Microfluidic manufacturing of tioconazole loaded keratin nanocarriers: Development and optimization by design of experiments.

Fungal infections of the skin, nails, and hair are a common health concern affecting a significant proportion of the population worldwide. The current treatment options include topical and systematic agents which have low permeability and prolonged treatment period, respectively. Consequently, there is a growing need for a permeable, effective, and safe treatment. Keratin nanoparticles are a promising nanoformulation that can improve antifungal agent penetration, providing sustainable targeted drug delivery. In this study, keratin nanoparticles were prepared using a custom-made 3D-printed microfluidic chip and the manufacturing process was optimized using the design of experiments (DoE) approach. The total flow rate (TFR), flow rate ratio (FRR), and keratin concentration were found to be the most influential factors of the size and polydispersity index (PDI) of the nanoparticles. The crosslinking procedure by means of tannic acid as safe and biocompatible compound was also optimized. Keratin nanoparticles loaded with a different amount of tioconazole showed a size lower than 200 nm, a PDI lower than 0.2 and an encapsulation efficiency of 91 ± 1.9 %. Due to their sustained drug release, the formulations showed acceptable in vitro biocompatibility. Furthermore, a significant inhibitory effect compared to the free drug against Microsporum canis.

3D-printed EVA-based patches manufactured by direct powder extrusion for personalized transdermal therapies.

In recent years, 3D printing has attracted great interest in the pharmaceutical field as a promising tool for the on-demand manufacturing of patient-centered pharmaceutical forms. Among the existing 3D printing techniques, direct powder extrusion (DPE) resulted as the most practical approach thanks to the possibility to directly process excipients and drugs in a single step. The main goal of this work was to determine whether different grades of ethylene vinyl acetate (EVA) copolymer might be employed as new feedstock materials for the DPE technique to manufacture transdermal patches. By selecting two model drugs with different thermal behavior, (i.e., ibuprofen and diclofenac sodium) we also wanted to pay attention to the versatility of EVA excipient in preparing patches for customized transdermal therapies. EVA was combined with 30 % (w/w) of each model drugs. The physicochemical composition of the printed devices was investigated through Fourier-transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analyses. FT-IR spectra confirmed that the starting materials were effectively incorporated into the final formulation, and thermal analyses demonstrated that the extrusion process altered the crystalline morphology of the raw polymers inducing the formation of crystals at lower thicknesses. Lastly, the drug release and permeation profile of the printed systems was evaluated for 48 h and showed to be dependent on the VA content of the EVA grade (74.5 % of ibuprofen released from EVA 4030AC matrix and 12.6 % of diclofenac sodium released from EVA1821A matrix). Hence, this study demonstrated that EVA and direct powder extrusion technique could be promising tools for manufacturing transdermal patches. By selecting the EVA grade with the appropriate VA content, drugs with dissimilar melting points could be printed preserving their thermal stability. Moreover, the desired drug release and permeation profile of the drug can be achieved, representing an important advantage in terms of personalized medicine.

A microfluidic approach to fabricate sucrose decorated liposomes with increased uptake in breast cancer cells.

Developing targeted drug delivery systems is an urgent need to decrease the side effects and increase the drug's efficiency. Most cancer cells show an increased sugar consumption compared to healthy cells due to the deregulation of sugar transporters. Consequently, liposomes, as a biocompatible nanocarrier, could be surface decorated by sugars to enhance drug targeting into cancer cells. Our work outlines a new strategy to easily manufacture sucrose decorated liposomes using sucrose stearate, a biocompatible and biodegradable non-ionic surfactant, with a scalable microfluidic approach. Sucrose decorated liposomes were loaded with berberine hydrochloride, a well-known phytochemical compound to investigate its effects on triple-negative breast cancer cells (MDA-MB-231). Using the microfluidic manufacturing system, we prepared berberine-loaded liposomes using a mixture of phosphatidylcholine and cholesterol with and without sucrose stearate with a size up to 140 nm and narrow polydispersity. Stability was confirmed for 90 days, and the in vitro release profile was evaluated. The formulations showed acceptable in vitro biocompatibility and significantly higher anti-proliferative effect on MDA-MB-231 cell line. These results have been confirmed by an increased uptake evaluated by flow cytometry and confocal microscopy. Taken together, our findings represent an innovative, easy, and scalable approach to obtain sugar decorated liposomal formulations without any surface-chemistry reactions. They can be potentially used as an anticancer targeted drug delivery system.

Poly(3-hydroxybutyrate): A potential biodegradable excipient for direct 3D printing of pharmaceuticals.

During the past decades, 3D printing has revolutionised different areas of research. Despite the considerable progress achieved in 3D printing of pharmaceuticals, the limited choice of suitable materials remains a challenge to overcome. The growing search for sustainable excipients has led to an increasing interest in biopolymers. Poly(3-hydroxybutyrate) (PHB) is a biocompatible and biodegradable biopolymer obtained from bacteria that could be efficiently employed in the pharmaceutical field. Here we aimed to demonstrate its potential application as a thermoplastic material for personalised medicine through 3D printing. More specifically, we processed PHB by using direct powder extrusion, a one-step additive manufacturing technique. To assess and denote the feasibility and versatility of the process, a 3D square model was manufactured in different dimensions (sidexheight: 12x2 mm; 18x2 mm; 24x2 mm) and loaded with increasing percentages of a model drug (up to 30% w/w). The manufacturing process was influenced by the drug content, and indeed, an increase in the amount of the drug determined a reduction in the printing temperature, without affecting the other parameters (such as the layer height). The composition of the model squares was investigated using Fourier-transform infrared spectroscopy, the resulting spectra confirmed that the starting materials were successfully incorporated into the final formulations. The thermal behaviour of the printed systems was characterized by differential scanning calorimetry, and thermal gravimetric analysis. Moreover, the sustained drug release profile of the formulations was performed over 21 days and showed to be dependent on the dimensions of the printed object and on the amount of loaded drug. Indeed, the formulation with 30% w/w in the dimension 24x2 mm released the highest amount of drug. Hence, the results suggested that PHB and direct powder extrusion technique could be promising tools for the manufacturing of prolonged release and personalised drug delivery forms.

A Hydrogen-Bonded Extracellular Matrix-Mimicking Bactericidal Hydrogel with Radical Scavenging and Hemostatic Function for pH-Responsive Wound Healing Acceleration.

Generation of reactive oxygen species, delayed blood clotting, prolonged inflammation, bacterial infection, and slow cell proliferation are the main challenges of effective wound repair. Herein, a multifunctional extracellular matrix-mimicking hydrogel is fabricated through abundant hydrogen bonding among the functional groups of gelatin and tannic acid (TA) as a green chemistry approach. The hydrogel shows adjustable physicochemical properties by altering the concentration of TA and it represents high safety features both in vitro and in vivo on fibroblasts, red blood cells, and mice organs. In addition to the merit of facile encapsulation of cell proliferation-inducing hydrophilic drugs, accelerated healing of skin injury is obtained through pH-dependent release of TA and its multifaceted mechanisms as an antibacterial, antioxidant, hemostatic, and anti-inflammatory moiety. The developed gelatin-TA (GelTA) hydrogel also shows an outstanding effect on the formation of extracellular matrix and wound closure in vivo via offered cell adhesion sites in the backbone of gelatin that provide increased re-epithelialization and better collagen deposition. These results suggest that the multifunctional GelTA hydrogel is a promising candidate for the clinical treatment of full-thickness wounds and further development of wound dressing materials that releases active agents in the neutral or slightly basic environment of infected nonhealing wounds.