Analytical rheology as a tool for the structural investigation of citrus pectin.

Rheological analysis of citrus pectin at pH 3 and 7 elucidates its structural dynamics, revealing distinct behaviors influenced by pH. At pH 3, pectin exhibits shear-thinning, with solvent-independent unified rheological profiles identifying three concentration regimes: 0.5%-1.5%, 2%-3%, and 3.5%-4%. These regimes, alongside Cox-Merz superpositions, outline the semi-dilute (c*) and concentrated (c**) transitions at 1.5%-2% and 3%-3.5%, respectively. Moreover, a Morris equation exponent of 0.65 indicates flexible, mobility-restricted macromolecules. Conversely, at pH 7, increased viscosities and Morris plot linearity for p = .1 suggest rigid chain behavior due to electrostatic repulsion among ionized acidic groups. This rigidity leads to concentration-dependent self-assembly structures that diverge from expected unified rheological profiles, a deviation amplified by heating-cooling cycles. This study clarifies the impact of pH on citrus pectin's rheology and emphasizes the intricate relationship between polymeric chain rigidity, self-assembly, and viscosity. By providing a refined understanding of these mechanisms, our findings contribute to the broader field of polysaccharide research, offering insights critical for developing and optimizing pectin-based applications in various industries.

Development and characterization of solid lipid-based formulations (sLBFs) of ritonavir utilizing a lipolysis and permeation assay.

As a high number of active pharmaceutical ingredients (APIs) under development belong to BCS classes II and IV, the need for improving bioavailability is critical. A powerful approach is the use of lipid-based formulations (LBFs) that usually consist of a combination of liquid lipids, cosolvents, and surfactants. In this study, ritonavir loaded solid LBFs (sLBFs) were prepared using solid lipid excipients to investigate whether sLBFs are also capable of improving solubility and permeability. Additionally, the influence of polymeric precipitation inhibitors (PVP-VA and HPMC-AS) on lipolysis triggered supersaturation and precipitation was investigated. One step intestinal digestion and bicompartmental permeation studies using an artificial lecithin-in-dodecane (LiDo) membrane were performed for each formulation. All formulations presented significantly higher solubility (5 to >20-fold higher) during lipolysis and permeation studies compared to pure ritonavir. In the combined lipolysis-permeation studies, the formulated ritonavir concentration increased 15-fold in the donor compartment and the flux increased up to 71 % as compared to non-formulated ritonavir. The formulation with the highest surfactant concentration showed significantly higher ritonavir solubility compared to the formulation with the highest amount of lipids. However, the precipitation rates were comparable. The addition of precipitation inhibitors did not influence the lipolytic process and showed no significant benefit over the initial formulations with regards to precipitation. While all tested sLBFs increased the permeation rate, no statistically significant difference was noted between the formulations regardless of composition. To conclude, the different release profiles of the formulations were not correlated to the resulting flux through a permeation membrane, further supporting the importance of making use of combined lipolysis-permeation assays when exploring LBFs.

Exploring the use of modified in vitro digestion assays for the evaluation of ritonavir loaded solid lipid-based formulations.

Solid lipid-based formulations (sLBFs) have the potential to increase the oral bioavailability of drugs with poor solubility in water, while counteracting some of the disadvantages of liquid LBFs. The most common experimental set-up to study the performance of LBFs in vitro is the lipolysis assay, during which the LBFs are digested by lipases in an environment mimicking the human small intestine. However, this assay has failed in many cases to correctly predict the performance of LBFs in vivo, highlighting the need for new and improved in vitro assays to evaluate LBFs at the preclinical stage. In this study, the suitability of three different in vitro digestion assays for the evaluation of sLBFs was assessed; the classic one-step intestinal digestion assay, a two-step gastrointestinal digestion assay and a bicompartmental assay permitting the simultaneous monitoring of digestion and permeation of the active pharmaceutical ingredient (API) across an artificial membrane (Lecithin in Dodecane - LiDo). Three sLBFs (M1-M3) with varied composition and ritonavir as model drug were prepared and examined. When comparing the ability of these formulations to keep the drug solubilized in the aqueous phase, all three assays show that M1 performs better, while M3 presents poor performance. However, the classic in vitro intestinal digestion assay fails to provide a clear ranking of the three formulations, something that is more evident when using the two modified and more physiologically relevant assays. Also, the two modified assays provide additional information about the performance of the formulations including the performance in the gastric environment and intestinal flux of the drug. These modified in vitro digestion assays are valuable tools for the development and evaluation of sLBFs to make better informed decisions of which formulations to pursue for in vivo studies.

