Novel long-acting treatment for schizophrenia based on paliperidone dissolving and implantable microarray patches.

Schizophrenia is a severe mental disorder that affects millions of people worldwide. Several atypical antipsychotic medications, including paliperidone (PPD), has been developed and proven effective in treating it. To date, four PPD extended-release products have been launched commercially, providing up to six months of therapeutic effect with a single administration. However, the need for hospital injections by professional healthcare workers not only lead to poor patients' adherence, but also put additional pressure on the healthcare system. Therefore, three PPD microarray patch (PPD MAP) systems based on dissolving microneedle technology and implantable microneedle technology were developed in this work. The two dissolving microarray patch systems contained either PPD crude drug (PPD DMAP-CD) or PPD nanocrystal (PPD DMAP-NC) and the implantable MAP contained PPD crude drug (PPD IMAP). All three types of PPD MAPs showed excellent mechanical and insertion properties as they achieved over 256 µm insertion depth in skin model. In vitro release study showed that PPD released from IMAP in a much more sustained manner (up to 14 days) than PPD did from DMAPs (7 days), with only 20 % initial burst release from IMAP compared with 43-71 % from DMAPs. The MAP dissolution study showed that both DMAPs can be immediately dissolved within less than 3 min once inserted into the skin, indicating a faster action potential compared with IMAP. Ex vivo delivery study showed that 1.68 ±â€¯0.23 mg, 1.39 ±â€¯0.07 mg, and 1.18 ±â€¯0.12 mg were delivered from DMAP-CD, DMAP-NC and IMAP, respectively, demonstrating that over 50 % and up to 70 % of PPD in the MAPs can be delivered into the skin. The IMAP offers most sustained release of PPD whereas DMAP-NC exhibits fastest PPD release (11.19 % vs 20.01 % into Franz cell receiver compartment over 24 h). This work presents a promising alternative for the sustained delivery of antipsychotic drugs, allowing for patient self-administration and extended release concurrently. Patients may potentially use both DMAP and IMAP to achieve a sustained release of PPD while also avoid having an initial therapeutic lag.

Development of Norelgestromin Dissolving Bilayer Microarray Patches for Sustained Release of Hormonal Contraceptive.

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 µg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects.

Developing and validating a scale to measure the perceptions of safety, usability and acceptability of microarray patches for vaccination: a study protocol.

Background: Vaccination is a fundamental tenet of public and population health. Several barriers to vaccine uptake exist, exacerbated post-COVID-19, including misconceptions about vaccine efficacy and safety, vaccine hesitancy, vaccine inequity, costs, religious beliefs, and insufficient education and guidance for healthcare professionals. Vaccine uptake may be aided using microarray patches (MAPs) due to reduced pain, no hypodermic needle, enhanced thermostability, and potential for self and lay administration. Objectives: This protocol outlines the development of a scale that aims to accurately measure the perceived safety, usability, and acceptability of MAPs for vaccination among laypeople, MAP recipients, clinicians, and parents or guardians of children. Methods and analysis: This study will follow three phases of scale development and validation, including (1) item development, (2) scale development, and (3) scale evaluation. Inductive (interviews) and deductive methods (literature searches) will be used to develop scale items, which experts from target populations will assess through an online survey. Cognitive interviews will be conducted to observe their processes of answering the draft survey. Thematic analysis will be conducted to analyse qualitative data. Lastly, four surveys will be administered online to our target populations over two time points to determine their repeatability. Exploratory and confirmatory factor analyses, Cronbach's alpha, and construct validity will be performed. Ethics: This study was approved by Metro South Health (HREC/2021/QMS/81653) and Western Sydney Local Health District (2023/ETH00705) Human Research Ethics Committees. Discussion: The scale will support a standardised approach to assessing the social and behavioural aspects of MAP vaccines, enabling comparison of outcomes across studies. Once validated, this scale will assist vaccination programmes in developing effective strategies for integrating MAPs and overcoming barriers to vaccination. This includes improving vaccine equity and accessibility, especially in lower- and middle-income countries and rural or remote locations.

