Development of a novel single-use microneedle design platform for increased patient compliance

Microneedles (MN) skin patches are novel medical devices in micron scale with a needle array which offers an alternative drug delivery system to conventional methods. MN patches are applied onto the skin reaching the dermal layer where the drug molecules are released at a specific rate. There is a lack of knowledge surrounding some determinant factors required to define an efficient MN application into the user skin. The aim of the project is to determine the optimum application parameters to fabricate a polymeric MN patch and to design a disposable single-use MN applicator with enhanced usability

Parenteral protein formulations: an overview of approved products within the European Union

The study presented is a comprehensive overview of commercial parenteral protein formulations, approved by the European Medicines Agency (EMA), 1995-2018. The objective of this overview was to analyse current trends in the design of commercial parenteral protein products and thereby support formulation scientists in the design of new formulations. The main data source was the publicly available European Public Assessment Reports (EPARs) published by the EMA for each authorised product. An analysis of the percentage of formulations in a liquid and lyophilised form was conducted. In addition, the number of products containing individual excipients, classified into functional categories is provided. Finally, the overview includes comprehensive details of product compositions obtained from EMA, US Food and Drug Administration (FDA) and product Marketing Authorisation Holder. Data analysis highlighted trends in the number of products approved, and the higher percentage of liquid parenteral protein formulations (66%) compared to lyophilised formulations (34%). This overview identifies the most commonly incorporated excipients employed as buffering agents, stabilisers/bulking agents, surfactants, preservatives and tonicifiers, including their concentration ranges of use in both liquid and lyophilised formulation approaches. Finally, antibody-based formulations were a particular focus of this overview. The relationship between parenteral routes of administration and antibody concentrations in approved products was also investigated

The application of percolation threshold theory to predict compaction behaviour of pharmaceutical powder blends

Percolation theory provides a statistical model which can be used to predict the behaviour of powder blends based on particle-particle interactions. The aim of this study was to investigate if percolation theory could be used to predict the drug loading concentration of pharmaceutical tablets, and the relative density of a blend, above which tablet tensile strength is reduced, resulting in the production of unsatisfactory products. The model blend studied contained ibuprofen as the API, which exhibits poor flow and compressibility, and microcrystalline cellulose (MCC) as the excipient, which exhibits good flowability and compressibility. Two MCC grades with differing physical properties were investigated, Vivapur® 102 (air streamed dried quality), and Emcocel® 90 (spray dried quality) to test the theory. Blends containing 2.5 to 40% w/w of ibuprofen were compacted at a range of pressures and the values of the powder true density, compaction pressure, tablet envelope density, and tablet tensile strength were used to calculate the percolation thresholds mathematically. The drug loading threshold values predicted with the model (19.08% w/w and 17.76% w/w respectively for Vivapur® 102 and Emcocel® 90) were found to be in good agreement when compared to experimental data and the infinite cluster of drug was visually confirmed on the surface of tablets using Raman imaging. The capability of multivariate analysis to predict the drug loading threshold was also tested. Principal component analysis was unable to identify the threshold, but provided an overview of the changes of the analysed properties as ibuprofen drug loading increased. It was also able to identify differences between blends containing Vivapur® or Emcocel®. In conclusion, percolation theory was able to predict the maximum acceptable drug loading for this binary system of API and excipient. This methodology could be employed for other binary systems to predict maximum drug loading potential without the need for time consuming and expensive tablet production

A TLR9-adjuvanted vaccine formulated into dissolvable microneedle patches or cationic liposomes protects against leishmaniasis after skin or subcutaneous immunization

Re-emergence and geographic expansion of leishmaniasis is accelerating efforts to develop a safe and effective Leshmania vaccine. Vaccines using Leishmania recombinant antigens, such as LiHyp1, which is mostly present in the amastigote parasite form, are being developed as a next generation to crude killed parasite-based vaccines. The main objective of this work was to develop a LiHyp1-based vaccine and determine if it can induce protective immunity in BALB/c mice when administered using a dissolvable microneedle (DMN) patch by the skin route. The LiHyp1 antigen was incorporated into cationic liposomes (CL), with or without the TLR9 agonist, CpG. The LiHyp1-liposomal vaccines were characterized with respect to size, protein encapsulation rates and retention of their physical characteristics after incorporation into the DMN patch. DMN mechanical strength and skin penetration ability were tested. A vaccine composed of LiHyp1, CpG and liposomes and subcutaneously injected or a vaccine containing antigen and CpG in DMN patches, without liposomes, induced high antibody responses and significant levels of protection against L. donovani parasite infection. This study progresses the development of an efficacious leishmania vaccine by detailing promising vaccine formulations and skin delivery technologies and it addresses protective efficacy of a liposome-based dissolvable microneedle patch vaccine system

