title: Formulation of hydrophobic peptides for skin delivery via coated microneedles.
abstract: Microneedles (MNs) have been investigated as a minimally-invasive delivery technology for a range of active pharmaceutical ingredients (APIs). Various formulations and methods for coating the surface of MNs with therapeutics have been proposed and exemplified, predominantly for hydrophilic drugs and particulates. The development of effective MN delivery formulations for hydrophobic drugs is more challenging with dosing restrictions and the use of organic solvents impacting on both the bioactivity and the kinetics of drug release. In this study we propose a novel formulation that is suitable for MN coating of hydrophobic auto-antigen peptides currently being investigated for antigen specific immunotherapy (ASI) of type 1 diabetes. The formulation, comprising three co-solvents (water, 2-methyl-2-butanol and acetic acid) and polyvinylalcohol 2000 (PVA2000) can dissolve both hydrophilic and hydrophobic peptide auto-antigens at relatively high, and clinically relevant, concentrations (25mg/ml or 12.5mg/ml). The drug:excipient ratio is restricted to 10:1 w/w to maximise dose whilst ensuring that the dry-coated payload does not significantly impact on MN skin penetration performance. The coating formulation and process does not adversely affect the biological activity of the peptide. The delivery efficiency of the coated peptide into skin is influenced by a number of parameters. Electropolishing the metal MN surface increases delivery efficiency from 2.0±1.0% to 59.9±6.7%. An increased mass of peptide formulation per needle, from 0.37μg to 2μg peptide dose, resulted in a thicker coating and a 20% reduction in the efficiency of skin delivery. Other important performance parameters for coated MNs include the role of excipients in assisting dissolution from the MNs, the intrinsic hydrophobicity of the peptide and the species of skin model used in laboratory studies. This study therefore both exemplifies the potential of a novel formulation for coating hydrophobic and hydrophilic peptides onto MN devices and provides new insight into the factors that influence delivery efficiency from coated MNs. Importantly, the results provide guidance for identifying critical attributes of the formulation, coating process and delivery device, that confer reproducible and effective delivery from coated MNs, and thus contribute to the requirements of the regulators appraising these devices.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK; School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK. Electronic address: coulmansa@cf.ac.uk.
authors.forename: Sion A
authors.initials: SA
authors.lastname: Coulman
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Hanna
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK. Electronic address: birchalljc@cf.ac.uk.
authors.forename: James C
authors.initials: JC
authors.lastname: Birchall
mesh_terms: D019342:Acetic Acid / Q000737:chemistry; D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D016503:Drug Delivery Systems; D004867:Equipment Design / Q000295:instrumentation*; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D016688:Mice, Inbred NOD; D008845:Microinjections / Q000379:methods; D008855:Microscopy, Electron, Scanning / Q000379:methods; D009339:Needles; D000439:Pentanols / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D010599:Pharmacokinetics; D011142:Polyvinyl Alcohol / Q000737:chemistry; D012867:Skin / Q000378:metabolism; D012996:Solutions; D013499:Surface Properties; D014867:Water
chemical_list: D005079:Excipients; D000439:Pentanols; D010455:Peptides; D012996:Solutions; D014867:Water; C032765:tert-amyl alcohol; D011142:Polyvinyl Alcohol; D019342:Acetic Acid
keywords: Coating; Formulation; Hydrophobic; Microneedle; Peptide