Correction: Andreadis et al. The Advent of a New Era in Digital Healthcare: A Role for 3D Printing Technologies in Drug Manufacturing? Pharmaceutics2022, 14, 609.

In the original publication [...].

Stability and rheology of plant-derived hydrocolloid-mucin mixtures.

Mixtures of mucin with pectin were investigated in a range of pectin to mucin ratios and pH values. The phase stability was first studied as absorbance measured at 500 nm (turbidity). Co-existence of the two materials did not result in co-sedimentation or relevant phase separations, while lower pH enhanced aggregation and partial sedimentation of individual components, especially for mucin. The above are in line with the recorded zeta potential values, which are negative for both components at neutral pH and drop down to almost zero at acidic values. The sizes of the particles, as recorded by dynamic light scattering, show a similar trend to the absorbance values, indicating that phase separations are in line with events at the scale of a few hundred nm. Such interactions reflect in shear rheology: The viscosity corresponding to 50 s-1 decreases upon substitution of pectin with mucin at pH 7 and 3, suggesting a flow dominated by changes in the space occupancy by the two components and by changes in the size of the self-assembled structures. The results were compared with those of more complex and typical hydrocolloids extracted from olive compost: The overall shape of the stability diagram of the two ingredients match, suggesting similar modes of action in the presence of mucin for other natural materials. These data throw some light in the norms during the co-existence of food polysaccharides and mucin in oral and gastrointestinal environments.

The Advent of a New Era in Digital Healthcare: A Role for 3D Printing Technologies in Drug Manufacturing?

The technological revolution has physically affected all manufacturing domains, at the gateway of the fourth industrial revolution. Three-dimensional (3D) printing has already shown its potential in this new reality, exhibiting remarkable applications in the production of drug delivery systems. As part of this concept, personalization of the dosage form by means of individualized drug dose or improved formulation functionalities has concentrated global research efforts. Beyond the manufacturing level, significant parameters must be considered to promote the real-time manufacturing of pharmaceutical products in distributed areas. The majority of current research activities is focused on formulating 3D-printed drug delivery systems while showcasing different scenarios of installing 3D printers in patients' houses, hospitals, and community pharmacies, as well as in pharmaceutical industries. Such research presents an array of parameters that must be considered to integrate 3D printing in a future healthcare system, with special focus on regulatory issues, drug shortages, quality assurance of the product, and acceptability of these scenarios by healthcare professionals and public parties. The objective of this review is to critically present the spectrum of possible scenarios of 3D printing implementation in future healthcare and to discuss the inevitable issues that must be addressed.

In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment.

Most common intraocular pressure (IOP) reduction regimens for the management of glaucoma include the topical use of eye drops, a dosage form that is associated with short residence time at the site of action, increased dosing frequency, and reduced patient compliance. In situ gelling nanofiber films comprising poly(vinyl alcohol) and Poloxamer 407 were fabricated via electrospinning for the ocular delivery of timolol maleate (TM), aiming to sustain the IOP-lowering effect of the ß-blocker, compared to conventional eye drops. The electrospinning process was optimized, and the physicochemical properties of the developed formulations were thoroughly investigated. The fiber diameters of the drug-loaded films ranged between 123 and 145 nm and the drug content between 5.85 and 7.83% w/w. Total in vitro drug release from the ocular films was attained within 15 min following first-order kinetics, showing higher apparent permeability (Papp) values across porcine corneas compared to the drug's solution. The fabricated films did not induce any ocular irritation as evidenced by both the hen's egg test on chorioallantoic membrane and the in vivo Draize test. In vivo administration of the ocular films in rabbits induced a faster onset of action and a sustained IOP-lowering effect up to 24 h compared to TM solution, suggesting that the proposed ocular films are promising systems for the sustained topical delivery of TM.

Physico-mechanical and finite element analysis evaluation of 3D printable alginate-methylcellulose inks for wound healing applications.

