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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. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [Display omitted] • A novel method for the transdermal depot delivery of hydrophobic agents through hydrogel-forming microarray patches. • The incorporation of ATR in PEG-based SD reservoirs was effective in facilitating its transdermal delivery via HF-MAPs. • A single application of HF-MAPs for 24 h in vivo resulted in a sustained release of therapeutic levels of ATR over 2 weeks. • In vivo studies results had proven, for the first time, the depot formation of ATR within the skin. [ABSTRACT FROM AUTHOR]

[Display omitted] Schizophrenia is a psychiatric disorder that results from abnormal levels of neurotransmitters in the brain. Risperidone (RIS) is a common drug prescribed for the treatment of schizophrenia. RIS is a hydrophobic drug that is typically administered orally or intramuscularly. Transdermal drug delivery (TDD) could potentially improve the delivery of RIS. This study focused on the development of RIS nanocrystals (NCs), for the first time, which were incorporated into dissolving microneedle array patches (DMAPs) to facilitate the drug delivery of RIS. RIS NCs were formulated via wet-media milling technique using poly(vinylalcohol) (PVA) as a stabiliser. NCs with particle size of 300 nm were produced and showed an enhanced release profile up to 80 % over 28 days. Ex vivo results showed that 1.16 ± 0.04 mg of RIS was delivered to both the receiver compartment and full-thickness skin from NCs loaded DMAPs compared to 0.75 ± 0.07 mg from bulk RIS DMAPs. In an in vivo study conducted using female Sprague Dawley rats, both RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) were detected in plasma samples for 5 days. In comparison with the oral group, DMAPs improved the overall pharmacokinetic profile in plasma with a ∼ 15 folds higher area under the curve (AUC) value. This work has represented the novel delivery of the antipsychotic drug, RIS, through microneedles. It also offers substantial evidence to support the broader application of MAPs for the transdermal delivery of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] Hydrogel-forming microneedle array patches (HFMAPs) are microneedles that create microconduits upon insertion and swelling in the skin, potentially allowing prolonged drug delivery without generating sharps waste. Delivering hydrophobic drugs using HFMAPs poses challenges, which can be addressed using solubility enhancers such as cyclodextrins (CDs). This study aimed to deliver risperidone (RIS) transdermally using HFMAPs. To enhance the aqueous solubility of RIS hydroxypropyl-beta-cyclodextrin (HP-β-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) were utilised and their performance was tested using phase solubility studies. The aqueous solubility of RIS was enhanced by 4.75-fold and 2-fold using HP-β-CD and HP-γ-CD, respectively. RIS-HP-β-CD complex (CX) and physical mixture (PM) directly compressed tablets were prepared and combined with HFMAPs. Among the tested formulations, RIS-HP-β-CD PM reservoirs with 11 x 11 PVA/PVP HFMAPs exhibited the best performance in ex vivo studies and were further evaluated in in vivo experiments using female Sprague Dawley rats. The extended wear time of the MAPs resulted in the sustained release of RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in plasma samples, lasting from 3 to 5 days with a 1-day application and up to 10 days with a 5-day application. For a 1-day application, HFMAPs showed greater systemic exposure to RIS compared to intramuscular control (AUC 0-t : 13330.05 ± 2759.95 ng/mL/hour versus 2706 ± 1472 ng/mL/hour). Moreover, RIS exposure was extended to 5 days (AUC 0-t : 12292.37 ± 1801.94 ng/mL/hour). In conclusion, HFMAPs could serve as an alternative for delivering RIS in a sustained manner, potentially improving the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial stewardship (ASP) is considered a key prevention strategy in addressing the worldwide concern of accelerating antimicrobial resistance. Limited research is available regarding healthcare providers' knowledge and attitude toward antimicrobial stewardship and the barriers for its implementation. Methods: The present cross-sectional study was conducted on pharmacists and healthcare prescribers (HCPs) in different hospital sites across Jordan. A validated survey was used to evaluate HCPs and pharmacists' knowledge, and attitudes towards ASP and the barriers for its implementation. Logistic and linear regression were conducted to identify the factors associated with knowledge and attitude toward ASP, respectively. Results: A total of 603 participants, 69 (11.4%) pharmacists and 534 (88.6%) HCPs completed the study questionnaire, with a response rate of 80.4%. The overall mean knowledge about ASP was 7.16 out of 10, ranging from 0 to 10 (SD 2.22). Being a pharmacist and increased awareness/familiarity about ASP were associated with improved ASP knowledge. The overall average attitude score was = 3.8 ± 0.49 (range: 1.8–4.8). Results revealed that being a pharmacist and improved knowledge were associated with improved attitude toward ASP. Lack of specialized staff with expertise in ASP and lack of access to education and training programs were the major barriers hinder ASP implementation. Conclusion: Despite the reasonable knowledge and the positive attitude toward the ASP, several barriers were reported, particularly by the pharmacists. Therefore, promoting the presence of adequately skilled healthcare personnel, creating easily accessible online courses, and establishing a comprehensive database of ASP resources are all suggested approaches to improve the application of ASP in healthcare settings. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Dissolving microneedle array patches (DMAP) enable efficient and painless delivery of therapeutic molecules across the stratum corneum and into the upper layers of the skin. Furthermore, this delivery strategy can be combined with the sustained release of nanoparticles to enhance the therapeutic potential in a wide variety of pathological scenarios. Among the different types of nanoparticles that can be included in microneedle formulations, mesoporous silica nanoparticles (MSN) of tunable pore sizes constitute a promising tool as drug delivery systems for cargos of a wide range of molecular weights. In this work, a new preparation method was developed to produce DMAP containing ca. 2.3 mg of MSN of different pore sizes located mainly in the microneedle tips. The successful insertion of these DMAPs was confirmed in vitro (using Parafilm), ex vivo (using excised neonatal porcine skin) and in vivo (in the back of mice). The dissolution of the microneedles and deposition of the nanoparticles inside the skin were also confirmed both ex vivo and in vivo using fluorescent nanoparticles (with an intradermal deposition of 20.9 ± 7.26 % of the MSN in each DMAP in neonatal porcine skin). Finally, the in vivo release of the cargo from nanoparticles deposited inside mouse skin after microneedle insertion was confirmed through in vivo fluorescence measurements. [ABSTRACT FROM AUTHOR]

[Display omitted] Throughout history, psychedelic compounds have been used for religious, spiritual and recreational purposes. A plethora of studies have reported the use of psychedelic compounds in the treatment of various conditions, such as alcoholism, addictions, depressive state to borderline schizophrenia, personality disorder, among other mental disorders. Psychedelic microdosing, a common technique in recent years, involves the consumption of small doses of psychedelic drugs for therapeutic purposes. This study investigated the potential of hydrogel-forming microarray patches (HF-MAPs) to deliver N,N- dimethyltryptamine (DMT), 5-methoxy- N,N- dimethyltryptamine (5-MeO-DMT), and mescaline (MES) in small doses through the skin. To this purpose, HF-MAPs were prepared using poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP), using citric acid as the crosslinker. Two different reservoirs, containing PVP and PVA as the main components and poly(ethylene)glycol 400 (PEG400) and glycerol as plasticising agents, were used to deliver all the drugs from the HF-MAPs. Franz cells studies in excised neonatal porcine skin demonstrated that the permeation of DMT, 5-MeO-DMT and MES was better from the PEG400 reservoir, showing a permeation of 60.71 %, 59.61 % and 41.85 % respectively. Pharmacokinetic studies in rats showed that HF-MAP technology as a strategy for microdosing psychedelic compounds was also demonstrated with DMT. AUC t0-final for the HF-MAP cohort (7186 ± 1296 ng/mL*h) was significantly greater than the IM cohort (1803 ± 53.25 ng/mL*h) (p = 0.0020), with a relative bioavailability of ∼ 72 %. Considering their pharmacokinetic profile, the frequency of DMT dosing could be reduced with HF-MAP when compared to the IM route. [ABSTRACT FROM AUTHOR]

Poorly soluble drugs constitute more than 60% of currently marketed pharmaceuticals with over two‐thirds of promising new chemical entities failing to enter a clinical setting due to solubility issues. Although oral formulations have made some impact, alternative enhancement strategies for administration of such molecules are actively sought. Over the last decade, innovation on a global scale has enabled the expansion of the frontiers of microarray patches (MAPs) further than ever before. Initially designed to load low doses of hydrophilic and potent therapeutic agents, MAPs are now becoming a viable strategy for the immediate and long‐acting delivery of poorly soluble drugs through the skin. This together with the advantages of transdermal administration over the oral and parenteral routes, make of MAPs an appealing platform for the development of products with increased patient compliance. Undoubtedly, MAPs will soon become a readily available therapeutic alternative, and experts from academia, industry and regulatory bodies are working together aiming to facilitate the progression of MAPs toward safe and effective clinical use. This review aims to highlight the ability of MAPs to deliver poorly soluble actives, discuss the mechanisms behind in‐skin drug absorption, and evaluate the future direction of the field. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fabrication of low temperature cured PVA/PVP/CA was successfully carried out with satisfactory mechanical properties. • Diffusion coefficient could potentially be used to predict the permeation patterns of the drug integrated with HF-MAPs. • The PVA/PVP/CA HF-MAPs can be used both as therapeutic drug monitoring and drug delivery platform. The characteristics of multifunctional polymeric hydrogel-forming microarray patches based on poly(vinyl alcohol)/poly(vinylpyrrolidone)/citric acid composite crosslinked at 80 °C were investigated. The swelling study showed that this composite possesses a higher swelling degree than the same polymer heated at 130 °C due to a lower crosslink density, which was then confirmed by FTIR examination. Solid-state studies revealed that lower-temperature crosslinking does not provide enough energy for the polymer to rearrange itself into a crystalline form. However, this composite polymer was shown to possess acceptable mechanical strength to insert/penetrate into the skin. The patch can function both as a means to sample model hydrophilic drugs from the skin and to deliver them when combined with a melt-type polyethylene glycol reservoir. The hydrophilic interaction between the hydrogel and drugs was investigated. A drug with a higher diffusion coefficient, modelled by theophylline (diffusion coefficient = 16.17 × 10-6 cm2/s), can be delivered more efficiently than fluorescent sodium (diffusion coefficient = 2.32 × 10-6 cm2/s) or cyanocobalamin (diffusion coefficient = 7.31 × 10-6 cm2/s). This is mainly due to theophylline's high permeability (permeability coefficient = 7.40 × 10-5 cm/s) and weak ability to interact with the hydrogel (coefficient of partitioning = 1.3). These results indicated that the diffusion coefficient could be a useful predictive parameter to determine the delivery efficiency of the system. Furthermore, the results provide insight into how to select a suitable hydrogel for drug monitoring or delivery involving hydrophilic compounds based on the hydrophilic interaction between the polymer and the drug. [ABSTRACT FROM AUTHOR]

In this work, we introduce, for the first time, novel hybrid microneedle patches with implantable poly(lactic- co -glycolic acid) (PLGA) tips aligned with hydrogel-forming microneedle bases (HFMB) using a dissolvable material. A model dye, Nile red, and an antifungal drug, amphotericin B, were loaded into the PLGA tips in a controlled manner by multiple castings. Three different types of pre-formed microneedle bases including conventional dissolving baseplates (MN0), HFMB with needle heights of 600 μm (MN6) and HFMB with needle heights of 800 μm (MN8) were investigated. Compared to the conventional dissolving baseplate (MN0)-based PLGA tipped implantable microneedle design, the addition of the pre-formed HFMB (MN8) improved in vitro and ex vivo insertion capacities of the patches, increased ex vivo drug delivery efficiency up to 80% of the loaded drug and speeded up the implantation process to within 1 min. An adhesion test indicated that the hydrogel baseplate used in this study was easier to peel off from the skin than the dissolving baseplate. In vitro release studies demonstrated that the release of amphotericin B from the drug loading PLGA tips lasts for a week. Antifungal tests of the inserted amphotericin B loaded PLGA tips revealed their antifungal effects against Candida albicans. The MN8 did not dissolve, leaving no viscous residue but absorbed water and disintegrated after immersion into water. The hybrid PLGA-tipped microneedle system will be ideal for rapid implantation and sustained release of amphotericin B for dermal fungal infections. This hybrid patch design is a novel promising technology for delivering drug-eluting microimplants into the skin while ensuring easy and complete removal of the HFMB. It could have many potential applications in implantable intradermal drug delivery. • PLGA microneedle tips were fabricated in a controlled manner by multiple castings. • PLGA tips containing amphotericin B showed a prolonged release up to a week. • Delivery efficiency was enhanced by aligning hydrogel-forming microneedle base. • The implantation of PLGA microneedle tips took <1 min. • Hydrogel-forming microneedles promoted efficient and rapid skin deposition. [ABSTRACT FROM AUTHOR]