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This research focuses on developing and characterizing islatravir-loaded dissolving microarray patches (MAPs) to provide an effective, minimally invasive treatment option for human immunodeficiency virus (HIV-1) prevention and treatment. The research involves manufacturing these MAPs using a double-casting approach, and conducting in vitro and in vivo evaluations. Results show that the MAPs have excellent needle fidelity, structural integrity, and mechanical strength. in vitro studies demonstrate that the MAPs can penetrate skin up to 580 µm and dissolve within 2 hours. Permeation studies reveal that the delivery efficiency of islatravir across the skin is around 40%. In rodent models, these dissolving MAPs sustain islatravir delivery for up to 3 months. Scaling up the MAPs and increasing drug loading produced detectable levels in minipig. Projections from animal data suggest that these dissolving MAPs can achieve effective islatravir levels for a month after a single application in humans. These findings indicate dissolving MAPs as a minimally invasive approach to sustained release of islatravir., (© 2025 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Skin and soft tissue infections (SSTIs) present significant treatment challenges. These infections often require systemic antibiotics such as vancomycin, which poses a risk for increased bacterial resistance. Topical treatments are hindered by the barrier function of the skin, and microneedles (MNs) offer a promising solution, increasing patient compliance and negating the need for traditional needles., Methods: This study focused on the use of sodium alginate MNs for vancomycin delivery directly to the site of infection via a cost-effective micromolding technique. Dissolving polymeric MNs made of sodium alginate and loaded with vancomycin were fabricated and evaluated in terms of their physical properties, delivery ability, and antimicrobial activity., Results: The MNs achieved a 378 μm depth of insertion into ex vivo skin and a 5.0 ± 0 mm zone of inhibition in agar disc diffusion assays. Furthermore, in ex vivo Franz cell experiments, the MNs delivered 34.46 ± 11.31 μg of vancomycin with around 35% efficiency, with 9.88 ± 0.57 μg deposited in the skin after 24 h., Conclusions: These findings suggest that sodium alginate MNs are a viable platform for antimicrobial agent delivery in SSTIs. Future in vivo studies are essential to confirm the safety and effectiveness of this innovative method for clinical use.

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., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Therapeutic proteins and peptides (PPTs) have become one of the most important biological molecules for the management of many common and complex diseases due to their high specificity and high bioactivity. However, these biomolecules are mainly given by the hypodermic injection, which often leads to poor patient compliance due to the invasive nature of this route of administration. The oral route has been considered the most convenient and patient-friendly route for drug delivery relative to hypodermic injections. Despite the ease and simplicity conferred by oral administration, this drug delivery route suffers rapid peptide degradation in gastric fluid and low intestinal uptake. In order to circumvent these issues, several strategies, such as enzyme inhibitors, permeation enhancers, chemical modification, mucoadhesive and stimuli-responsive polymers, and specialised particulate formulation have been developed. Such strategies are designed with the aim of protecting PPTs from the harsh gastrointestinal environment as well as providing a strategy to enhance the uptake of the therapeutic across the gastrointestinal tract. This review aims to provide an overview of the current development in enteral drug delivery strategies for PPTs. The design of these drug delivery systems in overcoming physical and chemical barriers along the gastrointestinal tract while improving oral bioavailability will be highlighted and discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Schizophrenia is a severe chronic mental illness characterised by impaired emotional and cognitive functioning. To treat this condition, antipsychotics are available in limited dosage forms, mainly oral and injectable formulations. Although injectable antipsychotics were designed to enhance adherence, they are invasive, painful and require a healthcare professional to be administered. To overcome such administration issues, extensive research has been focused on developing transdermal antipsychotic formulations. In this work, three microneedle (MN) systems were developed to deliver fluphenazine (FLU) systemically. A decanoic prodrug of FLU called fluphenazine decanoate (FLUD) was used in two of the MN formulations due to its high lipophilicity. FLU-D was loaded into dissolving MNs and nanoemulsion (NE)-loaded MNs. The parent drug FLU was loaded into poly(lactic-co-glycolic acid) (PLGA)-tipped MNs. All MN systems were characterised and evaluated in vitro and in vivo. The in vivo evaluation of the three developed MN systems showed their ability to deliver FLU into the systemic circulation, as the C max of FLU-D dissolving MNs was 36.11 ± 12.37 ng/ml. However, the C max of FLU-D NE loaded dissolving MNs was 12.92 ± 6.3 ng/ml and for FLU-PLGA tipped MNs was 21.57 ± 2.45 ng/ml. Compared to an intramuscular (IM) injection of FLU-D in sesame oil, the relative bioavailabilities were 26.96 %, 21.73 % and 42.45 % for FLU-D dissolving MNs, FLU-D NE dissolving MNs and FLU-PLGA tipped MNs, respectively. FLU plasma levels were maintained above the minimum human therapeutic limits for a week. Consequently, these various MN formulations are considered to be a viable options for the transdermal delivery of fluphenazine and its prodrug. The three MN systems developed offer patients a user-friendly, painless, and convenient long-acting delivery method for FLU. Reducing dosing frequency and using less invasive drug administration methods can enhance adherence and foster positive therapeutic outcomes. This study demonstrates the capability and adaptability of MNs technology to transport hydrophobic molecules from the skin to the systemic circulation., Competing Interests: Declaration of competing interest Ryan Donnelly is an inventor of patents that have been licenced to companies developing microneedle-based products and is a paid advisor to companies developing microneedle-based products. The resulting potential conflict of interest has been disclosed and is managed by Queen's