Dissolving microarray patches loaded with a rotigotine nanosuspension: A potential alternative to Neupro® patch.

Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of -15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm2 and demonstrated greater amount of drug delivered per unit area (∼0.52 mg/0.5 cm2) than Neupro® (∼0.20 mg/1 cm2) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm2 for dissolving MAPs and 6 cm2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment.

Poly(acrylic acid)/Poly(vinyl alcohol) Microarray Patches for Continuous Transdermal Delivery of Levodopa and Carbidopa: In Vitro and In Vivo Studies.

Levodopa (LD) has been the most efficacious medication and the gold standard therapy for Parkinson's disease (PD) for decades. However, its long-term administration is usually associated with motor complications, which are believed to be the result of the fluctuating pharmacokinetics of LD following oral administration. Duodopa® is the current option to offer a continuous delivery of LD and its decarboxylase inhibitor carbidopa (CD); however, its administration involves invasive surgical procedures, which could potentially lead to lifelong complications, such as infection. Recently, dissolving microarray patches (MAPs) have come to the fore as an alternative that can bypass the oral administration route in a minimally invasive way. This work explored the potential of using dissolving MAPs to deliver LD and CD across the skin. An acidic polymer poly(acrylic acid) (PAA) was used in the MAP fabrication to prevent the potential oxidation of LD at neutral pH. The drug contents of LD and CD in the formulated dissolving MAPs were 1.82 ± 0.24 and 0.47 ± 0.04 mg/patch, respectively. The in vivo pharmacokinetic study using female Sprague-Dawley® rats (Envigo RMS Holding Corp, Bicester, UK) demonstrated a simultaneous delivery of LD and CD and comparable AUC values between the dissolving MAPs and the oral LD/CD suspension. The relative bioavailability for the dissolving MAPs was calculated to be approximately 37.22%. Accordingly, this work highlights the use of dissolving MAPs as a minimally invasive approach which could potentially bypass the gastrointestinal pathway and deliver both drugs continuously without surgery.

Selective Delivery of Clindamycin Using a Combination of Bacterially Sensitive Microparticle and Separable Effervescent Microarray Patch on Bacteria Causing Diabetic Foot Infection.

INTRODUCTION: Diabetic foot infection (DFI) is one of the complications of diabetes mellitus. Clindamycin (CLY) is one of the antibiotics recommended to treat DFI, but CLY given orally and intravenously still causes many side effects. METHODS: In this study, we encapsulated CLY in a bacteria sensitive microparticle system (MP-CLY) using polycaprolactone (PCL) polymer. MP-CLY was then delivered in a separable effervescent microarray patch (MP-CLY-SEMAP), which has the ability to separate between the needle layer and separable layer due to the formation of air bubbles when interacting with interstitial fluid in the skin. RESULT: The characterization results of MP-CLY proved that CLY was encapsulated in large amounts as the amount of PCL polymer used increased, and there was no change in the chemical structure of CLY. In vitro release test results showed increased CLY release in media cultured with Staphylococcus aureus bacteria and showed controlled release. The characterization results of MPCLY-SEMAP showed that the developed formula has optimal mechanical and penetration capabilities and can separate in 56 ± 5.099 s. An ex vivo dermatokinetic test on a bacterially infected skin model showed an improvement of CLY dermatokinetic profile from MP-CLY SEMAP and a decrease in bacterial viability by 99.99%. CONCLUSION: This research offers proof of concept demonstrating the improved dermatokinetic profile of CLY encapsulated in a bacteria sensitive MP form and delivered via MP-CLY-SEMAP. The results of this research can be developed for future research by testing MP-CLY-SEMAP in vivo in appropriate animal models.

