Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa

The currently available antifungal therapy for oral candidiasis (OC) has various limita- tions restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In par- ticular, solid lipid microparticles (SLMs) resulted as a particularly promising penetration enhancer carrier for lipophilic drugs, such as the antifungal miconazole (MCZ). Based on these considera- tions, cetyl decanoate (here synthesized without the use of metal catalysis) was employed together with 1-hexadecanol to prepare MCZ-loaded SLMs. These resulted in a powder composed of 45–300 µm diameter solid spherical particles, able to load a high amount of MCZ in the amorphous form and characterized by a melting temperature range perfectly compatible with oromucosal admin- istration (35–37 °C). Moreover, when compared to Daktarin ® 2% oral gel in ex vivo experiments, SLMs were able to increase up to three-fold MCZ accumulation into the porcine buccal mucosa. The prepared SLMs were then loaded into a buccal gel or a microcomposite mucoadhesive buccal film and evaluated in terms of MCZ permeation and/or accumulation into porcine buccal mucosa by using lower doses than the conventional dosage form. The promising results obtained high- lighted an enhancement in terms of MCZ accumulation even at low doses. Furthermore, the pre- pared buccal film was eligible as stable, reproducible and also highly mucoadhesive. Therefore, the formulated SLMs represent a penetration enhancer vehicle suitable to reduce the dose of lipophilic drugs to be administered to achieve the desired therapeutic effects, as well as being able to be ef- fectively embedded into easily administrable solid or semisolid dosage forms

Buccal Thin Films as Potent Permeation Enhancers for Cytisine Transbuccal Delivery

Cytisine (CYT) is a powerful anti-smoking compound which could greatly benefit from transbuccal delivery because of both its unfavorable pharmacokinetics after oral administration and its intrinsic ability to permeate the buccal mucosa. This work aims to design CYT-loaded buccal thin films suitable for transbuccal drug delivery due to its capability of promoting the interaction between CYT and the buccal membrane. The solvent casting method was employed to prepare several thin films combining various excipients such as matrixing polymers, mucoadhesion agents, plasticizers and other compounds as humectants and sweeteners, component ratios and solvents. A total of 36 compositions was prepared and four of them emerged as the most promising in terms of aspect and flexibility. They all demonstrated homogeneity, thinness, low swelling degree, and controlled drug release according to the Power Law and Peppas-Sahlin mathematical models. Mainly, they proved able to interact with the ex vivo porcine buccal mucosa producing mucoadhesive effects, and act as potent permeation enhancers. In particular, Film B emerged as suitable as it produced a 10.6-fold Kp enhancement and a great Js value (52.33 μg/cm2·h-1), even when compared to highly concentrated CYT solutions

Inulin-Based Polymeric Micelles Functionalized with Ocular Permeation Enhancers: Improvement of Dexamethasone Permeation/Penetration through Bovine Corneas

Ophthalmic drug delivery is still a challenge due to the protective barriers of the eye. A common strategy to promote drug absorption is the use of ocular permeation enhancers, while an innovative approach is the use of polymeric micelles. In the present work, the two mentioned approaches were coupled by conjugating ocular permeation enhancers (PEG2000, carnitine, creatine, taurine) to an inulin-based co-polymer (INU-EDA-RA) in order to obtain self-assembling biopolymers with permeation enhancer properties for the hydrophobic drug dexamethasone (DEX). Inulin derivatives were properly synthetized, were found to expose about 2% mol/mol of enhancer molecules in the side chain, and resulted able to self-assemble at various concentrations by varying the pH and the ionic strength of the medium. Moreover, the ability of polymeric micelles to load dexamethasone was demonstrated, and size, mucoadhesiveness, and cytocompatibility against HCE cells were evaluated. Furthermore, the efficacy of the permeation enhancer was evaluated by ex vivo permeation studies to determine the performance of the used enhancers, which resulted in PEG2000 > CAR > TAU > CRE, while entrapment ability studies resulted in CAR > TAU > PEG2000 > CRE, both for fluorescent-labelled and DEX-loaded micelles. Finally, an increase in terms of calculated Kp and Ac parameters was demonstrated, compared with the values calculated for DEX suspension

Green next generation biomaterials from virtuous recovery of grape processing waste bentonite