University Belfast. The companies had no role in the design of the present studies, in the collection, analyses or interpretation of the data, in the writing of the manuscript or in the decision to publish the work. Other all authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Transdermal drug delivery is an alternative route of administration that offers avoidance of the associated drawbacks of orally and parenterally administered hydrophobics. However, owing to the extremely specific set of physicochemical characteristics required for passive transdermal drug permeation, the development of marketed transdermal products containing poorly soluble drugs has been severely limited. Microarray patches (MAPs) are a type of transdermal patch that differ from the traditional patch design due to the presence of tiny, micron-sized needles that permit enhanced drug permeation on their application surface. To date, MAPs have predominantly been used to deliver hydrophilic compounds. However, this work challenges this trend and focuses on the use of MAPs, in combination with commonly utilized solubility-enhancing techniques, to deliver the hydrophobic drug olanzapine (OLP) across the skin. Specifically, cyclodextrin (CD) complexation and particle size reduction were employed in tandem with hydrogel-forming and dissolving MAPs, respectively. In vivo experimentation using a female Sprague-Dawley rat model confirmed the successful delivery of OLP from hydrogel-forming MAPs ( C max = 611.13 ± 153.34 ng/mL, T max = 2 h) and dissolving MAPs ( C max = 690.56 ± 161.33 ng/mL, T max = 2 h) in a manner similar to that of oral therapy in terms of the rate and extent of drug absorption, as well as overall drug exposure and bioavailability. This work is the first reported use of polymeric MAPs in combination with the solubility-enhancing techniques of CD complexation and particle size reduction to successfully deliver the poorly soluble drug OLP via the transdermal route. Accordingly, this paper provides significant evidence to support an expansion of the library of molecules amenable to MAP-mediated drug delivery to include those that exhibit poor aqueous solubility.

HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood-brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less. Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a C max was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a C max was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marco Abbate reports financial support was provided by Northern Ireland Department for the Economy., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In a brachytherapy room irradiated with an Iridium-192 ( 192 Ir) source, the spatial distributions of photon dose rates were measured and calculated for the dose distribution both inside and outside the room. The spatial distributions were measured using a thermoluminescent dosimeter (LiF-100) on the surfaces of the concrete walls and barriers of the irradiation room. The calculations were performed using the particle and heavy ion transport code system (PHITS) by considering the detailed model of the brachytherapy room and the radiation source used in the measurements. The measured and calculated doses exhibited a similar distribution pattern within and outside the brachytherapy room. To reduce the edge effect at the entrance door, the addition of a 3-mm thick lead layer on the surface of the concrete wall on the left doorstop is recommended. For the 60 Co source, with the existing walls and lead door thickness, the dose at the control console and in front of the entrance maze increased by a factor of approximately 60., (© 2023. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Microneedles have the clinical advantage of being able to deliver complex drugs across the skin in a convenient and comfortable manner yet haven't successfully transitioned to medical practice. Diabetes mellitus is a complicated disease, which is commonly treated with multiple daily insulin injections, contributing to poor treatment adherence. Firstly, this review determines the clinical prospect of microneedles, alongside considerations that ought to be addressed before microneedle technology can be translated from bench to bedside. Thereafter, we use diabetes as a case study to consider how microneedle-based-technology may be successfully harnessed. Here, publications referring to insulin microneedles were evaluated to understand whether insertion efficiency, angle of insertion, successful dose delivery, dose adjustability, material biocompatibility and therapeutic stability are being addressed in early stage research. Moreover, over 3,000 patents from 1970 to 2019 were reviewed with the search term '"microneedle" AND "insulin"' to understand the current status of the field. In conclusion, the reporting of early stage microneedle research demonstrated a lack of consistency relating to the translational factors addressed. Additionally, a more rational design, based on a patient-centred approach is required before microneedle-based delivery systems can be used to revolutionise the lives of people living with diabetes following regulatory approval., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The oral route is the most common and practical means of drug administration, particularly from a patient's perspective. However, the pharmacokinetic profile of oral drugs depends on the rate of drug absorption through the intestinal wall before entering the systemic circulation. However, the enteric epithelium represents one of the major limiting steps for drug absorption, due to the presence of efflux transporters on the intestinal membrane, mucous layer, enzymatic degradation, and the existence of tight junctions along the intestinal linings. These challenges are more noticeable for hydrophilic drugs, high molecular weight drugs, and drugs that are substrates of the efflux transporters. Another challenge faced by oral drug delivery is the presence of first-pass hepatic metabolism that can result in reduced drug bioavailability. Over the years, a wide range of compounds have been investigated for their permeation-enhancing effect in order to circumvent these challenges. There is also a growing interest in developing nanocarrier-based formulation strategies to enhance the drug absorption. Therefore, this review aims to provide an overview of the challenges faced by oral drug delivery and selected strategies to enhance the oral drug absorption, including the application of absorption enhancers and nanocarrier-based formulations based on in vitro, in vivo, and in situ studies.