Development of pH-Sensitive Nanoparticle Incorporated into Dissolving Microarray Patch for Selective Delivery of Methotrexate.

PURPOSE: Rheumatoid arthritis (RA) is a systemic autoimmune disease that attacks human joints. Methotrexate (MTX), as one the most effective medications to treat RA, has limitations when administered either orally or by injection. To overcome this limitation, we formulated MTX through a smart nanoparticle (SNP) combined with dissolving microarray patch (DMAP) to achieve selective-targeted delivery of RA. METHODS: SNP was made using the combination of polyethylene glycol (PEG) and polycaprolactone (PCL) polymers, while DMAP was made using the combination of hyaluronic acid and polyvinylpyrrolidone K-30. SNP-DMAP was then evaluated for its mechanical and chemical characteristics, ex vivo permeation test, in vivo pharmacokinetic study, hemolysis, and hen's egg test-chorioallantoic membrane (HET-CAM) test. RESULT: The results showed that the characteristics of the SNP-DMAP-MTX formulas meet the requirements for transdermal delivery, with the particle size of 189.09 ±12.30 nm and absorption efficiency of 65.40 ± 5.0%. The hemolysis and HET-CAM testing indicate that this formula was non-toxic and non-irritating. Ex vivo permeation shows a concentration of 51.50 ± 3.20 µg/mL of SNP-DMAP-MTX in PBS pH 5.0. The pharmacokinetic profile of SNP-DMAP-MTX showed selectivity and sustained release compared with oral and DMAP-MTX with values of t1/2 (4.88 ± 0 h), Tmax (8 ± 0 h), Cmax (0.50 ± 0.04 µg/mL), AUC (3.15 ± 0.54 µg/mL.h), and mean residence time (MRT) (9.13 ± 0 h). CONCLUSION: The developed SNP-DMAP-MTX has been proven to deliver MTX transdermal and selectively at the RA site, potentially avoiding conventional MTX side effects and enhancing the effectiveness of RA therapy.

A Bilayer Microarray Patch (MAP) for HIV Pre-Exposure Prophylaxis: The Role of MAP Designs and Formulation Composition in Enhancing Long-Acting Drug Delivery.

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of MAP delivery of micronized cabotegravir sodium (CAB Na) for HIV pre-exposure prophylaxis (PrEP). The refinement of microneedle design parameters, including needle length, shape, density, and arrangement, and the formulation properties, such as solubility, viscosity, polymer molecular weight, and stability, are crucial for improving penetration and release profiles. Additionally, a bilayer MAP optimization step was conducted by diluting the CAB Na polymeric mixture to localize the drug into the tips of the needles to enable rapid drug deposition into the skin following MAP application. Six MAP designs were analyzed and investigated with regard to delivery efficiency into the skin in ex vivo and in vivo studies. The improved MAP design and formulations were found to be robust and had more than 30% in vivo delivery efficiency, with plasma levels several-fold above the therapeutic concentration over a month. Repeated weekly dosing demonstrated the robustness of MAPs in delivering a consistent and sustained dose of CAB. In summary, CAB Na MAPs were able to deliver therapeutically relevant levels of drug.

Enhancement of cellular immunity following needle-free vaccination of mice with SARS-CoV-2 spike protein.

The COVID-19 pandemic has highlighted the need for vaccines capable of providing rapid and robust protection. One way to improve vaccine efficacy is delivery via microarray patches, such as the Vaxxas high-density microarray patch (HD-MAP). We have previously demonstrated that delivery of a SARS-CoV-2 protein vaccine candidate, HexaPro, via the HD-MAP induces potent humoral immune responses. Here, we investigate the cellular responses induced by HexaPro HD-MAP vaccination. We found that delivery via the HD-MAP induces a type one biassed cellular response of much greater magnitude as compared to standard intramuscular immunization.

The promise of microneedle technologies for drug delivery.

