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.

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.

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.

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.

Microarray patches for managing infections at a global scale.

Since the first patent for micro array patches (MAPs) was filed in the 1970s, research on utilising MAPs as a drug delivery system has progressed significantly, evidenced by the transition from the simple 'poke and patch' of solid MAPs to the development of bio responsive systems such as hydrogel-forming and dissolving MAPs. In addition to the extensive research on MAPs for improving transdermal drug delivery, there is a growing interest in using these devices to manage infectious diseases. This is due to the minimally invasive nature of this drug delivery platform which enable patients to self-administer therapeutics without the aid of healthcare professionals. This review aims to provide a critical analysis on the potential utility of MAPs in managing infectious diseases which are still endemic at a global scale. The range of diseases covered in this review include tuberculosis, skin infections, malaria, methicillin-resistant Staphylococcus aureus infections and Covid-19. These diseases exert a considerable socioeconomic burden at a global scale with their impact magnified in low- and middle-income countries (LMICs). Due to the painless and minimally invasive nature of MAPs application, this technology also provides an efficient solution not only for the delivery of therapeutics but also for the administration of vaccine and prophylactic agents that could be used in preventing the spread and outbreak of emerging infections. Furthermore, the ability of MAPs to sample and collect dermal interstitial fluid that is rich in disease-related biomarkers could also open the avenue for MAPs to be utilised as a minimally invasive biosensor for the diagnosis of infectious diseases. The efficacy of MAPs along with the current limitations of such strategies to prevent and treat these infections will be discussed. Lastly, the clinical and translational hurdles associated with MAP technologies will also be critically discussed.

Fluorescence-Coupled Techniques for Determining Rose Bengal in Dermatological Formulations and Their Application to Ex Vivo Skin Deposition Studies.

Rose Bengal (RB) is a fluorescent dye with several potential biomedical applications, particularly in dermatology. Due to RB's poor physicochemical properties, several advanced delivery systems have been developed as a potential tool to promote its permeation across the skin. Nevertheless, no validated quantitative method to analyse RB within the skin is described in the literature. Considering RB exhibits a conjugated ring system, the current investigation proposes fluorescence-based techniques beneficial for qualitatively and quantitatively determining RB delivered to the skin. Notably, the development and validation of a fluorescence-coupled HPLC method to quantify RB within the skin matrix are herein described for the first time. The method was validated based on the ICH, FDA and EMA guidelines, and the validated parameters included specificity, linearity, LOD, LLOQ, accuracy and precision, and carry-over and dilution integrity. Finally, the method was applied to evaluate RB's ex vivo permeation and deposition profiles when loaded into dermatological formulations. Concerning qualitative determination, multiphoton microscopy was used to track the RB distribution within the skin strata, and fluorescence emission spectra were investigated to evaluate RB's behaviour when interacting with different environments. The analytical method proved specific, precise, accurate and sensitive to analyse RB in the skin. In addition, qualitative side-analytical techniques were revealed to play an essential role in evaluating the performance of RB's dermatological formulation.

Engineering and Development of a Tissue Model for the Evaluation of Microneedle Penetration Ability, Drug Diffusion, Photothermal Activity, and Ultrasound Imaging: A Promising Surrogate to Ex Vivo and In Vivo Tissues.

Driven by regulatory authorities and the ever-growing demands from industry, various artificial tissue models have been developed. Nevertheless, there is no model to date that is capable of mimicking the biomechanical properties of the skin whilst exhibiting the hydrophilicity/hydrophobicity properties of the skin layers. As a proof-of-concept study, tissue surrogates based on gel and silicone are fabricated for the evaluation of microneedle penetration, drug diffusion, photothermal activity, and ultrasound bioimaging. The silicone layer aims to imitate the stratum corneum while the gel layer aims to mimic the water-rich viable epidermis and dermis present in in vivo tissues. The diffusion of drugs across the tissue model is assessed, and the results reveal that the proposed tissue model shows similar behavior to a cancerous kidney. In place of typical in vitro aqueous solutions, this model can also be employed for evaluating the photoactivity of photothermal agents since the tissue model shows a similar heating profile to skin of mice when irradiated with near-infrared laser. In addition, the designed tissue model exhibits promising results for biomedical applications in optical coherence tomography and ultrasound imaging. Such a tissue model paves the way to reduce the use of animals testing in research whilst obviating ethical concerns.