Hydrogel-forming microarray patches (HF-MAPs) offer minimally invasive, pain-free and prolonged drug delivery. These devices are designed to be self-administered and self-disabling, avoiding contaminated sharps waste generation. Cabotegravir sodium (CAB-Na) is a poorly soluble anti- human immunodeficiency virus (HIV) drug for the treatment and pre-exposure prophylaxis of HIV infection that lends itself to depot formation following intradermal delivery but presents significant challenges when delivered via HF-MAPs, whose nature is aqueous. Herein, we have investigated, for the first time, the use of hydroxypropyl-β-cyclodextrin (HP-β-CD) to enhance the solubility of CAB-Na, and its effect on intradermal delivery via HF-MAPs. Accordingly, tablet reservoirs containing CAB-Na and HP-β-CD were formulated. These novel reservoirs were combined with two different HF-MAP formulations (MAP1 (Gantrez S97® + poly (ethylene glycol) 10,000 + Na 2 CO 3 ) and MAP2 (poly (vinyl pyrrolidone) 58 kDa + poly (vinyl alcohol) 85-120 kDa + citric acid)) to form fully integrated MAP devices which were tested in both ex vivo and in vivo settings. Ex vivo skin deposition results for MAP1 and MAP2 showed that 141 ± 40 μg and 342 ± 34 μg of CAB-Na was deposited into 0.5 cm 2 of excised neonatal porcine skin after 24 h, respectively. Based on these findings, the in vivo pharmacokinetics of MAP2 were investigated over 28 days using a Sprague-Dawley rat model. After 24 h patch application, MAP2 demonstrated an extended drug release profile and an observed C max of 53.4 ± 10.16 μg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (C max of 43.6 ± 5.3 μg/mL). Consequently, this tablet integrated MAP device is considered to be a viable option for the intradermal delivery of hydrophobic anti-HIV drugs., (Copyright © 2022. Published by Elsevier B.V.)

A new high-performance liquid chromatographic method coupled with UV detection (HPLC-UV) to quantify ethambutol (ETH) post permeation studies following microneedle administration has been developed. This method involves the derivatization of ETH with phenethyl isocyanate (PEIC) at room temperature for 90 min. The separation of the derivative was performed using a C18 column that utilised a mobile phase consisting of 25 mM sodium dihydrogen phosphate buffer (with 1% v/v triethylamine, pH 3.0 adjusted using orthophosphoric acid) and methanol (25 : 75 v/v). The developed analytical method was validated according to the standards set by the International Council on Harmonization (ICH) guidelines. The method is linear for drug concentrations within the range of 0.39-12.5 μg mL -1 ( R 2 = 0.9999). The validated method was found to be specific, precise, and accurate. Moreover, the ETH derivative was found to be stable under specific storage conditions. In addition, a simple and straightforward extraction procedure for extracting and quantifying ETH from the skin was developed and evaluated. The extraction procedure displayed recovery rates that range from 101.77 ± 7.10% to 102.33 ± 8.69% indicating high extraction efficiency. The developed method was utilised in assessing the permeation of ETH across dermatomed neonatal porcine skin following microneedle application. Collectively, the simple and stable HPLC method developed in this study may be of great utility in screening formulations for ethambutol within a preclinical setting through in vitro permeation studies.