Microneedle (MN) technologies offer the opportunity to improve patient access and target delivery of drugs and vaccines to specific tissues. When in the form of skin patches, MNs can be administered by personnel with minimal training, or could be self-administered by patients, which can improve access to medication, especially those usually requiring injection. Because MNs are small (usually sub-millimetre), they can be used for precise tissue targeting. MN patches have been extensively studied to administer vaccines and drugs in preclinical work as well as in multiple clinical trials. When formulated with biodegradable polymer, MNs can enable long-acting therapies by slowly releasing drug as the MNs biodegrade. Targeted drug delivery by hollow MNs has resulted in FDA-approved products that are able to inject vaccines to skin-resident immune cells to improve immune response and to target specific parts of the eye (e.g., suprachoroidal space) for increased efficacy and avoidance of side effects in other parts of the eye. Cosmetic products based on MN technologies are already in widespread use, mostly as anti-aging agents. With extensive research coupled with FDA-approved products, MN technology promises to continue is growth in research leading to products that can benefit patients.

Validation of spectrophotometric and colorimetric methods to quantify clindamycin in skin tissue: application to in vitro release and ex vivo dermatokinetic studies from separable effervescent microarray patch loaded bacterially sensitive microparticle.

Diabetes mellitus can cause diabetic foot infection (DFI) complications. DFI is generally caused by infection from bacteria and Methicillin-Resistant Staphylococcus aureus (MRSA) which is resistant to several antibiotics. Application therapy of clindamycin (CLY) administration with the oral route has low bioavailability and non-selective distribution of antibiotics towards bacteria intravenously. In this research, CLY was developed into bacterially sensitive microparticles (MPs) which were further incorporated into a separable effervescent microarray patch (SEMAP) system to increase the selective and responsive to DFI-causing bacteria of CLY. To support this formulation, we explore the potential of silver nanoparticles (AgNPs) towards the UV-Vis spectrophotometry method. The analytical method was validated in phosphate-buffered saline (PBS), tryptic soy broth (TSB), and skin tissue to quantify CLY, CLY loaded in microparticle, and SEMAP system. The developed analytical method was suitable for the acceptance criteria of ICH guidelines. The results showed that the correlation coefficients were linear ≥ 0.999. The values of LLOQ towards PBS, TSB, and skin tissue were 2.02 µg/mL, 4.29 µg/mL, and 2.31 µg/mL, respectively. These approaching methods were also found to be accurate and precise without being affected by dilution integrity. The presence of Staphylococcus aureus bacteria culture can produce lipase enzymes that can lysing the microparticle matrix. Drug release studies showed that bacterial infection in the high drug release microparticle sensitive bacteria and high drug retention in ex vivo dermatokinetic in rat skin tissue media. In addition, in vivo studies were required to quantify the CLY inside in further analytical validation methods.

Safety, Tolerability, and Immunogenicity of Measles and Rubella Vaccine Delivered with a High-Density Microarray Patch: Results from a Randomized, Partially Double-Blinded, Placebo-Controlled Phase I Clinical Trial.