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.

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.

Soluplus®-based dissolving microarray patches loaded with colchicine: towards a minimally invasive treatment and management of gout.

Considered as one of the most common inflammatory arthritis, gout is characterised by a sudden onset of severe joint pain. As the first-line drug of choice used in treating acute gout, colchicine (CLC) is hindered by poor gastrointestinal permeability as well as unfavourable gastrointestinal side effects. Herein, we present, for the first time, the preparation of microarray array patches (MAPs) made of a polymeric solubiliser, Soluplus®, loaded with CLC for its systemic delivery. The fabricated MAPs displayed acceptable mechanical properties and were capable of being inserted into the skin to a depth of ≈500 µm in full thickness ex vivo neonatal porcine skin, as evidenced by optical coherence tomography. In vitro dermatokinetic studies utilising full thickness neonatal porcine skin demonstrated that the CLC-loaded MAPs delivered CLC across all skin strata, resulting in a delivery efficiency of 73% after 24 hours. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell proliferation assays along with LIVE/DEAD™ staining on the 3T3-L1 cell line showed that the MAP formulation displayed minimal toxicity, with acceptable biocompatibility. Lastly, the anti-inflammatory properties of the formulation were evaluated using a THP-1 macrophage cell line. It was shown that treatment of THP-1 macrophages that are exposed to lipopolysaccharide (LPS) with CLC-loaded MAPs caused a significant (p < 0.05) reduction of TNF-α production, a pro-inflammatory cytokine typically associated with the early onset of acute gout. Accordingly, CLC-loaded MAPs could represent a new minimally-invasive alternative strategy for management of acute gout.

Elucidating the Impact of Surfactants on the Performance of Dissolving Microneedle Array Patches.

The need for biocompatible polymers capable of dissolving in the skin while exhibiting reasonable mechanical features and delivery efficiency limits the range of materials that could be utilized in fabricating dissolving microneedle array patches (MAPs). The incorporation of additives, such as surfactants, during microneedle fabrication might be an alternative solution to overcome the limited range of materials used in fabricating dissolving MAPs. However, there is a lacuna in the knowledge on the effect of surfactants on the manufacture and performance of dissolving MAPs. The current study explores the role of surfactants in the manufacture and performance of dissolving MAPs fabricated from poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) loaded with the model drugs, ibuprofen sodium and itraconazole. Three nonionic surfactants, Lutrol F108, Pluronic F88, and Tween 80, in solutions at varying concentrations (0.5, 1.0, and 2.0% w/w) were loaded into these dissolving MAPs. It was discovered that all of the dissolving MAPs that incorporated surfactant displayed a lower reduction in the microneedle height (≈10%) relative to the control formulation (≈20%) when subjected to a compressive force of 32 N. In addition, the incorporation of surfactants in some instances enhanced the insertion profile of these polymeric MAPs when evaluated using ex vivo neonatal porcine skin. The incorporation of surfactant into ibuprofen sodium-loaded dissolving MAPs improved the insertion depth of MAPs from 400 µm down to 600 µm. However, such enhancement was not apparent when the MAPs were loaded with the model hydrophobic drug, itraconazole. Skin deposition studies highlighted that the incorporation of surfactant enhanced the delivery efficiency of both model drugs, ibuprofen sodium and itraconazole. The incorporation of surfactant enhanced the amount of ibuprofen sodium delivered from 60.61% up to ≈75% with a majority of the drug being delivered across the skin and into the receptor compartment. On the other hand, when surfactants were added into MAPs loaded with the model hydrophobic drug itraconazole, we observed enhancement in intradermal delivery efficiency from 20% up to 30%, although this did not improve the delivery of the drug across the skin. This work highlights that the addition of nonionic surfactant is an alternative formulation strategy worth exploring to improve the performance and delivery efficiency of dissolving MAPs.

Development and characterization of a dry reservoir-hydrogel-forming microneedles composite for minimally invasive delivery of cefazolin.

