged from 10 to 180 s, which was dependent upon PVP's MW. In vitro studies showed significant enhancement of macromolecule permeation when MNs were used, across both the corneal and scleral tissues, in comparison to topically applied aqueous solutions. Confocal images showed that the macromolecules formed depots within the tissues, which led to sustained permeation. However, use of MNs did not significantly benefit the permeation of small molecules; nevertheless, MN application has the potential for drug retention within the selected ocular tissues unlike topical application for small molecules. The material used in the fabrication of the MNs was found to be biocompatible with retinal cells (i.e. ARPE-19). Overall, this study reported the design and fabrication of minimally invasive rapidly dissolving polymeric MN arrays which were able to deliver high MW molecules to the eye via the intrastromal or intrascleral route. Thus, dissolving MNs have potential applications in enhancing ocular delivery of both small and macromolecules.
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK. r.thakur@qub.ac.uk.
authors.forename: Raghu Raj Singh
authors.initials: RR
authors.lastname: Thakur
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.|Faculty of Pharmacy, Aleppo University, Aleppo, Syria.
authors.forename: Ismaiel A
authors.initials: IA
authors.lastname: Tekko
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Farhan
authors.initials: F
authors.lastname: Al-Shammari
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Ahlam A
authors.initials: AA
authors.lastname: Ali
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: McCarthy
authors.affiliation: School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Donnelly
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D002460:Cell Line; D003315:Cornea / Q000378:metabolism*; D003911:Dextrans / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D019793:Fluorescein / Q000008:administration & dosage / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry; D066298:In Vitro Techniques; D008845:Microinjections; D009339:Needles; D011205:Povidone / Q000008:administration & dosage* / Q000737:chemistry; D012590:Sclera / Q000378:metabolism*; D013552:Swine
chemical_list: D003911:Dextrans; D020100:Hydrogels; C015219:fluorescein isothiocyanate dextran; D011205:Povidone; D016650:Fluorescein-5-isothiocyanate; D019793:Fluorescein
keywords: Cornea; FITC-dextran; Microneedles; Ocular drug delivery; Polyvinylpyrrolidone (PVP); Sclera