The waste valorisation, by conversion of discharge products into novel high value-added biomaterials, represents a virtuous strategy to contribute to the ecological transition while producing social, economic and scientific repercussions. Even more, the recycle of wastes from the local resources could maximize the impact of the circular economy idea by enhancing the territorial resources and creating new products free from additional raw materials consumption. About this, the grape processing industry is an undoubted Sicilian prestige, but it also produces abundant both organic and inorganic wastes. While grape pomace has been extensively valorised in the last years, the inorganic wastes have never been considered yet. The latter are mainly the fining agents, among which bentonite is the most common one. It is a mineral clay widely used due to low cost, abundance in nature, high clarifying power and ease of separation from the fined product by sedimentation. So far, the bentonite is just an abundant waste (100g of bentonite to fine 1hL of must/wine) then the aim of this work is to recognize it as a precious source of polyphenols to be given new life by extraction. The frozen waste black bentonite was supplied by Bono&Ditta S.p.A. Once arrived at the University of Palermo it was subjected to pulverization, sieved, divided into aliquots identified as belonging to the same lot and stored at -80°C. Samples of bentonite were subjected to green extraction by maceration (1h, 25°C, constant stirring, in the dark) choosing unconventional extraction solvents among well-known and currently used hydrophilic liquid excipients for pharmaceuticals and cosmetics. They were PEGs (PEG200, PEG400, PEG600), propylene glycol and glycerine, selected due to their high solvent power toward polyphenols and biocompatibility. The coloured liquid extracts were characterized and compared in terms of antioxidant power/scavenging activity by DPPH assay, chromatographic profile and extracted amount of some representative polyphenols by HPLC-DAD analyses, total phenolic and protein contents by Folin-Ciocalteu and Bradford assays respectively. The best extract was obtained by using PEG200 and was then further studied. It resulted stable at easily achievable storage conditions (4°C, in the dark) for at least 6 months. Furthermore, it is suitable as a novel, value-added biomaterial for biomedical and cosmetic purposes as nor skin/eye irritation neither skin sensitising potential emerged by the in vitro tests, according to OECD 439/492/442E guidelines. Importantly, the “green soul” of this work is not just related to waste bentonite valorisation. The extraction procedure can be considered eco-friendly both in terms of employed technique and chosen extraction solvents. This choice perfectly fit with an industrial, easily scalable and waste-to-market approach as well as with the SDGs 12, 8 and 3 of the UN agenda 2030

HYALURONIC ACID DERIVATIVE MICELLES AS OCULAR PLATFORMS TO DRUG RELEASE AND CORNEAL PERMEATION

In traditional ocular formulations, only small amount of the administered drug penetrates the cornea to reach the intraocular tissue. One approach to improve the drug ocular bioavailability was to develop colloidal drug delivery systems. Polymeric micelles seem to be very promising for their capacity to dissolve a variety of hydrophobic drugs by enhancing their water solubility and so their bioavailability. They are able to increase ocular drug permeability due to interact with the complex corneal structure. Considering the advantages to use mucoadhesive polymer to increase drug residence time on the ocular surface, the aim of this work was to prepare hyaluronic acid-based micelles as a platform to release corticosteroids on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA), bearing different amount of hexadecylamine chains (C16), were synthesised and characterized. These are able to form micelles by using the co-solvent evaporation method. All HAC16 derivatives have shown the ability of durable mucoadhesive interactions and resulted potentially useful for corticosteroids encapsulation. Drug-loaded micelles were prepared and characterized in term of drug loading amount and particle size. Moreover, the in vitro drug release studies from micellar systems were carried out in comparison with the dissolution profile of the free drug suspension. Cytocompatibility studies also were performed with HCEpiC cells. HAC16b (DDC16mol%=12%) micelles are selected as the best nanosystems, and their capacity to improve the drugs permeability across corneal barrier are evaluated. Thus, the ex vivo permeation studies were conducted using bovine corneas and Franz type diffusion cells

Lipid Nanoparticles Loaded With Resveratrol And Glycyrrhetinic Acid As New Tool For Wound Healing