Microarray patches (MAPs) have the potential to be a safer, more acceptable, easier-to-use, and more cost-effective means for the administration of vaccines than injection by needle and syringe. Here, we report findings from a randomized, partially double-blinded, placebo-controlled Phase I trial using the Vaxxas high-density MAP (HD-MAP) to deliver a measles rubella (MR) vaccine. Healthy adults (N = 63, age 18-50 years) were randomly assigned 1:1:1:1 to four groups: uncoated (placebo) HD-MAPs, low-dose MR HD-MAPs (~3100 median cell-culture infectious dose [CCID50] measles, ~4300 CCID50 rubella); high-dose MR-HD-MAPs (~9300 CCID50 measles, ~12,900 CCID50 rubella); or a sub-cutaneous (SC) injection of an approved MR vaccine, MR-Vac (≥1000 CCID50 per virus). The MR vaccines were stable and remained viable on HD-MAPs when stored at 2-8 °C for at least 24 months. When MR HD-MAPs stored at 2-8 °C for 24 months were transferred to 40 °C for 3 days in a controlled temperature excursion, loss of potency was minimal, and MR HD-MAPs still met World Health Organisation (WHO) specifications. MR HD-MAP vaccination was safe and well-tolerated; any systemic or local adverse events (AEs) were mild or moderate. Similar levels of binding and neutralizing antibodies to measles and rubella were induced by low-dose and high-dose MR HD-MAPs and MR-Vac. The neutralizing antibody seroconversion rates on day 28 after vaccination for the low-dose HD-MAP, high-dose HD-MAP and MR-Vac groups were 37.5%, 18.8% and 35.7%, respectively, for measles, and 37.5%, 25.0% and 35.7%, respectively, for rubella. Most participants were seropositive for measles and rubella antibodies at baseline, which appeared to negatively impact the number of participants that seroconverted to vaccines delivered by either route. The data reported here suggest HD-MAPs could be a valuable means for delivering MR-vaccine to hard-to-reach populations and support further development. Clinical trial registry number: ACTRN12621000820808.

Microarray patches: scratching the surface of vaccine delivery.

INTRODUCTION: Microneedles are emerging as a promising technology for vaccine delivery, with numerous advantages over traditional needle and syringe methods. Preclinical studies have demonstrated the effectiveness of MAPs in inducing robust immune responses over traditional needle and syringe methods, with extensive studies using vaccines targeted against different pathogens in various animal models. Critically, the clinical trials have demonstrated safety, immunogenicity, and patient acceptance for MAP-based vaccines against influenza, measles, rubella, and SARS-CoV-2. AREAS COVERED: This review provides a comprehensive overview of the different types of microarray patches (MAPs) and analyses of their applications in preclinical and clinical vaccine delivery settings. This review also covers additional considerations for microneedle-based vaccination, including adjuvants that are compatible with MAPs, patient safety and factors for global vaccination campaigns. EXPERT OPINION: MAP vaccine delivery can potentially be a game-changer for vaccine distribution and coverage in both high-income and low- and middle-income countries. For MAPs to reach this full potential, many critical hurdles must be overcome, such as large-scale production, regulatory compliance, and adoption by global health authorities. However, given the considerable strides made in recent years by MAP developers, it may be possible to see the first MAP-based vaccines in use within the next 5 years.

Vaccine microarray patch self-administration: An innovative approach to improve pandemic and routine vaccination rates.

The high-density microprojection array patch (HD-MAP) is a novel vaccine delivery system with potential for self-administered vaccination. HD-MAPs provide an alternative to needle and syringe (N&S) vaccination. Additional advantages could include reduced cold-chain requirements, reduced vaccine dose, reduced vaccine wastage, an alternative for needle phobic patients and elimination of needlestick injuries. The drivers and potential benefits of vaccination by self-administering HD-MAPs are high patient acceptance and preference, higher vaccination rates, speed of roll-out, cost-savings, and reduced sharps and environmental waste. The HD-MAP presents a unique approach in pandemic preparedness and routine vaccination of adults. It could alleviate strain on the healthcare workforce and allows vaccine administration by minimally-trained workers, guardian or subjects themselves. Self-vaccination using HD-MAPs could occur in vaccination hubs with supervision, at home after purchasing at the pharmacy, or direct distribution to in-home settings. As a result, it has the potential to increase vaccine coverage and expand the reach of vaccines, while also reducing labor costs associated with vaccination. Key challenges remain around shifting the paradigm from medical professionals administrating vaccines using N&S to a future of self-administration using HD-MAPs. Greater awareness of HD-MAP technology and improving our understanding of the implementation processes required for adopting this technology, are critical factors underpinning HD-MAP uptake by the public.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

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.

Microarray patch for HIV prevention and as a multipurpose prevention technology to prevent HIV and unplanned pregnancy: an assessment of potential acceptability, usability, and programmatic fit in Kenya.