Investigating microcrystalline cellulose crystallinity using Raman spectroscopy

Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm−1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed

Lack of influence of social media on vaccine decision-making by university students in Ireland

ABSTRACTVaccine hesitancy is a complex, context-specific issue that negatively impacts vaccine uptake. During the COVID-19 pandemic, vaccine mis- and dis-information on social media negatively impacted on COVID-19 vaccine acceptance. University students’ beliefs and behaviors surrounding vaccine decision-making is less studied, but this population is important in disease transmission, vaccine uptake and effectiveness. Here, we surveyed students in a third-level Irish university, in September 2022, when pandemic restrictions had been removed, to primarily determine if their use of, and influence by, mainstream and social media correlated with their willingness to receive a COVID-19 vaccine or any vaccine. We analyzed 151 responses and found no significant correlation between students’ willingness to receive either a COVID-19 vaccine or any vaccine and their use of social media. There were significant links between vaccine acceptance and a range of factors, namely accommodation type, social media behaviors, perceived exposure to vaccine mis- or dis-information and previous vaccine uptake. This study provides a preliminary insight into drivers of university student COVID-19 and general vaccine willingness. It provides initial data, in the context of post-pandemic restrictions, to support further development of interventions to enhance vaccine uptake in third-level students in Ireland

Comparative efficacy evaluation of different penetration enhancement strategies for dermal delivery of poorly soluble drugs – A case with sertaconazole nitrate

The aim of this study was to compare the efficacy of different approaches for enhancement of dermal availability of the highly lipophilic antifungal model drug – sertaconazole nitrate (SN). For this purpose, a physical penetration enhancer – dissolving microneedles (MNs) was fabricated by filling moulds with liquid formulation based on polyvinylpyrrolidone and loaded with SN. Dissolving MNs were characterised regarding their morphological and mechanical characteristics. A penetration enhancement efficacy of MNs was evaluated in vitro using porcine ear skin in parallel with the efficacy of formerly developed chemical penetration enhancer – biocompatible microemulsion (ME) formulation. Moreover, an ability of solid silicon MNs to significantly improve delivery of SN from ME into the skin has also been investigated. The obtained results showed that dissolving MNs had satisfying morphological properties and mechanical strength. This type of MNs provided comparable drug deposition in the skin as ME formulation, but also revealed an indication of percutaneous absorption of a portion of the administered drug dose. However, the penetration/permeation study results were largely influenced by experimental setup and dosing regimen. Although solid silicon MNs assisted SN dermal delivery led to increase of drug cutaneous retention (1.9-fold) under infinite dosing regimen, the synergistic action of solid MNs and ME applied under finite dosing was more pronounced in comparison with the application either of physical (dissolving MNs) or chemical enhancer (ME) alone. Namely, SN amount accumulated into the skin increased up to 4.67 and 4.37 folds in comparison with ME and dissolving MNs alone, respectively, while reaching a significant decrease in drug permeation through the skin compared to the use of dissolving MNs. Application of ME per se was the only approach that provided selective in vitro dermal drug delivery without SN permeation across the skin. However, despite both types of the used MNs lead to SN permeation in vitro, the ratio between the drug amount deposited in the skin and SN content permeated was significantly higher for the combined approach (12.05) than for dissolving MNs (2.10). Therefore, a combination of solid silicon MNs and biocompatible ME favoured more pronouncedly SN skin accumulation, which is preferable in the treatment of skin fungal infections

The influence of process parameters on the physical characteristics of ceramic microneedles, evaluated using a factorial design

The paper presents the application of the factorial Design of Experiments (DoE) to evaluate the influence of process parameters on the physical characteristics of ceramic microneedles (CMN). In this study, an understanding of the fabrication process was achieved by performing a DoE based on varying two levels of five parameters. Statistical analyses were performed on the data to investigate whether the process parameters have a significant effect on the production of a patch of 25 microneedles (MN) with sharp tips. The study showed that four out of five main effects as well as an interaction between two parameters were significant

Application of percolation threshold to disintegration and dissolution of ibuprofen tablets with different microcrystalline cellulose grades

The study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0–30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC