Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

Seeing eye to eye: trustworthy embodiment for task-based conversational agents.

Smart speakers and conversational agents have been accepted into our homes for a number of tasks such as playing music, interfacing with the internet of things, and more recently, general chit-chat. However, they have been less readily accepted in our workplaces. This may be due to data privacy and security concerns that exist with commercially available smart speakers. However, one of the reasons for this may be that a smart speaker is simply too abstract and does not portray the social cues associated with a trustworthy work colleague. Here, we present an in-depth mixed method study, in which we investigate this question of embodiment in a serious task-based work scenario of a first responder team. We explore the concepts of trust, engagement, cognitive load, and human performance using a humanoid head style robot, a commercially available smart speaker, and a specially developed dialogue manager. Studying the effect of embodiment on trust, being a highly subjective and multi-faceted phenomena, is clearly challenging, and our results indicate that potentially, the robot, with its anthropomorphic facial features, expressions, and eye gaze, was trusted more than the smart speaker. In addition, we found that embodying a conversational agent helped increase task engagement and performance compared to the smart speaker. This study indicates that embodiment could potentially be useful for transitioning conversational agents into the workplace, and further in situ, "in the wild" experiments with domain workers could be conducted to confirm this.

Microneedle array patches for sustained delivery of fluphenazine: A micron scale approach for the management of schizophrenia.

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 Cmax of FLU-D dissolving MNs was 36.11 ± 12.37 ng/ml. However, the Cmax 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.

Polymeric Microarray Patches for Enhanced Transdermal Delivery of the Poorly Soluble Drug Olanzapine.

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 (Cmax = 611.13 ± 153.34 ng/mL, Tmax = 2 h) and dissolving MAPs (Cmax = 690.56 ± 161.33 ng/mL, Tmax = 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.

Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND).

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 Cmax 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 Cmax 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.

Development of 3D-printed subcutaneous implants using concentrated polymer/drug solutions.

Implantable drug-eluting devices that provide therapeutic cover over an extended period of time following a single administration have potential to improve the treatment of chronic conditions. These devices eliminate the requirement for regular and frequent drug administration, thus reducing the pill burden experienced by patients. Furthermore, the use of modern technologies, such as 3D printing, during implant development and manufacture renders this approach well-suited for the production of highly tuneable devices that can deliver treatment regimens which are personalised for the individual. The objective of this work was to formulate subcutaneous implants loaded with a model hydrophobic compound, olanzapine (OLZ) using robocasting - a 3D-printing technique. The formulated cylindrical implants were prepared from blends composed of OLZ mixed with either poly(caprolactone) (PCL) or a combination of PCL and poly(ethylene)glycol (PEG). Implants were characterised using scanning electron microscopy (SEM), thermal analysis, infrared spectroscopy, and X-ray diffraction and the crystallinity of OLZ in the formulated devices was confirmed. In vitro release studies demonstrated that all the formulations were capable of maintaining sustained drug release over a period of 200 days, with the maximum percentage drug release observed to be c.a. 60 % in the same period.

Hydrogel-forming microarray patches with cyclodextrin drug reservoirs for long-acting delivery of poorly soluble cabotegravir sodium for HIV Pre-Exposure Prophylaxis.

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-ß-cyclodextrin (HP-ß-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-ß-CD were formulated. These novel reservoirs were combined with two different HF-MAP formulations (MAP1 (Gantrez S97® + poly (ethylene glycol) 10,000 + Na2CO3) 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 cm2 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 Cmax of 53.4 ± 10.16 µg/mL, superior to that of an FDA-approved CAB-nanosuspension administered via intramuscular application (Cmax 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.

Novel transdermal bioadhesive surfactant-based system for release and solubility improvement of antimalarial drugs artemether-lumefantrine.

Artemether (ART) and lumefantrine (LUM) are the gold standard antimalarial drugs used for the treatment of malaria in children and pregnant women. Typically, ART and LUM are delivered orally in the form of a combined tablet, however, the appropriateness of this route of administration for these drugs is questionable due to the poor absorption and therefore bioavailability observed unless administered alongside lipid-rich foods. Transdermal drug delivery in the form of a patch-type system has been identified as a viable alternative to the conventional tablet-based therapy. A novel, surfactant-based ART-LUM formulation (S3AL), developed for transdermal delivery, may eliminate the shortcomings associated with oral delivery; namely poor drug absorption which is caused by the inherently low solubility of ART and LUM. Moreover, by successfully delivering these antimalarials transdermally, first-pass metabolism will be avoided leading to enhanced drug bioavailability in both cases. The S3AL formulation contained ART and LUM at equal concentrations (2.5% w/w of each) as well as Procetyl® AWS (30% w/w), oleic acid (10% w/w), 1-methyl-2-pyrrolidone (10% w/w), and water (45% w/w). The addition of LUM to the formulation changed the system from a striae structure to a dark field structure when visualized by a polarized light microscope. Additionally, this system possessed higher viscosity and superior skin bioadhesion, as evidenced by mechanical characterization, when compared to a similar formulation containing ART alone. S3AL was also proven to be biocompatible to human keratinocyte cells. Finally,in vitrostudies demonstrated the propensity of S3AL for successful delivery via the transdermal route, with 2279 ± 295 µg cm-2of ART and 94 ± 13 µg cm-2of LUM having permeated across dermatomed porcine skin after 24 h, highlighting its potential as a new candidate for the treatment of malaria.