The present study reports on the comprehensive physico-mechanical evaluation of 3D printable alginate-methylcellulose hydrogels with bioactive components (Manuka honey, aloe vera gel, eucalyptus essential oil) using a combined experimental-numerical approach. The 3D printable carbohydrate inks demonstrated good swelling properties under moist conditions and adequate antimicrobial and antibiofilm efficacy against both Gram positive and negative bacteria. The effect of the bioactive compounds on the viscosity and mechanical properties of the 3D printable hydrogels was assessed with rheological, nanoindentation and shear test measurements. All hydrogel compositions showed good biocompatibility on human dermal fibroblasts, stimulating cell growth as confirmed by an in vitro wound healing assay. Finite element analysis simulation was employed to further advance the calculation accuracy of the nanoindentation tests, concluding that combination of an experimental and a numerical technique may constitute a useful method to characterize the mechanical behavior of composite hydrogel films for use in wound healing applications.

Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) Containing Rice Bran Oil for Enhanced Fenofibrate Oral Delivery: In Vitro Digestion, Ex Vivo Permeability, and In Vivo Bioavailability Studies.

Lipid-based drug delivery systems (LbDDS), such as self-nanoemulsifying drug delivery systems (SNEDDS), constitute a prominent formulation approach for enhancing the aqueous solubility and oral bioavailability of poorly water-soluble compounds. Utilization of biorefinery wastes, such as oil from rice bran, may prove advantageous to both improving drug solubilization and absorption and to achieving sustainable agri-food waste valorization. Here, we assessed the effect of four SNEDDS compositions differing in the oil (rice bran oil and corn oil) and surfactant type (Kolliphor RH40 and EL) on the oral bioavailability of fenofibrate, a BCS class II compound. Prior to the in vivo oral administration of the SNEDDS in rats, drug solubilization was tested in vitro using the static digestion model, followed by the ex vivo permeability study of the predigested SNEDDS using the non-everted gut sac model. No significant variation was observed in the solubilization capacity within the different SNEDDS formulations. On the other hand, the ex vivo permeability data of the predigested SNEDDS correlated well with the in vivo bioavailability data designating the superiority of rice bran oil with Kolliphor EL as the surfactant, to enhance the oral absorption of fenofibrate. Results indicated that valorization of agro-industrial waste such as rice bran oil may prove useful in enhancing the oral performance of LbDDS in the case of fenofibrate, while at the same time maximizing the use of agricultural by-products via the creation of new sustainable value chains in the pharmaceutical field.

A CADx scheme for mammography empowered with topological information from clustered microcalcifications' atlases.

A computer-aided diagnosis (CADx ) framework for the diagnosis of clustered microcalcifications (MCs) has already been developed, which is based on the analysis of MCs' morphologies,the shape of the cluster they form and the texture of the surrounding tissue. In this study, we investigate the diagnostic information that the relative location of the cluster inside the breast may provide. Breast probabilistic maps are generated and adopted in the CADx pipeline, expecting to empower its diagnostic procedure. We propose a flowchart combining alternative classification algorithms and the aforementioned probabilistic maps in order to provide a final risk for malignancy for new considered mammograms. For the evaluation performance, a large dataset of mammograms provided from the Digital Database of Screening Mammography (DDSM) has been used. The obtained results indicate that the proposed modifications lead to the enhancement of the diagnostic process, as the classification results are further improved. Additionally, a straightforward comparison between the CADx pipeline and the radiologists who assessed the same mammograms, reveal that the CADx pipeline performs toward the right direction, as the sensitivity remains at high levels, while improving both the accuracy, from 51.4% to 69%, and the specificity, from 16.6% to 54.7%.

Detecting complexity abnormalities in dyslexia measuring Approximate Entropy of electroencephalographic signals.

Dyslexia constitutes a specific reading disability, a condition characterized by severe difficulty in the mastery of reading despite normal intelligence or adequate education. Electroencephalogram (EEG) signal may be able to play an important role in the diagnosis of dyslexia. The Approximate Entropy (ApEn) is a recently formulated statistical parameter used to quantify the regularity of a time series data of physiological signals. In this paper, we initially estimated the ApEn values in signals recorded from controls subjects and dyslectic children. These values were firstly used for the statistical analysis of the two groups and secondly as feature input in a classification scheme. We also used the cross-ApEn methodology to get a measure of the asynchrony of the signals recorded from different electrodes. This preliminary study provides promising results towards correct identification of dyslexic cases, analyzing the corresponding EEG signals.