3D-printed implantable devices with biodegradable rate-controlling membrane for sustained delivery of hydrophobic drugs

Implantable drug delivery systems offer an alternative for the treatments of long-term conditions (i.e. schizophrenia, HIV, or Parkinson's disease among many others). The objective of the present work was to formulate implantable devices loaded with the model hydrophobic drug olanzapine (OLZ) using robocasting 3D-printing combined with a pre-formed rate controlling membrane. OLZ was selected as a model molecule due to its hydrophobic nature and because is a good example of a molecule used to treat a chronic condition schizophrenia. The resulting implants consisted of a poly(ethylene oxide) (PEO) implant coated with a poly(caprolactone) (PCL)-based membrane. The implants were loaded with 50 and 80% (w/w) of OLZ. They were prepared using an extrusion-based 3D-printer from aqueous pastes containing 36-38% (w/w) of water. The printing process was carried out at room temperature. The resulting implants were characterized by using infrared spectroscopy, scanning electron microscopy, thermal analysis, and X-ray diffraction. Crystals of OLZ were present in the implant after the printing process. release studies showed that implants containing 50% and 80% (w/w) of OLZ were capable of providing drug release for up to 190 days. On the other hand, implants containing 80% (w/w) of OLZ presented a slower release kinetics. After 190 days, total drug release was ca. 77% and ca. 64% for implants containing 50% and 80% (w/w) of OLZ, respectively. The higher PEO content within implants containing 50% (w/w) of OLZ allows a faster release as this polymer acts as a co-solvent of the drug

Systemic delivery of tenofovir alafenamide using dissolving and implantable microneedle patches

The human immunodeficiency virus (HIV) remains a global health concern, with 37.7 million people currently living with the infection and 1.5 million new cases every year. Current antiretroviral (ARV) therapies are administered through the oral route daily, often in lifelong treatments, leading to pill fatigue and poor treatment adherence. Therefore, the development of novel formulations for the administration ARV drugs using alternative routes is actively sought out. In this sense, microneedle array patches (MAPs) offer a unique user-centric platform that can be painlessly self-applied to the skin and deliver drugs to the systemic circulation. In this work, dissolving and implantable MAPs loaded with the tenofovir alafenamide (TAF) were developed with the aim of releasing the drug systemically. Both MAPs were sufficiently strong to pierce excised neonatal full-thickness porcine skin and form drug depots. In vitro release experiments performed in dialysis membrane models, demonstrated a relatively fast delivery of the drug in all cases. Franz cells experiments revealed that dissolving and implantable MAPs deposited 47.87 ​± ​16.33 ​μg and 1208.04 ​± ​417.9 ​μg of TAF in the skin after 24 ​h. Pharmacokinetic experiments in rats demonstrated a fast metabolization of TAF into tenofovir, with a rapid elimination of the metabolite from the plasma. The MAPs described in this work could be used as an alternative to current oral treatments for HIV management

Trilayer dissolving polymeric microneedle array loading Rose Bengal transfersomes as a novel adjuvant in early-stage cutaneous melanoma management

Melanoma remains a global concern, but current therapies present critical limitations pointing out the urgent need for novel strategies. Among these, the cutaneous delivery of drugs selectively damaging cancer cells is highly attractive. Rose Bengal (RB) is a dye exhibiting selective cytotoxicity towards melanoma, but the high water solubility and low permeability hinder its therapeutic potential. We previously developed RB-loaded transfersomes (RBTF) to mediate the RB dermal delivery; however, a platform efficiently delivering RBTF in the deepest strata is essential for a successful therapeutic activity. In this regard, dissolving microneedles release the encapsulated cargo up to the dermis, painlessly piercing the outmost skin layers. Therefore, herein we developed and characterised a trilayer dissolving microneedle array (RBTF-TDMNs) loading RBTF to maximise RBTF intradermal delivery in melanoma management. RBTF-TDMNs were proven strong enough to pierce excised porcine skin and rapidly dissolve and deposit RBTF intradermally while maintaining their physicochemical properties. Also, 3D visualisation of the system itself and while penetrating the skin was performed by multi-photon microscopy. Finally, a dermatokinetic study showed that RBTF-TDMNs offered unique delivery efficiency advantages compared to RBTF dispersion and free drug-loaded TDMNs. The proposed RBTF-TDMNs represent a valuable potential adjuvant tool for the topical management of melanoma

Quality Improvement Project to Increase Hepatitis C Virus Screening for Ambulatory GME Internal Medicine Clinic Patients

