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.

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.

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.

Hollow microneedles: A perspective in biomedical applications.

Microneedles (MN) have the potential to become a highly progressive device for both drug delivery and monitoring purposes as they penetrate the skin and pierce the stratum corneum barrier, allowing the delivery of drugs in the viable skin layers and the extraction of body fluids. Despite the many years of research and the different types of MN developed, only hollow MN have reached the pharmaceutical market under the path of medical devices. Therefore, this review focuses on hollow MN, materials and methods for their fabrication as well as their application in drug delivery, vaccine delivery and monitoring purposes. Furthermore, novel approaches for the fabrication of hollow MN are included as well as prospects of microneedle-based products on the market.

Inclusion Complexes of Rifampicin with Native and Derivatized Cyclodextrins: In Silico Modeling, Formulation, and Characterization.

Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (ßCD, hydroxypropyl-ßCD, γCD, hydroxypropyl-γCD) in aqueous solutions at different pH values was investigated to assess the interactions between RIF and cyclodextrins (CDs). Molecular modeling was performed to determine the possible interactions between RIF and CDs at several pH values. The inclusion complexes were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, and scanning electron microscopy. Moreover, this study evaluated the dissolution profile and antibacterial activity of the formed complexes. Phase solubility analysis suggested the formation of RIF-CD affirmed 1:1 stoichiometry at all pH values (except RIF-ßCD at pH 4.0 and both ßCD and γCD at pH 9.0). The inclusion complexation of RIF with CD successfully increased the percentage of RIF released in in vitro studies. The inclusion complexes of RIF exhibited more than 60% of RIF released in 2 h which was significantly higher (p < 0.05) than release of pure RIF, which was only less than 10%. Antibacterial activity of RIF-CD complexes (measured by the minimum inhibitory concentration of RIF against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) was lower for both RIF-ßCD and RIF-HPγCD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both ßCD and γCD can be used to enhance the solubility of RIF and thus, improve the effectivity of RIF by decreasing the required daily dose of RIF for the treatment of bacterial infections.

Enhancing intradermal delivery of tofacitinib citrate: Comparison between powder-loaded hollow microneedle arrays and dissolving microneedle arrays.

Autoimmune-mediated inflammatory skin diseases, such as psoriasis, alopecia areata, and vitiligo, have been reported as the 4th leading cause of nonfatal disease burden worldwide. This is mainly related to the poor quality of life experienced by these patients. Although topical and systemic steroids represent the most common treatment, the variability in success rates and side effects often lead to treatment discontinuation. Recent off-label clinical studies using oral Janus Kinase (JAK) inhibitors (e.g., ruxolitinib, tofacitinib, baraticinib) have shown promising results. However, frequent side effects, such as infections and blood clots have been reported. Therefore, the aim of this research was to enhance the intradermal delivery of tofacitinib citrate with MN arrays. Using crosslinked hydrogels containing modifying agents (urea, sorbitol and sodium chloride), hollow MN arrays were fabricated and then loaded with tofacitinib citrate. Their efficiency in intradermal delivery of tofacitinib was compared with dissolving MN arrays and a control (Aqueous cream BP), using neonatal porcine skin. Despite the fact that the hydrogel was only present on the outer surface, hollow MN arrays showed comparable resistance to compression values and insertion capabilities to dissolving MN arrays. Although hollow MN arrays containing NaCl in the formulation led to slightly higher depositions of tofacitinib in epidermis and dermis of neonatal porcine skin when compared to a control cream, dissolving MN arrays showed superiority in terms of tofacitinib deposition in the dermis. Indeed, at 24 h of the study, control cream and dissolving MN arrays delivered 143.98 ug/cm2 and 835 ug/cm2 of drug in the dermis, respectively, confirming the enhanced intradermal drug delivery capacity of MN arrays and their potential for treatment of autoimmune skin diseases.

Versatility of hydrogel-forming microneedles in in vitro transdermal delivery of tuberculosis drugs.