Cefazolin (CFZ) is one of the most extensively used cephalosporins. This antibiotic exerts its bactericidal activity by interfering with bacterial cell wall formation, leading to bacteriolysis. CFZ is highly polar, resulting in the drug having poor oral bioavailability. Accordingly, the antibiotic is administered via intramuscular or intravenous injections, which are both painful and invasive. Due to these limitations, there is an impetus to explore alternative drug delivery platforms which offer a minimally invasive approach to delivery CFZ into and across the skin. The current work presents the development of a composite pharmaceutical system composed of hydrogel-forming microneedles (MNs) in tandem with CFZ dry reservoirs. The hydrogel system was fabricated from Gantrez® S-97 and Carbopol® 974P NF crosslinked with PEG 10,000. Swelling kinetic studies showed that the hydrogel system developed was capable of achieving 4000% swelling in PBS pH 7.4. In addition, results from a solute diffusion study showed that CFZ was able to achieve ≈100% cumulative permeation across the swollen hydrogel film. When formulated into MNs, the hydrogel system was capable of breaching the stratum corneum, resulting in intradermal insertion of the hydrogel forming MNs into ex vivo neonatal porcine skin, as evidenced from optical coherence tomography. In addition, two different CFZ loaded dry reservoirs consisting of directly compressed tablets (DCT) and lyophilised (LYO) wafers were formulated and characterised. These dry reservoir systems showed fast dissolution, dissolving in phosphate buffer saline pH 7.4 in less than one minute. In vitro permeation studies, using full thickness ex vivo neonatal porcine skin were conducted. HPLC analysis demonstrated the dry reservoir combination consisting of DCT with hydrogel-forming MNs was capable of achieving up to 80 µg CFZ delivery into the epidermis within 2 h of application. In addition, DCT reservoir coupled with hydrogel-forming MNs were able to deliver CFZ up to 1.8 mg into and across the skin at 24 h. Should this system be translated into clinical practice, it may provide a minimally invasive strategy to administer CFZ for the treatment of infections such as septic arthritis, osteomyelitis and cellulitis.

Synthesis and characterization of sorbitol laced hydrogel-forming microneedles for therapeutic drug monitoring.

The dermal interstitial fluid (ISF) is rich in biomarkers that are of great heuristic value for disease diagnosis and therapeutic drug monitoring. Nevertheless, the current strategies for sampling dermal ISF are both technical and invasive, limiting the potential utility of ISF for clinical medicine and research purposes. In the current work, we present, for the first time, the development, characterization, and evaluation of a novel sorbitol-laced hydrogel-forming microneedles (Sor-Hyd-MN) for sampling dermal ISF. The hydrogel system is fabricated from sorbitol and PEG 10,000 crosslinked with Gantrez® S-97 via esterification in a solvent-free manner. The sorbitol-laced hydrogel rapidly absorbs fluid when placed in aqueous media, reaching a total rise in the mass of 685% relative to the control hydrogel that only reached 436% within 15 mins. When formulated into MNs, the Sor-Hyd-MN exhibited significantly superior (p < 0.001) mechanical properties as evidenced by the minimal MN height reduction (0.9%) relative to the control-MN (3.9%) and Man-Hyd-MN (28.5%) when subjected to a compressive force of 32 N, an analog of patients' thumb pressure. The skin insertion capability of the Sor-Hyd-MN and the control-MN formulation was demonstrated using the in vitro skin simulant, Parafilm® M, and ex vivo neonatal porcine skin. When inserted into ex vivo neonatal porcine skin, the Sor-Hyd-MN showed rapid imbibement of dermal ISF within 15 mins, evidenced via the formation of swollen microchannels, which was 1.2-folds wider than the control formulation. In addition, we also demonstrated for the first time that incorporating sorbitol into Gantrez® S-97 hydrogel-forming MN improved the utility of this formulation in sampling dermal ISF. This was shown from the capability of the Sor-Hyd-MN in extracting the model compounds, isoniazid and theophylline, present within the ISF of ex vivo porcine skin. The Sor-Hyd-MN exhibited an extraction efficiency of 52.4% for isoniazid and 54.4% for theophylline which was significantly higher (p < 0.05) relative to the control formulation in a simple and straightforward manner. This work illustrates that incorporating a hyperosmolyte, such as sorbitol, can further enhance the potential utility of hydrogel-forming MN as a minimally-invasive tool for ISF sampling while providing a potential strategy to extract analytes with ease for subsequent sample analysis.