Background: Microarray patches (MAPs), a novel drug delivery system, are being developed for HIV pre-exposure prophylaxis (PrEP) delivery and as a multipurpose prevention technology (MPT) to protect from both HIV and unintended pregnancy. Prevention technologies must meet the needs of target audiences, be acceptable, easy to use, and fit health system requirements. Methodology: We explored perceptions about MAP technology and assessed usability, hypothetical acceptability, and potential programmatic fit of MAP prototypes using focus group discussions (FGD), usability exercises, and key informant interviews (KII) among key populations in Kiambu County, Kenya. Adolescent girls and young women (AGYW), female sex workers (FSW), and men who have sex with men (MSM) assessed the usability and acceptability of a MAP prototype. Male partners of AGYW/FSW assessed MAP acceptability as partners of likely users. We analyzed data using NVivo, applying an inductive approach. Health service providers and policymakers assessed programmatic fit. Usability exercise participants applied a no-drug, no-microneedle MAP prototype and assessed MAP features. Results: We implemented 10 FGD (4 AGYW; 2 FSW; 2 MSM; 2 male partners); 47 mock use exercises (19 AGYW; 9 FSW; 8 MSM; 11 HSP); and 6 policymaker KII. Participants reported high interest in MAPs due to discreet and easy use, long-term protection, and potential for self-administration. MAP size and duration of protection were key characteristics influencing acceptability. Most AGYW preferred the MPT MAP over an HIV PrEP-only MAP. FSW saw value in both MAP indications and voiced need for MPTs that protect from other infections. Preferred duration of protection was 1-3 months. Some participants would accept a larger MAP if it provided longer protection. Participants suggested revisions to the feedback indicator to improve confidence. Policymakers described the MPT MAP as "killing two birds with one stone," in addressing AGYW needs for both HIV protection and contraception. An MPT MAP is aligned with Kenya's policy of integrating health care programs. Conclusions: MAPs for HIV PrEP and as an MPT both were acceptable across participant groups. Some groups valued an MPT MAP over an HIV PrEP MAP. Prototype refinements will improve usability and confidence.

Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Ab─a broadly neutralizing Ab against HIV-1─maintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.

Hydrogel-forming microarray patch mediated transdermal delivery of tetracycline hydrochloride.

Antibiotic resistance is one of the most serious health problems today and is expected to worsen in the coming decades. It has been suggested that antibiotic administration routes that bypass the human gut could potentially tackle this problem. In this work, an antibiotic hydrogel-forming microarray patch (HF-MAP) system, which can be used as an alternative antibiotic delivery technology, has been fabricated. Specifically, poly(vinyl alcohol)/poly(vinylpyrrolidone) (PVA/PVP) microarray showed excellent swelling properties with >600% swelling in PBS over 24 h. The tips on the HF-MAP were proven to be able to penetrate a skin model which is thicker than stratum corneum. The antibiotic (tetracycline hydrochloride) drug reservoir was mechanically robust and dissolved completely in an aqueous medium within a few minutes. In vivo animal studies using a Sprague Dawley rat model showed antibiotic administration using HF-MAP achieved a sustained release profile, in comparison with animals receiving oral gavage and intravenous (IV) injection, with a transdermal bioavailability of 19.1% and an oral bioavailability of 33.5%. The maximum drug plasma concentration for HF-MAP group reached 7.40 ± 4.74 µg/mL at 24 h, whereas the drug plasma concentration for both oral (5.86 ± 1.48 µg/mL) and IV (8.86 ± 4.19 µg/mL) groups peaked soon after drug administration and had decreased to below the limit of detection at 24 h. The results demonstrated that antibiotics can be delivered by HF-MAP in a sustained manner.

Hydrogel-forming microarray patches with solid dispersion reservoirs for transdermal long-acting microdepot delivery of a hydrophobic drug.

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