Ryan F. Donnelly’s research while affiliated with Queen's University Belfast and other places

Ascorbic acid (AA) and caffeine (CAFF) work to protect cells from ultraviolet (UV) radiation and slow down the photoaging process of the skin. However, cosmetic application of AA and CAFF is limited due to poor penetration across the skin and rapid oxidation of AA. The aim of this study was to design and evaluate the dermal delivery of dual antioxidants utilizing microneedles (MNs) loaded with AA and CAFF niosomes. The niosomal nanovesicles were prepared using the thin film method and had particle sizes ranging from 130.6–411.2 nm and a negative Zeta potential of around −35 mV. The niosomal formulation was then combined with polyvinylpyrrolidone (PVP) and polyethylene glycol 400 (PEG 400) to create an aqueous polymer solution. The best skin deposition of AA and CAFF was achieved with the formulation containing 5% PEG 400 (M3) and PVP. Furthermore, the role of AA and CAFF as antioxidants in preventing cancer formation has been well-established. Here we validated the antioxidant properties of ascorbic acid (AA) and caffeine (CAFF) in a novel niosomal formulation referred to as M3 by testing its ability to prevent H2O2-indued cell damage and apoptosis in MCF-7 breast cancer cells. Results showed that M3 was able to shield MCF-7 cells from H2O2 induced damage at concentrations below 2.1 µg/mL for AA and 1.05 µg/mL for CAFF, and also exhibited anticancer effects at higher concentrations of 210 µg/mL for AA and 105 µg/mL. The formulations were stable for two months at room temperature in terms of moisture and drug content. The use of MNs and niosomal carriers could be a promising approach for dermal delivery of hydrophilic drugs like AA and CAFF.

Eradicating HIV/AIDS by 2030 is a central goal of the World Health Organization. Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long‐acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine [AZT]) over 28 days. The formulation is a self‐assembling ultrashort d or l‐α peptide hydrogelator, namely phosphorylated (naphthalene‐2‐ly)‐acetyl‐diphenylalanine‐lysine‐tyrosine‐OH (NapFFKY[p]‐OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrates phosphatase enzyme instructed self‐assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggest hydrogels form narrow radius (≈2 nm), large length fibers closely fitting the flexible cylinder elliptical model. d‐Peptides are particularly promising for long‐acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progress under physiological conditions (37 °C, pH 7.4, H2O). Subcutaneous administration of Napffk(AZT)Y[p]G‐OH in Sprague Dawley rats demonstrate zidovudine blood plasma concentrations within the half maximal inhibitory concentration (IC50) range (30–130 ng mL⁻¹) for 35 days. This work is a proof‐of‐concept for the development of a long‐acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society.

Hydrogel-forming microarray patches (HF-MAPs) are used to circumvent the skin barrier and facilitate the noninvasive transdermal delivery of many hydrophilic substances. However, their use in the delivery of hydrophobic agents is a challenging task. This work demonstrates, for the first time, the successful transdermal long-acting delivery of the hydrophobic atorvastatin (ATR) via HF-MAPs using poly(ethylene)glycol (PEG)-based solid dispersion (SD) reservoirs. PEG-based SDs of ATR were able to completely dissolve within 90 s in vitro. Ex vivo results showed that 2.05 ± 0.23 mg of ATR/0.5 cm2 patch was delivered to the receiver compartment of Franz cells after 24 h. The in vivo study, conducted using Sprague Dawley rats, proved the versatility of HF-MAPs in delivering and maintaining therapeutically-relevant concentrations (> 20 ng·mL-1) of ATR over 14 days, following a single HF-MAP application for 24 h. The long-acting delivery of ATR suggests the successful formation of hydrophobic microdepots within the skin, allowing for the subsequent sustained delivery as they gradually dissolve over time, as shown in this work. When compared to the oral group, the use of the HF-MAP formulation improved the overall pharmacokinetics profile of ATR in plasma, where significantly higher AUC values resulting in ~10-fold higher systemic exposure levels were obtained. This novel system offers a promising, minimally-invasive, long-acting alternative delivery system for ATR that is capable of enhancing patient compliance and therapeutic outcomes. It also proposes a unique promising platform for the long-acting transdermal delivery of other hydrophobic agents.

Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is intended as a local anesthetic, so the level of LiH in systemic circulation should be minimized to avoid toxicity and unwanted side effects such as hypotension and bradycardia. This study aimed to formulate and evaluate LiH-loaded dissolving microneedles (DMNs) with different polymer bases. Moreover, an in vitro permeation study using Franz diffusion cells and in vivo study were also performed. LiH-loaded DMNs were prepared using polymer groups of poly (vinyl pyrrolidone) (PVP-K30) and hyaluronic acid (HA). DMNs were created using the micro-molding method with centrifugation. The formulations selected based on the evaluation were F3 (HA 10%) and F5 (PVP-K30 25%). Based on the in vitro permeation study, the amount of drug permeated and deposited in the skin at F3 (HA 10%) was 247.1 ± 41.85 and 98.35 ± 12.86 μg, respectively. On the other hand, the amount of drug permeated and deposited in the skin at F5 (PVP-K30 25%) was 277.7 ± 55.88 and 59.46 ± 9.25 μg, respectively. Our in vivo drug-permeation study showed that only one rat from the PVP-K30 polymer group—with a concentration of 150.32 ng/mL—was detected on rat plasma. Therefore, LiH can be formulated into a DMN and can be deposited in the skin with a safe concentration of the drug permeating into systemic circulation.

Bacterial vaginosis (BV) is an abnormal condition caused by the change of microbiota in the vagina. One of the most common bacteria found in the case of BV is Gardnerella vaginalis, which is categorised as anaerobic facultative bacteria. Currently, the available treatment for BV is the use of antibiotics, such as metronidazole (MTZ), in topical and oral dosage forms. The limitation of the currently available treatment is that multiple administration is required and thus, the patient needs to apply the drug frequently to maintain the drug efficacy. To address these limitations, this research proposed prolonged delivery of MTZ in the form of intravaginal devices made from biodegradable and biocompatible polymers. Semi-solid extrusion (SSE) 3D printing was used to prepare the intravaginal devices. The ratio of high and low molecular weight poly(caprolactone) (PCL) was varied to evaluate the effect of polymer composition on the drug release. The versatility of SSE 3D printer was used to print the intravaginal devices into two different shapes (meshes and discs) and containing two different polymer layers made from PCL and a copolymer of methyl vinyl ether and maleic anhydride (Gantrez™-AN119), which provided mucoadhesive properties. Indeed, this layer made from Gantrez™-AN119 increased ca. 5 times the mucoadhesive properties of the final 3D-printed devices (from 0.52 to 2.57 N). Furthermore, MTZ was homogenously dispersed within the polymer matrix as evidenced by scanning electron microscopy analysis. Additionally, in vitro drug release, and antibacterial activity of the MTZ-loaded intravaginal devices were evaluated. Disc formulations were able to sustain the release of MTZ for 72 h for formulations containing 70/30 and 60/40 ratio of high molecular weight/low molecular weight PCL. On the other hand, the discs containing a 50/50 ratio of high molecular weight/low molecular weight PCL showed up to 9 days of release. However, no significant differences in the MTZ release from the MTZ-loaded meshes (60/40 and 50/50 ratio of high molecular weight/low molecular weight PCL) were found after 24 h. The results showed that the different ratios of high and low molecular weight PCL did not significantly affect the MTZ release. However, the shape of the devices did influence the release of MTZ, showing that larger surface area of the meshes provided a faster MTZ release. Moreover, MTZ loaded 3D-printed discs (5% w/w) were capable of inhibiting the growth of Gardnerella vaginalis. These materials showed clear antimicrobial properties, exhibiting a zone of inhibition of 19.0 ± 1.3 mm. Based on these findings, the manufactured represent a valuable alternative approach to the current available treatment, as they were able to provide sustained release of MTZ, reducing the frequency of administration and thus improving patient compliance.

Implantable drug delivery systems are an interesting alternative to conventional drug delivery systems to achieve local or systemic drug delivery. In this work, we investigated the potential of fused-deposition modelling to prepare reservoir-type implantable devices for sustained drug delivery. An antibiotic was chosen as a model molecule to evaluate the potential of this type of technology to prepare implants on-demand to provide prophylactic antimicrobial treatment after surgery. The first step was to prepare and characterize biodegradable rate-controlling porous membranes based on poly(lactic acid) (PLA) and poly(caprolactone) (PCL). These membranes were prepared using a solvent casting method. The resulting materials contained different PLA/PCL ratios. Cylindrical implants were 3D-printed vertically on top of the membranes. Tetracycline (TC) was loaded inside the implants and drug release was evaluated. The results suggested that membranes containing a PLA/PCL ratio of 50/50 provided drug release over periods of up to 25 days. On the other hand, membranes containing lower PCL content did not show a porous structure and accordingly the drug could not permeate to the same extent. The influence of different parameters on drug release was evaluated. It was established that film thickness, drug content and implant size are critical parameters as they have a direct influence on drug release kinetics. In all cases the implants were capable of providing drug release for at least 25 days. The antimicrobial properties of the implants were evaluated against E. coli and S. aureus. The resulting implants showed antimicrobial properties at day 0 and even after 21 days against both type of microorganisms. Finally, the biocompatibility of the implants was evaluated using endothelial cells. Cells exposed to implants were compared with a control group. There were no differences between both groups in terms of cell proliferation and morphology.

The ideal drug delivery system has a bioavailability comparable to parenteral dosage forms but is as convenient and easy to use for the patient as oral solid dosage forms. In recent years, there has been increased interest in transdermal drug delivery (TDD) as a non-invasive delivery approach that is generally regarded as being easy to administer to more vulnerable age groups, such as paediatric and geriatric patients, while avoiding certain bioavailability concerns that arise from oral drug delivery due to poor absorbability and metabolism concerns. However, despite its many merits, TDD remains restricted to a select few drugs. The physiology of the skin poses a barrier against the feasible delivery of many drugs, limiting its applicability to only those drugs that possess physicochemical properties allowing them to be successfully delivered transdermally. Several techniques have been developed to enhance the transdermal permeability of drugs. Both chemical (e.g., thermal and mechanical) and passive (vesicle, nanoparticle, nanoemulsion, solid dispersion, and nanocrystal) techniques have been investigated to enhance the permeability of drug substances across the skin. Furthermore, hybrid approaches combining chemical penetration enhancement technologies with physical technologies are being intensively researched to improve the skin permeation of drug substances. This review aims to summarize recent trends in TDD approaches and discuss the merits and drawbacks of the various chemical, physical, and hybrid approaches currently being investigated for improving drug permeability across the skin.

Implantable drug delivery systems offer an alternative for the treatments of long-term conditions (i.e. schizophrenia, HIV, or Parkinson’s disease among many others). The objective of the present work was to formulate implantable devices loaded with the model hydrophobic drug olanzapine (OLZ) using robocasting 3D-printing combined with a pre-formed rate controlling membrane. OLZ was selected as a model molecule due to its hydrophobic nature and because is a good example of a molecule used to treat a chronic condition schizophrenia. The resulting implants consisted of a poly(ethylene oxide) (PEO) implant coated with a poly(caprolactone) (PCL)-based membrane. The implants were loaded with 50 and 80% (w/w) of OLZ. They were prepared using an extrusion-based 3D-printer from aqueous pastes containing 36–38% (w/w) of water. The printing process was carried out at room temperature. The resulting implants were characterized by using infrared spectroscopy, scanning electron microscopy, thermal analysis, and X-ray diffraction. Crystals of OLZ were present in the implant after the printing process. In vitro release studies showed that implants containing 50% and 80% (w/w) of OLZ were capable of providing drug release for up to 190 days. On the other hand, implants containing 80% (w/w) of OLZ presented a slower release kinetics. After 190 days, total drug release was ca. 77% and ca. 64% for implants containing 50% and 80% (w/w) of OLZ, respectively. The higher PEO content within implants containing 50% (w/w) of OLZ allows a faster release as this polymer acts as a co-solvent of the drug.

Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation of complex MN prototypes with high accuracy and offers customizable MN devices with a desired shape and dimension. Moreover, 3D printing shows great potential in producing advanced transdermal drug delivery systems and medical devices by integrating MNs with a variety of technologies. This review aims to demonstrate the advantages of exploiting 3D printing technology as a new tool to microengineer MNs. Various 3D printing methods are introduced, and representative MNs manufactured by such approaches are highlighted in detail. The development of advanced MN devices is also included. Finally, clinical translation and future perspectives for the development of MNs using 3D printing are discussed.