Current therapy of tuberculosis (TB) has several limitations, such as risk of liver injury and intestinal dysbiosis due to frequent oral administration of antibiotics. Transdermal administration could be used to improve antibiotic delivery for treatment of Mycobacterium tuberculosis infection. Therefore, we developed a novel approach, using hydrogel-forming microneedle (MN) arrays to transdermally deliver TB drugs, namely rifampicin, isoniazid, pyrazinamide and ethambutol, which have different physicochemical properties. These drugs were individually prepared into three types of drug reservoirs, including lyophilised tablets, directly compressed tablets and poly(ethylene glycol) tablets. Formulations of each drug reservoir type were optimised to achieve a rapidly dissolving tablet, and further integrated with hydrogel-forming MN arrays for in vitro permeation studies. Three types of hydrogel formulation were manufactured using different type of polymers and crosslinking processes. These MN arrays were then evaluated in terms of swelling ability, morphology and physical properties. Results of solute diffusion studies showed that drug permeation across the swollen hydrogel membrane was affected mostly by physiochemical properties and functional groups of each drug. In the in vitro studies, the amount of permeated drug through the hydrogel-forming MN arrays across the dermatomed neonatal porcine skin was affected by the drug solubility and reservoir design. The highest permeation of rifampicin (3.64 mg) and ethambutol (46.99 mg) were achieved using MN arrays combined with the poly(ethylene glycol) tablets and directly compressed tablet, respectively. For isoniazid and pyrazinamide, the highest drug permeation was attained using lyophilised reservoir with the amount of drug delivered approximately 58.45 mg and 20.08 mg, respectively. These equate to transdermal delivery of approximately 75% (rifampicin), 79% (isoniazid), 20% (pyrazinamide) and 47% (ethambutol) of the drugs loaded into the reservoirs on average. Importantly, the results of this work have demonstrated the versatility of hydrogel formulations to deliver a TB drug regime using MN arrays. Accordingly, this is a promising approach to deliver high dose of TB drugs.

Plasmonic photothermal microneedle arrays and single needles for minimally-invasive deep in-skin hyperthermia.

We report, for the first time, crosslinked polymeric microneedle (MN) arrays and single needles (2 mm and 4.5 mm length) coated with gold nanorods (GnRs) to induce deep hyperthermia in a 3 mm-thickness skin model upon near infrared (NIR) laser irradiation. Using excised neonatal porcine skin as tissue model, it was seen that insertion capabilities of single prototypes were not affected by the coating, as around 80% of their length was inserted before and after coating. Insertion of MN arrays dropped from 74% to 55%, which could be attributed to a less sharp structure after the coating process. Nonetheless, GnRs-coated MN arrays achieved the highest increase in temperature in the skin model: over 15 °C after only 15 s of NIR laser irradiation (808 nm, 2 W cm-2). Surprisingly, removal of MN arrays after irradiation left no detectable polymer or plasmonic material behind, confirming the enhanced safety and minimally-invasive potential of this device for future biomedical applications of deep in skin hyperthermia.

Coated polymeric needles for rapid and deep intradermal delivery.

Two groups of single polymeric needles (crosslinked Gantrez®S-97 and poly(ethylene glycol)) of different lengths (2 mm and 4.5 mm) with defined base widths were fabricated and tested in terms of their mechanical strength and insertion abilities using two skin models (Parafilm® and porcine skin). For the shorter needles, application of an axial force (32 N) resulted in a height reduction of approximately 80%. Nonetheless, around 80% of total needle length was successfully inserted in both skin models. Optical coherence tomography showed that base width highly impacted insertion capabilities of the longer needles as only the thicker one (0.922 mm width at base) inserted into porcine skin. Additionally, needles were coated with rhodamine B and inserted into porcine skin. In comparison to a control, penetration depth of the model drug increased 2-fold for short and 4.5-fold for long needles, respectively. Moreover, quantification across skin sections showed that shorter needles delivered 10 µg of the compound in a depth of 1.5-2.0 mm while long needles were capable of delivering 5 µg into even deeper skin layers (2.0-3.0 mm), confirming the potential of coated polymeric needles for rapid and deep intradermal delivery.

Potential of Polymeric Films Loaded with Gold Nanorods for Local Hyperthermia Applications.

Current strategies for the treatment of superficial non-melanoma skin cancer (NMSC) lesions include topical imoquimod, 5-fluorouracil, and photodynamic therapy. Although these treatments are effective, burning pain, blistering, and dermatitis have been reported as frequent side effects, making these therapies far from ideal. Plasmonic materials have been investigated for the induction of hyperthermia and use in cancer treatment. In this sense, the effectiveness of intratumorally and systemically injected gold nanorods (GnRs) in inducing cancer cell death upon near-infrared light irradiation has been confirmed. However, the in vivo long-term toxicity of these particles has not yet been fully documented. In the present manuscript, GnRs were included in a crosslinked polymeric film, evaluating their mechanical, swelling, and adhesion properties; moreover, their ability to heat up neonatal porcine skin (such as a skin model) upon irradiation was tested. Inclusion of GnRs into the films did not affect mechanical or swelling properties. GnRs were not released after film swelling, as they remained entrapped in the polymeric network; moreover, films did not adhere to porcine skin, altogether showing the enhanced biocompatibility of the material. GnR-loaded films were able to heat up the skin model over 40 °C, confirming the potential of this system for non-invasive local hyperthermia applications.