Mucoadhesive electrospun patch delivery of lidocaine to the oral mucosa and investigation of spatial distribution in tissue using MALDI-mass spectrometry imaging

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a non-injectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anaesthetics from this system and their uptake by oral tissue has not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fibre patches, drug release, and subsequent uptake and permeation through porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 minutes (0.16 ± 0.04 mg) compared to from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 minutes, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionisation – mass spectrometry imaging (MALDI-MSI) was used to investigate localisation of lidocaine within oral tissue. Lidocaine in solution as well as from the mucoadhesive patch penetrated into buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 minutes. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anaesthetic drug delivery and may reduce the need for injection

Ion mobility mass spectrometry enhances low-abundance species detection in untargeted lipidomics

We describe a simple method for the detection of low intensity lipid signals in complex tissue samples, based on a combination of liquid chromatography/mass spectrometry and ion mobility mass spectrometry. The method relies on visual and software-assisted analysis of overlapped mobilograms (diagrams of mass-to-charge ratio, m/z, vs drift time, DT) and was successfully applied in untargeted lipidomics analyses of mouse brain tissue to detect relatively small variations in a scarce class of phospholipids (N-acyl phosphatidylethanolamines) generated during neural tissue damage, against a background of hundreds of lipid species. Standard analytical tools, including Principal Component Analysis, failed to detect such changes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-016-0971-3) contains supplementary material, which is available to authorized users

In vivo dermal delivery of bleomycin with electronic pneumatic injection:drug visualization and quantification with mass spectrometry

Background: Intralesional bleomycin (BLM) administration by needle injection is effective for keloids and warts but has significant drawbacks, including treatment-related pain and operator-depended success rates. Electronic pneumatic injection (EPI) is a promising, less painful, needle-free method that potentially enables precise and controlled dermal drug delivery. Here, we aimed to explore the cutaneous pharmacokinetics, biodistribution patterns, and tolerability of BLM administered by EPI in vivo. Research Design and Methods: In a pig model, EPI with BLM or saline (SAL) were evaluated after 1, 48 and 216 hours. Mass spectrometry quantification and imaging were used to assess BLM concentrations and biodistribution patterns in skin biopsies. Tolerability was assessed by scoring local skin reactions (LSR) and measuring transepidermal water loss (TEWL). Results: Directly after BLM injection a peak concentration of 109.2 µg/cm3 (43.9–175.2) was measured in skin biopsies. After 9 days BLM was undetectable. EPI resulted in a focal BLM biodistribution in the mid-dermal delivery zone resembling a triangular shape. Mild LSRs were resolved spontaneously and TEWL was unaffected. Conclusions: BLM administered by EPI resulted in quantifiable and focal mid-dermal distribution of BLM. The high skin bioavailability holds a great potential for clinical effects and warrants further evaluation in future human studies

Bleomycin administered by laser-assisted drug delivery or intradermal needle-injection results in distinct biodistribution patterns in skin: in vivo investigations with mass spectrometry imaging

Bleomycin (BLM) is being repositioned in dermato-oncology for intralesional and intra-tumoural use. Although conventionally administered by local needle injections (NIs), ablative fractional lasers (AFLs) can facilitate topical BLM delivery. Adding local electroporation (EP) can augment intracellular uptake in the target tissue. Here, we characterize and compare BLM biodistribution patterns, cutaneous pharmacokinetic profiles, and tolerability in an in vivo pig model following fractional laser-assisted topical drug delivery and intradermal NI, with and without subsequent EP. In vivo pig skin was treated with AFL and topical BLM or NI with BLM, alone or with additional EP, and followed for 1, 2 and 4 h and eventually up to 9 d. BLM biodistribution was assessed by spatiotemporal mass spectrometry imaging. Cutaneous pharmacokinetics were assessed by mass spectrometry quantification and temporal imaging. Tolerability was evaluated by local skin reactions (LSRs) and skin integrity measurements. AFL and NI resulted in distinct BLM biodistributions: AFL resulted in a horizontal belt-shaped BLM distribution along the skin surface, and NI resulted in BLM radiating from the injection site. Cutaneous pharmacokinetic analyses and temporal imaging showed a substantial reduction in BLM concentration within the first few hours following administration. LSRs were tolerable overall, and all interventions permitted almost complete recovery of skin integrity within 9 d. In conclusion, AFL and NI result in distinct cutaneous biodistribution patterns and pharmacokinetic profiles for BLM applied to in vivo skin. Evaluation of LSRs showed that both methods were similarly tolerable, and each method has potential for individualized approaches in a clinical setting