The role of microneedle arrays in drug delivery and patient monitoring to prevent diabetes induced fibrosis.

Diabetes affects approximately 450 million adults globally. If not effectively managed, chronic hyperglycaemia causes tissue damage that can develop into fibrosis. Fibrosis leads to end-organ complications, failure of organ systems occurs, which can ultimately cause death. One strategy to tackle end-organ complications is to maintain normoglycaemia. Conventionally, insulin is administered subcutaneously. Whilst effective, this delivery route shows several limitations, including pain. The transdermal route is a favourable alternative. Microneedle (MN) arrays are minimally invasive and painless devices that can enhance transdermal drug delivery. Convincing evidence is provided on MN-mediated insulin delivery. MN arrays can also be used as a diagnostic tool and monitor glucose levels. Furthermore, sophisticated MN array-based systems that integrate glucose monitoring and drug delivery into a single device have been designed. Therefore, MN technology has potential to revolutionise diabetes management. This review describes the current applications of MN technology for diabetes management and how these could prevent diabetes induced fibrosis.

Microarray patches: Breaking down the barriers to contraceptive care and HIV prevention for women across the globe.

Despite the existence of a variety of contraceptive products for women, as well as decades of research into the prevention and treatment of human immunodeficiency virus (HIV), there is still a globally unmet need for easily accessible, acceptable, and affordable products to protect women's sexual and reproductive health. Microarray patches (MAPs) are a novel platform being developed for the delivery of hormonal contraception and antiretroviral drugs. MAPs provide enhanced drug delivery to the systemic circulation via the transdermal route when compared to transdermal patches, oral and injectable formulations. These minimally invasive patches can be self-administered by the user, reducing the burden on health care personnel. Since MAPs represent needle-free drug delivery, no sharps waste is generated after application, thereby eliminating possible MAP reuse and risk of needle-stick injuries. This review discusses the administration of contraceptive and antiretroviral drugs using MAPs, their acceptability by end-users, and the future perspective of the field.

Design and Development of Liquid Drug Reservoirs for Microneedle Delivery of Poorly Soluble Drug Molecules.

The poor aqueous solubility of existing and emerging drugs is a major issue faced by the pharmaceutical industry. Water-miscible organic solvents, termed co-solvents, can be used to enhance the solubility of poorly soluble substances. Typically, drugs with poor aqueous solubility and Log P > 3 are not amenable to delivery across the skin. This study investigated the use of co-solvents as reservoirs to be used in combination with hydrogel-forming microneedles to enhance the transdermal delivery of hydrophobic compounds, namely Nile red, olanzapine and atorvastatin. A custom-made Franz cell apparatus was fabricated to test the suitability of a liquid drug reservoir in combination with polymeric microneedles. A co-solvency approach to reservoir formulation proved effective, with 83.30% ± 9.38% of Nile red dye, dissolved in 1 mL poly(ethylene glycol) (PEG 400), permeating neonatal porcine skin over 24 h. PEG 400 and propylene glycol were found to be suitable reservoir media for olanzapine and atorvastatin, with approximately 50% of each drug delivered after 24 h. This work provides crucial proof-of-concept evidence that the manipulation of microneedle reservoir properties is an effective method to facilitate microneedle-mediated delivery of hydrophobic compounds.

Strange Words: Autistic Traits and the Processing of Non-Literal Language.

Previous investigations into metonymy comprehension in ASD have confounded metonymy with anaphora, and outcome with process. Here we show how these confounds may be avoided, using data from non-diagnosed participants classified using Autism Quotient. Participants read sentences containing target words with novel or established metonymic senses (e.g., Finland, Vietnam) in literal- or figurative-supporting contexts. Participants took longer to read target words in figurative contexts, especially where the metonymic sense was novel. Importantly, participants with higher AQs took longer still to read novel metonyms. This suggests a focus for further exploration, in terms of potential differences between individuals diagnosed with ASD and their neurotypical counterparts, and more generally in terms of the processes by which comprehension is achieved.