In Vitro Permeation Studies on Carvedilol Containing Dissolving Microarray Patches Quantified Using a Rapid and Simple HPLC-UV Analytical Method.

Analytical method validation is a vital element of drug formulation and delivery studies. Here, high-performance liquid chromatography in conjunction with UV detection (HPLC-UV) has been used to produce a straightforward, quick, yet sensitive analytical approach to quantify carvedilol (CAR). A C18 column was used to isolate the analyte from the mixture by isocratic elution with a mobile phase comprising a mixture of 0.1% v/v trifluoroacetic acid in water and acetonitrile in a ratio of 65:35 v/v at a flow rate of 0.6 mL min-1. Linearity was observed for CAR concentrations within the range of 1.5-50 µg mL-1 (R2 = 0.999) in phosphate buffer saline and within the range of 0.2-6.2 µg mL-1 (R2 = 0.9999) in methanol. The International Council on Harmonization (ICH) requirements were followed throughout the validation of the isocratic approach, rendering it specific, accurate, and precise. Moreover, robustness tests indicated that the method remained selective and specific despite small deliberate changes to environmental and operational factors. An efficient extraction procedure was also developed to extract and quantify CAR from excised neonatal porcine skin, resulting in recovery rates ranging from 95 to 97%. The methods reported here have been successfully utilised to evaluate CAR permeation, both transdermally and intradermally following application of a dissolving microarray patch (MAP) to excised neonatal porcine skin.

Development, Evaluation, and Pharmacokinetic Assessment of Polymeric Microarray Patches for Transdermal Delivery of Vancomycin Hydrochloride.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections. Vancomycin remains the first-line antibiotic treatment for MRSA-derived infections. Nevertheless, as a peptide drug, it is poorly absorbed when administered orally because of its high molecular weight and low permeability in the gastrointestinal tract and is therefore administered intravenously for the treatment of systemic diseases. In order to circumvent some of the many drawbacks associated with intravenous injection, other routes of drug delivery should be investigated. One of the strategies which has been employed to enhance transdermal drug delivery is based on microarray patches (MAPs). This work, for the first time, describes successful transdermal delivery of vancomycin hydrochloride (VCL) using dissolving MAPs (DMAPs) and hydrogel-forming MAPs (HFMAPs). VCL was formulated into DMAPs and reservoirs [film dosage forms, lyophilized wafers, and compressed tablets (CSTs)] using excipients such as poly(vinyl pyrrolidone), poly(vinyl alcohol), sodium hyaluronate, d-sorbitol, and glycerol. In this study, HFMAPs were manufactured using aqueous blends containing poly(methylvinyl ether-co-maleic acid) cross-linked by esterification with poly(ethylene glycol). The VCL-loaded CSTs (60% w/w VCL) were the most promising reservoirs to be integrated with HFMAPs based on the physicochemical evaluations performed. Both HFMAPs and DMAPs successfully delivered VCL in ex vivo studies with the percentage of drug that permeated across the neonatal porcine skin recorded at 46.39 ± 8.04 and 7.99 ± 0.98%, respectively. In in vivo studies, the area under the plasma concentration time curve from time zero to infinity (AUC0-∞) values of 162.04 ± 61.84 and 61.01 ± 28.50 µg h/mL were achieved following the application of HFMAPs and DMAPs, respectively. In comparison, the AUC0-∞ of HFMAPs was significantly greater than that of the oral administration control group, which showed an AUC0-∞ of 30.50 ± 9.18 µg h/mL (p < 0.05). This work demonstrates that transdermal delivery of VCL is feasible using DMAPs and HFMAPs and could prove effective in the treatment of infectious diseases caused by MRSA, such as skin and soft tissue infections, lymphatic-related infections, and neonatal sepsis.

Exploring Important Attributes, the Potential Use Cases and Feasibility of Introduction of Measles and Rubella Microarray Patches (MR-MAPs): Insights from Nine Countries.

Background: Microarray patches (MAPs) are innovative, needle-free vaccine delivery systems, suitable for administration by minimally trained health care workers or trained community health workers. Their introduction may transform immunization programmes, particularly for vaccines where high coverage is required for population immunity, such as measles, and where vaccine delivery is challenging, such as in low- and middle-income countries. Recognizing the need to understand how best to tailor these products to reflect country priorities, workshops on measles and rubella MAPs (MR-MAPs) were conducted in multiple regions to collect insights on needs and preferences from relevant stakeholders at country level. Methods: The CAPACITI Innovation Framework was used to structure stakeholder discussions in nine countries in the period from August 2022 to July 2023. The discussions, building on the findings from a situation analysis on the barriers related to measles and rubella vaccine delivery, followed the four-step process outlined in the framework. Results: Key barriers hindering delivery of measles and rubella vaccines across the countries were in the categories of human resource management, service delivery, and demand generation. MR-MAP attributes that stakeholders believed would reduce or eliminate these barriers included ease of preparation and administration, improved thermostability, fewer (ancillary) components, and single-dose presentation. Some attributes such as the site of administration, wear time, and storage volume could exacerbate certain barriers. Based on an understanding of key barriers, product attributes, and underserved populations, stakeholders identified several potential use cases for MR-MAPs: (i) delivery at a fixed health post, (ii) delivery through outreach sessions conducted by health workers, and (iii) administration by community health workers. To enable robust national decision making about the introduction of MR-MAPs and successful implementation, global and national evidence on feasibility and acceptability of MR-MAPs should be generated. To prepare for the potential introduction of MR-MAPs, immunization programmes should evaluate their immunization policies based on their preferred use cases and modify them if needed, for example, to enable community health workers to administer vaccines, along with making programmatic adjustments to waste management and training. Conclusions: MR-MAPs have the potential to reduce key barriers to MR delivery. Yet, their future impact depends on the ability of global stakeholders to steer the development of MR-MAPs to be responsive to country needs and preferences. The generation of evidence to enable robust decision making, timely modification of vaccine policies, and addressing programmatic considerations will be key to successful uptake.

Transdermal delivery of bisphosphonates using dissolving and hydrogel-forming microarray patches: Potential for enhanced treatment of osteoporosis.

As of 2023, more than 200 million people worldwide are living with osteoporosis. Oral bisphosphonates (BPs) are the primary treatment but can cause gastrointestinal (GI) side effects, reducing patient compliance. Microarray (MAP) technology has the potential to overcome GI irritation by facilitating the transdermal delivery of BPs. This study examines the delivery of alendronic acid (ALN) and risedronate sodium (RDN) using dissolving and hydrogel-forming MAPs for osteoporosis treatment. In vivo testing on osteoporotic female Sprague Dawley rats demonstrated the efficacy of MAPs, showing significant improvements in mean serum and bone alkaline phosphatase levels, bone volume, and porosity compared to untreated bilateral ovariectomy (OVX) controls. Specifically, MAP treatment increased mean bone volume to 55.04 ± 2.25 % versus 47.16 ± 1.71 % in OVX controls and reduced porosity to 44.30 ± 2.97 % versus 52.84 ± 1.70 % in the distal epiphysis of the femur. In the distal metaphysis, bone volume increased to 43.32 ± 3.24 % in MAP-treated rats compared to 24.31 ± 3.21 % in OVX controls, while porosity decreased to 55.39 ± 5.81 % versus 75.69 ± 3.21 % in OVX controls. This proof-of-concept study indicates that MAP technology has the potential to be a novel, patient-friendly alternative for weekly osteoporosis management.

Quercetin loaded polymeric dissolving microarray patches: fabrication, characterisation and evaluation.

Quercetin, a natural compound, shows promising potential in wound healing by reducing fibrosis, limiting scar formation, and boosting fibroblast proliferation. However, its effectiveness is hindered by poor solubility, resulting in low bioavailability and necessitating high doses for therapeutic efficacy. This study presents a novel approach, fabricating quercetin-loaded microarray patches (MAPs) using widely employed solubility enhancement strategies. Fabricated MAPs exhibited favourable mechanical strength and could be inserted into excised porcine skin to a depth of 650 µm. Furthermore, formulations containing Soluplus® significantly increased the drug loading capacity, achieving up to 2.5 mg per patch and complete dissolution within an hour of application on excised porcine skin. In vitro studies on full-thickness neonatal porcine skin demonstrated that Soluplus®-enhanced MAPs effectively delivered quercetin across various skin layers, achieving a delivery efficiency exceeding 80% over 24 h. Additionally, these prototype MAPs displayed anti-inflammatory properties and demonstrated biocompatibility with human keratinocyte skin cells. Therefore, quercetin-loaded MAPs employing Soluplus® as a solubility enhancer present a promising alternative strategy for wound healing and anti-inflammatory therapy applications.

Dissolvable microarray patches of levodopa and carbidopa for Parkinson's disease management.

Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid enzymatic degradation and gastrointestinal issues, limiting their efficacy, and necessitating alternative delivery methods. This work presents a novel strategy employing dissolving microarray patches (MAPs) loaded with carbidopa and levodopa, formulated with Tween® 80 to improve their transdermal delivery. The fabricated MAPs demonstrated an acceptable mechanical strength, resisting pressures equivalent to manual human thumb application (32 N) onto the skin. Additionally, these MAPs exhibited an insertion depth of up to 650 µm into excised neonatal porcine skin. Ex vivo dermatokinetic studies could achieve delivery efficiencies of approximately 53.35 % for levodopa and 40.14 % for carbidopa over 24 h, demonstrating their significant potential in drug delivery. Biocompatibility assessments conducted on human dermal fibroblast cells corroborated acceptable cytocompatibility, confirming the suitability of these MAPs for dermal application. In conclusion, dissolving MAPs incorporating carbidopa and levodopa represent a promising alternative for improving the therapeutic management of Parkinson's disease.

Design of a Novel Delivery Efficiency Feedback System for Biphasic Dissolving Microarray Patches Based on Poly(Lactic Acid) and Moisture-Indicating Silica.

Dissolving microarray patches (DMAPs) represent an innovative approach to minimally invasive transdermal drug delivery, demonstrating efficacy in delivering both small and large therapeutic molecules. However, concerns raised in end-user surveys have hindered their commercialization efforts. One prevalent issue highlighted in these surveys is the lack of clear indicators for successful patch insertion and removal time. To address this challenge, a color-change-based feedback system is devised, which confirms the insertion and dissolution of DMAPs, aiming to mitigate the aforementioned problems. The approach combines hydrophilic needles containing model drugs (fluorescein sodium and fluorescein isothiocyanate (FITC)-dextran) with a hydrophobic poly(lactic acid) baseplate infused with moisture-sensitive silica gel particles. The successful insertion and subsequent complete dissolution of the needle shaft are indicated by the progressive color change of crystal violet encapsulated in the silica. Notably, distinct color alterations on the baseplate, observed 30 min and 1 h after insertion for FITC-dextran and fluorescein sodium DMAPs respectively, signal the full dissolution of the needles, confirming the complete cargo delivery and enabling timely patch removal. This innovative feedback system offers a practical solution for addressing end-user concerns and may significantly contribute to the successful commercialization of DMAPs by providing a visualized drug delivery method.

MAP-box: a novel, low-cost and easy-to-fabricate 3D-printed box for the storage and transportation of dissolving microneedle array patches.

Research on the use of microarray patches (MAPs) has progressed at an unprecedented rate over the years, leading to the development of many novel drug delivery systems. As the technology approaches patients, there are several key aspects that ought to be addressed in order to facilitate the smooth translation of MAPs from bench to bedside. One integral factor includes the choice of devices and packaging for the storage of MAPs. In the current work, a slide-and-seal box, MAP-box, was developed for the storage of dissolving MAPs, using fused-deposition modelling. The device has been designed to act as a pill-box for MAPs not only to provide protection for MAPs from the environment, but also to improve patient's adherence to treatment. The overall design of the MAP-box was simple, yet offers the capability of sealing and protecting dissolving MAPs up to 30 days. Donepezil HCl was formulated into a dissolvable MAP, which was used to treat dementia related to Alzheimer's disease. This compound was used as a model formulation to evaluate the utility of the 3D printed MAP-box when placed under three storage conditions: 5 °C and ambient humidity, 25 °C and 65% relative humidity and 40 °C and 75% relative humidity. It was shown that the slide-and-seal box was able to confer protection to MAPs for up to 30 days under accelerated stability study conditions as the drug loading, mechanical properties and insertion properties of MAPs remained unaffected when compared to the unpackaged MAPs stored under these same parameters. These preliminary data provide evidence that the MAP-box prototype may be of great utility for the storage of single or multiple MAPs. Nevertheless, future work will be needed to evaluate their patient usability and its application to different types of MAP systems to fully validate the overall robustness of the prototype.

Novel lipid nanovesicle-loaded dissolving microarray patches for fenretinide in breast cancer chemoprevention.

The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 µg/patch) and enhanced skin permeation of FENR (up to 40 µg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 µg/g on day 1 to <0.3 µg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients' needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.

A review of potential use cases for measles-rubella, measles-mumps-rubella, and typhoid-conjugate vaccines presented on microarray patches.

As an innovative vaccine delivery technology, vaccine microarray patches could have a meaningful impact on routine immunization coverage in low- and middle-income countries, and vaccine deployment during epidemics and pandemics. This review of the potential use cases for a subset of vaccine microarray patches in various stages of clinical development, including measles-rubella, measles-mumps-rubella, and typhoid conjugate, highlights the breadth of their applicability to support immunization service delivery and their potential scope of utilization within national immunization programs. Definition and assessment of the use cases for this novel vaccine presentation provide important insights for vaccine developers and policymakers into the strengths of the public health and commercial value propositions, and the preparatory requirements for public health systems for the future rollout of vaccine microarray patches. An in-depth understanding of use cases for vaccine microarray patches serves as a foundational input to overcoming the remaining technical, regulatory, and financial challenges. Additional efforts will help to realize the potential of vaccine microarray patches as part of the global effort to improve the coverage and equity of national immunization programs.

Tip loaded cyclodextrin-carvedilol complexes microarray patches.

Carvedilol, a ß-blocker prescribed for chronic heart failure, suffers from poor bioavailability and rapid first pass metabolism when administered orally. Herein, we present the development of tip microarray patches (MAPs) composed of ternary cyclodextrin (CD) complexes of carvedilol for transdermal delivery. The ternary complex with hydroxypropyl γ-cyclodextrin (HPγCD) and poly(vinyl pyrrolidone) (PVP) reduced the crystallinity of carvedilol, as evidenced by DSC, XRD, NMR, and SEM analysis. MAPs were fabricated using a two-step process with the ternary complex as the needle layer. The resulting MAPs were capable of breaching ex vivo neonatal porcine skin to a depth ≈600 µm with minimal impact to needle height. Upon insertion, the needle dissolved within 2 h, leading to the transdermal delivery of carvedilol. The MAPs displayed minimal toxicity and acceptable biocompatibility in cell assays. In rats, MAPs achieved significantly higher AUC levels of carvedilol than oral administration, with a delayed Tmax and sustained plasma levels over several days. These findings suggest that the carvedilol-loaded dissolving MAPs have the potential to revolutionise the treatment of chronic heart failure.

Primaquine and chloroquine nano-sized solid dispersion-loaded dissolving microarray patches for the improved treatment of malaria caused by Plasmodium vivax.

Malaria is a global parasitic infection that leads to substantial illness and death. The most commonly-used drugs for treatment of malaria vivax are primaquine and chloroquine, but they have limitations, such as poor adherence due to frequent oral administration and gastrointestinal side effects. To overcome these limitations, we have developed nano-sized solid dispersion-based dissolving microarray patches (MAPs) for the intradermal delivery of these drugs. In vitro testing showed that these systems can deliver to skin and receiver compartment up to ≈60% of the payload for CQ-based dissolving MAPs and a total of ≈42% of drug loading for PQ-based dissolving MAPs. MAPs also displayed acceptable biocompatibility in cell tests. Pharmacokinetic studies in rats showed that dissolving MAPs could deliver sustained plasma levels of both PQ and CQ for over 7 days. Efficacy studies in a murine model for malaria showed that mice treated with PQ-MAPs and CQ-MAPs had reduced parasitaemia by up to 99.2%. This pharmaceutical approach may revolutionise malaria vivax treatment, especially in developing countries where the disease is endemic. The development of these dissolving MAPs may overcome issues associated with current pharmacotherapy and improve patient outcomes.

Exploring potential applications of measles and rubella microarray patches (MR-MAPs): use case identification.

Introduction: Innovative vaccine products will be critical in helping to address the existing implementation barriers that have prevented the achievement of the measles and rubella (MR) vaccine coverage targets. Overcoming those barriers will be necessary to achieve the "Immunization Agenda 2030" goals. Microarray patches (MAPs), an innovative needle-free delivery device currently in clinical development, can be a potential game changer in this respect and contribute to the equitable delivery of vaccines in low- and middle-income countries and pandemic preparedness and response. Developing in-depth knowledge of the most desired and impactful uses of MRMAPs can prove critical to identifying the critical attributes of the target product profile, informing policy and adoption decisions, and helping to evaluate the potential public health and economic value of this technology. The first step in this process is the definition of the potential use cases for MR-MAPs, i.e., where and how this product is most likely to be used within the immunization programme. Methods: By applying a design-based user-centric approach, we implemented a three-step process, including a desk review, a survey, and interviews, to define the most relevant use cases for MR MAPS. Results: Six use cases have been identified as relevant across all different countries and immunization programme designs and validated by experts. Discussion: The identified use cases have already informed the demand estimate for MR-MAPs and provided the foundation for developing an initial full vaccine value assessment. We believe that, in the future, they will be highly valuable in ensuring that the roll-out of this promising innovation is designed in a way that maximizes the impact, particularly in populations and countries that are most in need.

A five-day treatment course of zanamivir for the flu with a single, self-administered, painless microneedle array patch: Revolutionizing delivery of poorly membrane-permeable therapeutics.

Seasonal influenza virus infections cause a substantial number of deaths each year. While zanamivir (ZAN) is efficacious against oseltamivir-resistant influenza strains, the efficacy of the drug is limited by its route of administration, oral inhalation. Herein, we present the development of a hydrogel-forming microneedle array (MA) in combination with ZAN reservoirs for treating seasonal influenza. The MA was fabricated from Gantrez® S-97 crosslinked with PEG 10,000. Various reservoir formulations included ZAN hydrate, ZAN hydrochloric acid (HCl), CarraDres™, gelatin, trehalose, and/or alginate. In vitro permeation studies with a lyophilized reservoir consisting of ZAN HCl, gelatin, and trehalose resulted in rapid and high delivery of up to 33 mg of ZAN across the skin with delivery efficiency of up to ≈75% by 24 h. Pharmacokinetics studies in rats and pigs demonstrated that a single administration of a MA in combination with a CarraDres™ ZAN HCl reservoir offered a simple and minimally invasive delivery of ZAN into the systemic circulation. In pigs, efficacious plasma and lung steady-state levels of ∼120 ng/mL were reached within 2 h and sustained between 50 and 250 ng/mL over 5 days. MA-enabled delivery of ZAN could enable a larger number of patients to be reached during an influenza outbreak.

Fabrication and characterisation of poly(sulfonated) and poly(sulfonic acid) dissolving microneedles for delivery of antibiotic and antifungal agents.

Skin and soft tissue infections (SSTIs) arise from microbial ingress into the skin. In this study, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), which has been reported to exhibit antimicrobial properties was synthesised for the manufacture of microarray patches (MAPs). The free acid and sodium salt of polyAMPS with controlled molar masses and narrow dispersity were synthesised via reversible addition - fragmentation chain-transfer (RAFT) polymerisation reaction with a monomer conversion of over 99%, as determined by 1H NMR. The polymers were shown to be biocompatible when evaluated using a fibroblast dermal cell line while agar plating assay using cultures of C. albican demonstrated that the acid form of polyAMPS exhibited antimicrobial inhibition, which is potentiated in the presence of antimicrobial agents. The synthesised polymers were then used to fabricate dissolving MAPs, which were loaded with either ITRA or levofloxacin (LEV). The MAPs displayed acceptable mechanical resistance and punctured ex vivo skin to a depth of 600 µm. Skin deposition studies revealed that the MAPs were able to administer up to âˆ¼ 1.9 mg of LEV (delivery efficiency: 94.7%) and âˆ¼ 0.2 mg of ITRA (delivery efficiency: 45.9%), respectively. Collectively, the synthesis and development of this novel pharmaceutical system may offer a strategy to manage SSTIs.

Accelerating the development of vaccine microarray patches for epidemic response and equitable immunization coverage requires investment in microarray patch manufacturing facilities.

INTRODUCTION: There is a need for investment in manufacturing for vaccine microarray patches (vMAPs) to accelerate vMAP development and access. vMAPs could transform vaccines deployment and reach to everyone, everywhere. AREAS COVERED: We outline vMAPs' potential benefits for epidemic preparedness and for outreach in low- and lower-middle-income countries (LMICs), share lessons learned from pandemic response, and highlight that investment in manufacturing-at-risk could accelerate vMAP development. EXPERT OPINION: Pilot manufacturing capabilities are needed to produce clinical trial material and enable emergency response. Funding vMAP manufacturing scale-up in parallel to clinical proof-of-concept studies could accelerate vMAP approval and availability. Incentives could mitigate the risks of establishing multi-vMAP manufacturing facilities early.

Accelerating the Development of Measles and Rubella Microarray Patches to Eliminate Measles and Rubella: Recent Progress, Remaining Challenges.

Measles and rubella microarray patches (MR-MAPs) are critical in achieving measles and rubella eradication, a goal highly unlikely to meet with current vaccines presentations. With low commercial incentive to MAP developers, limited and uncertain funding, the need for investment in a novel manufacturing facility, and remaining questions about the source of antigen, product demand, and regulatory pathway, MR-MAPs are unlikely to be prequalified by WHO and ready for use before 2033. This article describes the current progress of MR-MAPs, highlights challenges and opportunities pertinent to MR-MAPs manufacturing, regulatory approval, creating demand, and timelines to licensure. It also describes activities that are being undertaken by multiple partners to incentivise investment in and accelerate the development of MR-MAPs.

Enhancing the Transdermal Delivery of 'Next Generation' Variable New Antigen Receptors Using Microarray Patch Technology: a Proof-of-Concept Study.

Heavy chain only binding proteins, such as variable new antigen receptors (VNARs), have emerged as an alternative to the highly successful therapeutic monoclonal antibodies (mAb). Owing to their small size (∼ 11 kDa) and single chain only architecture, they are amenable to modular reformatting and can be produced using inexpensive expression systems. Furthermore, due to their low molecular weight (MW) and high stability, they may be suitable for alternative delivery strategies, such as microarray array patches (MAPs). In this study, the transdermal delivery of ELN22-104, a multivalent anti-hTNF-α VNAR, was examined using both dissolving and hydrogel-forming MAPs. For dissolving MAPs, the cumulative in vitro permeation of ELN22-104 reached a plateau after 2 h (12.24 ± 0.17 µg). This could be important for bolus dosing. Assessing two hydrogel-forming MAPs in vitro, PVP/PVA hydrogel-forming MAPs delivered significantly higher drug doses when compared to 'super swelling' MAPs, equivalent to 43.13 ± 10.36 µg and 23.13 ± 5.66 µg, respectively (p < 0.05). Consequently, this study has proven that by modifying the MAP system, the transdermal delivery of a VNAR across the skin can be enhanced. Furthermore, this proof-of-concept study has shown that transdermal delivery of 'next generation' biotherapeutics is achievable using MAP technology.

Metronidazole nanosuspension loaded dissolving microarray patches: An engineered composite pharmaceutical system for the treatment of skin and soft tissue infection.

Bacteroides fragilis is one of the most common causative group of microorganisms that is associated with skin and soft tissue infections (SSTI). Metronidazole (MTZ) is the drug of choice used in the treatment of SSTI caused by the bacterium. However, owing to its physiochemical properties, MTZ have limited skin permeation, which render the drug unsuitable for the treatment of deep-rooted SSTIs. One strategy to overcome this limitation is to reformulate MTZ into nanosuspension which will then be loaded into dissolving microarray patches (MAPs) for the treatment of SSTIs caused by B. fragilis. Herein, we report for the first time on the preparation and optimisation of MAP loaded with MTZ nanosuspension (MTZ-NS). After screening a range of polymeric surfactants, we identified that Soluplus® resulted in the formation of MTZ-NS with the smallest particle size (115 nm) and a narrow PDI of 0.27. Next, the MTZ-NS was further optimised using a design of experiments (DoE) approach. The optimised MTZ-NS was then loaded into dissolving MAPs with varying MTZ-NS content. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell proliferation assays along with LIVE/DEAD™ staining on the 3T3L1 cell line showed that the MTZ-NS loaded dissolving MAPs displayed minimal toxicity and acceptable biocompatibility. In vitro dermatokinetic studies showed that the MTZ-NS loaded MAPs were able to deliver the nitroimidazole antibiotic across all strata of the skin resulting in a delivery efficiency of 95 % after a 24-hour permeation study. Lastly, agar plating assay using bacterial cultures of B. fragilis demonstrated that MTZ-NS loaded MAP resulted in complete bacterial inhibition in the entire plate relative to the control group. Should this formulation be translated into clinical practice, this pharmaceutical approach may provide a minimally invasive strategy to treat SSTIs caused by B. fragilis.