Background: In 2020, CDC established new guideline expanding Hepatitis C virus (HCV) screening to all adults aged 18 to 79 years. Our QI project objective is to enhance HCV screening amongst the UTRGV-DHR IM department by establishing suitable reminders and educational sessions. Methods: We reviewed HCV screening status of all adult patients 18 to 79 years old from June 1st 2020 to December 1st 2020. We then provided one lecture on the new screening recommendation from CDC 2020 guideline. We also encouraged residents to educate patients on the importance of HCV screening, and to identify and overcome barriers against screening. We then measured HCV screening performed from March 1st 2021 to May 1st 2021. The primary objective is to increase HCV screening in the ambulatory setting by 50%. Results: Among 843 patients from June 1st 2020 to December 1st 2020, 219 patients were screened for HCV (26%). The results from March 1st 2021 to May 1st 2021 was 190 out 548 patients (35%). The difference was significant with p-value of 0.0005 using Chi-square statistical analysis. Conclusions: Even though we did not achieve our primary objective, HCV screening performance in our clinic had increased significantly from 26% to 35%. With this positive result, we will continue to enhance awareness among the residents by implementing didactic lectures to support evidence –based medicine practice about HCV screening. It is also important to identify the drawbacks of HCV screening including stress on patients and their family, future costs and side-effects of further testing and treatments

Atorvastatin-Loaded Dissolving Microarray Patches for Long-Acting Microdepot Delivery: Comparison of Nanoparticle and Microparticle Drug Formulations

The increasing popularity of prolonged-release dosage forms, owing to their ability to provide continuous drug release after administration, has significantly improved patient compliance and overall quality of life. However, achieving prolonged release beyond 24 h frequently requires the use of invasive methods, including injections or implants, which may prove challenging for people suffering from needle phobia. This study introduces atorvastatin (ATR) microparticles (MPs) or nanocrystal (NCs) dissolving microarray patches (D-MAPs) as a noninvasive alternative for intradermal drug delivery over a two-week period for the management of hyperlipidemia. The MP-loaded D-MAPs exhibited an average drug loading of 5.15 ± 0.4 mg of ATR per patch, surpassing the 2.4 ± 0.11 mg/patch observed with NC-loaded D-MAPs. Skin deposition studies demonstrated the superior performance of MP D-MAPs, which delivered 2.0 ± 0.33 mg of ATR per 0.75 cm2 patch within 24 h, representing 38.76% of the initial amount of drug loaded. In contrast, NC D-MAPs delivered approximately 0.89 ± 0.12 mg of ATR per 0.75 cm2 patch at 24 h, equivalent to 38.42 ± 5.13% of the initial ATR loaded. Due to their favorable results, MP D-MAPs were chosen for an in vivo study using Sprague–Dawley rats. The findings demonstrated the capacity of D-MAPs to deliver and attain therapeutically relevant ATR concentrations (>20 ng/mL) for 14 days after a single 24-h application. This study is the first to successfully demonstrate the long-acting transdermal delivery of ATR using MP-loaded D-MAPs after a 24-h single-dose application. The innovative D-MAP system, particularly when loaded with MP, arises as a promising, minimally invasive, long-acting substitute for ATR delivery. This technology has the potential to improve patient compliance and therapeutic outcomes while also significantly advancing the field of transdermal drug delivery

UHPLC-MS Phenolic Fingerprinting, Aorta Endothelium Relaxation Effect, Antioxidant, and Enzyme Inhibition Activities of Azara dentata Ruiz & Pav Berries