Skin and mucous membranes maintain the homeostasis of the full body and are the first barriers against microbial infections. Therefore, their integrity is crucial and any lesion or injury must be quickly treated. In healthy people, several steps, such as inflammation, production of pro-oxidative species, cells proliferation and remodelling, follow each other creating a cascade process that determine the total restoration of the injured tissue. However, even a single discrepancy in these phases can delay the wound healing or irreversibly compromise the tissue. A smart strategy to promote wound healing could be the administration of natural compounds such as polyphenols and triterpenoids which are characterized by strong antioxidant and anti-inflammatory activities, antimicrobial properties and low side effects. However, the beneficial effects of these molecules are limited by their disadvantageous physico-chemical properties (e.g., low solubility in water, degradation) that compromise their bioavailability and thereby their clinical use. Based on these considerations, the aim of this work was to prepare and characterize a novel drug delivery system in form of multicomponent lipid nanoparticles (LNPs) constituted by a complex mixture of PEGylated lipid, Glyceryl monoester and Menthol able to entrap the polyphenol Resveratrol (RSV) and the triterpenoid Glycyrrhetinic Acid (GA) in order to protect them from degradation and maximize their effectiveness so as to make them useful for the wound management. Following optimization of the lipid blend composition and excipient ratios, it resulted homogeneous, with a melting range temperature of 57-61°C and containing GA (2.73 ± 0.23%w/w) and RSV (4.56 ± 0.04%w/w) in the amorphous form. The LNPs, obtained by homogenization followed by high-frequency sonication, were characterized by DLS and SEM analyses resulting almost monodispersed (PDI: 0.267 ± 0.010), with spherical shape (by SEM), nanometric size (162.86 ± 3.12nm) and suitable Z-potential (-21.40 ± 7.33mV). The quantitative analyses showed high encapsulation efficiency for both RSV and GA having a suitable DR% (96.82 ± 1.34% and 99.6 ± 1.29%, respectively) and LE% (96.82 ± 1.34% and 97.15 ± 0.19%, respectively) values. RSV release studies highlighted a sustained and controlled pattern of discharge to different chemical environments simulating the wound conditions. Moreover, LNPs showed significant scavenger properties evaluated by the DPPH assay. Last, the biological evaluations (scratch assay) highlighted an enhanced fibroblasts proliferation and migration at extremely low doses (LNPs 22 μg/mL corresponding to RSV 5 μM). Furthermore, a promising antibiofilm effect against Staphilococcus aureus was observed in a dose-dependent manner. In conclusion, these novel multicomponent LNPs could represent a next generation carrier constituting a promising tool for wound healing purposes

Multicomponent Antibiofilm Lipid Nanoparticles as Novel Platform to Ameliorate Resveratrol Properties: Preliminary Outcomes on Fibroblast Proliferation and Migration

: The well-being of skin and mucous membranes is fundamental for the homeostasis of the body and thus it is imperative to treat any lesion quickly and correctly. In this view, polyphenols might assist and enhance a successful wound healing process by reducing the inflammatory cascade and the production of free radicals. However, they suffer from disadvantageous physico-chemical properties, leading to restricted clinical use. In this work, a complex mixture of PEGylated lipid, Glyceryl monoester, 18-β-Glycyrrhetinic Acid and Menthol was designed to entrap Resveratrol (RSV) as the active ingredient and further produce lipid nanoparticles (LNPs) by homogenization followed by high-frequency sonication. The nanosystem was properly characterized in terms of particle size (DLS, SEM), zeta potential, drug loading, antioxidant power (DPPH), release behaviour, cytocompatibility, wound healing and antibiofilm properties. The optimized lipid mixture was homogeneous, melted at 57-61 °C and encapsulated amorphous RSV (4.56 ± 0.04% w/w). The RSV-loaded LNPs were almost monodispersed (PDI: 0.267 ± 0.010), with nanometric size (162.86 ± 3.12 nm), scavenger properties and suitable DR% and LE% values (96.82 ± 1.34% and 95.17 ± 0.25%, respectively). The release studies were performed to simulate the wound conditions: 1-octanol to mimic the lipophilic domains of biological tissues (where the First Order kinetic was observed) and citrate buffer pH 5.5 according to the inflammatory wound exudate (where the Korsmeyer-Peppas kinetic was followed). The biological and microbiological evaluations highlighted fibroblast proliferation and migration effects as well as antibiofilm properties at extremely low doses (LNPs: 22 μg/mL, corresponding to RSV 5 µM). Thus, the proposed multicomponent LNPs could represent a valuable RSV delivery platform for wound healing purposes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population