Azara dentata Ruiz & Pav. is a small Chilean native plant from Patagonia, a producer of small white reddish berries. For the first time, the proximal analysis of the fruits, phenolic fingerprinting, the antioxidant activity, and the enzymatic inhibition and relaxation effects in rat aorta induced by the ethanolic extract of these fruits were investigated. The proximal composition and the mineral (Ca: 2434 ± 40 mg/kg; Mg: 702 ± 13 mg/kg; Fe: 117.1 ± 1.6 mg/kg; Zn: 16.1 ± 0.4 mg/kg) and heavy metal (As: 121 ± 11 µg/kg; Cd: 152 ± 5 µg/kg; Hg: 7.7 ± 1.3 µg/kg; Pb 294 ± 4 µg/kg) contents were analyzed. Anthocyanins, flavonoids, phenolic acids, and coumarins were identified using UHPLC-PDA-QTOF-MS. The ethanolic extracts showed a total phenolic content of 23.50 ± 0.93 mg GAE/g extract. In addition, the antioxidant activity was assessed using both DPPH and TEAC (28.64 ± 1.87 and 34.72 ± 2.33 mg Trolox/g of dry fruit, respectively), FRAP (25.32 ± 0.23 mg Trolox equivalent/g dry fruit), and ORAC (64.95 ± 1.23 mg Trolox equivalents/g dry fruit). The inhibition of enzymatic activities (acetylcholinesterase IC50: 2.87 + 0.23 µg extract/mL, butyrylcholinesterase IC50: 6.73 + 0.07 µg extract/mL, amylase IC50: 5.6 ± 0.0 µg extract/mL, lipase IC50: 30.8 ± 0.0 µg extract/mL, and tyrosinase IC50: 9.25 ± 0.15 µg extract/mL) was also assessed. The extract showed 50–60% relaxation in rat aorta (intact), mediated thorough the release of endothelial nitric oxide. Our results suggest that A. dentata is a good source of compounds with the capacity to inhibit important enzymes, can be hypotensive, and can thus have good potentiality as supplements in the amelioration of neurodegenerative diseases and could also have potential to be used to develop new functional foods. The study highlights the benefits of these neglected small fruits and could boost their consumption.Fil: Cuesta Ramos, Lucia. Universidad de Valencia; EspañaFil: Palacios, Javier. Universidad Arturo Prat (unap);Fil: Barrientos, Ruth E.. Universidad Austral de Chile; ChileFil: Gómez Pelaytay, Jessica Belén. Universidad Nacional de San Juan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Castagnini, Juan Manuel. Universidad de Valencia; EspañaFil: Barba, Francisco J.. Universidad de Valencia; EspañaFil: Tapia, Alejandro. Universidad Nacional de San Juan; ArgentinaFil: Paredes, Adrián. Universidad de Antofagasta (uantof);Fil: Cifuentes, Fredi. Universidad de Antofagasta (uantof);Fil: Simirgiotis, Mario J.. Universidad Austral de Chile; Chil

Ring inserts as a useful strategy to prepare tip-loaded microneedles for long-acting drug delivery with application in HIV pre-exposure prophylaxis

The role of microneedle array patches (MAPs) and, in particular, dissolving MAPs in transdermal drug delivery has increased exponentially over the last decade. MAPs are able to form drug depots in the viable skin from where poorly soluble drugs dissolve in a long-acting fashion, showing promise in the management of multiple diseases. The manufacture of these systems can present some challenges, including the presence of bubbles in the baseplates and consequent lack of uniformity in microneedle formation and drug content. Here, we present a simple method based on ring inserts to produce tip-loaded MAPs using the antiretroviral drug cabotegravir sodium (CAB). The obtained MAPs presented a high uniformity in terms of microneedle formation, and a suitable insertion capability, as per the mechanical characterisation performed. An optimisation based on design of experiments revealed that centrifugation parameters had a significant impact on the skin deposition of the MAPs in excised neonatal porcine skin using Franz cells, with values ranging from 62.24 ± 47.13 µg to 174.13 ± 41.10 µg of CAB. Pharmacokinetic studies carried out in rats evidenced the capacity of the MAPs to maintain therapeutic plasma levels of CAB for 14 days, with Tmax values reached between 5 and 8 days

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-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 + 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

N=1 SQCD-like theories with N_f massive flavors from AdS/CFT and beta functions

We study new supergravity solutions related to large-$N_c$ ${\cal N}=1$ supersymmetric gauge field theories with a large number $N_f$ of massive flavors. We use a recently proposed framework based on configurations with $N_c$ color D5 branes and a distribution of $N_f$ flavor D5 branes, governed by a function $N_f S(r)$. Although the system admits many solutions, under plausible physical assumptions the relevant solution is uniquely determined for each value of $x\equiv N_f/N_c$. In the IR region, the solution smoothly approaches the deformed Maldacena-N\'u\~nez solution. In the UV region it approaches a linear dilaton solution. For $x<2$ the gauge coupling $\beta_g$ function computed holographically is negative definite, in the UV approaching the NSVZ $\beta$ function with anomalous dimension $\gamma_0= -1/2$ (approaching $-3/(32\pi^2)(2N_c-N_f)g^3$)), and with $\beta_g \to-\infty$ in the IR. For $x=2$, $\beta_g$ has a UV fixed point at strong coupling, suggesting the existence of an IR fixed point at a lower value of the coupling. We argue that the solutions with $x>2$ describe a "Seiberg dual" picture where $N_f-2N_c$ flips sign.Comment: 18 pages, 10 figure

El mazateco de Oaxaca

El proyecto analiza la variación y el cambio en la fonología, léxico, morfología y sintaxis del mazateco que se habla en las Regiones de la Cuenca y la Cañada (Santo Domingo del Río, Xalapa de Díaz, Huautla de Jiménez y Santa María Asunción) del estado de Oaxaca de la República Mexican