In their article, Casiraghi, A. et al. describe a few relevant methods to assess the quality of a pharmaceutical preparation of oral viscous budesonide, intended to be swallowed, and treat the esophagus in eosinophilic esophagitis patients. They choose the following methods for this purpose: rheological properties, syringeability, mucoadhesiveness, and in vitro penetration of budesonide in porcine esophageal tissue. At the end of the article, they concluded that the best formulation of oral viscous budesonide was the one already being used in hospitals, based on xanthan gum. In their article, the authors did not emphasize that this specific formula was developed by the compounding pharmacist Eyal Zur from Israel and was published eight years before, as part of an article in the International Journal of Pharmaceutical Compounding. The purpose of this comment is to give the appropriate credit to the pharmacist who first developed and published this well designed formulation. Full article

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of −10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC₅₀), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX. Full article

Delivering active pharmaceutical agents to disease sites using soft polymeric nanoparticles continues to be a topical area of research. It is becoming increasingly evident that the composition of amphiphilic macromolecules plays a significant role in developing efficient nanoformulations. Branched architectures with asymmetric polymeric arms emanating from a central core junction have provided a pivotal venue to tailor their key parameters. The build-up of miktoarm stars offers vast polymer arm tunability, aiding in the development of macromolecules with adjustable properties, and allows facile inclusion of endogenous stimulus-responsive entities. Miktoarm star-based micelles have been demonstrated to exhibit denser coronae, very low critical micelle concentrations, high drug loading contents, and sustained drug release profiles. With significant advances in chemical methodologies, synthetic articulation of miktoarm polymer architecture, and determination of their structure-property relationships, are now becoming streamlined. This is helping advance their implementation into formulating efficient therapeutic interventions. This review brings into focus the important discoveries in the syntheses of miktoarm stars of varied compositions, their aqueous self-assembly, and contributions their formulations are making in advancing the field of drug delivery. Full article

Amorphous silica nanoparticles (SiO₂NPs) have been widely used in medicine including targeted drug/DNA delivery, cancer therapy, and enzyme immobilization. Nevertheless, SiO₂NPs should be used with caution due to safety concerns associated with unique physical and chemical characteristics. The objective of this study was to determine the effects of SiO₂NPs on genotoxic and non-genotoxic mechanisms associated with abnormal gap junctional intercellular communication (GJIC) in multistage carcinogenesis. The SiO₂NPs exhibited negative responses in standard genotoxicity tests including the Ames test, chromosome aberration assay, and micronucleus assay. In contrast, the SiO₂NPs significantly induced DNA breakage in comet assay. Meanwhile, SiO₂NPs inhibited GJIC based on the results of scrape/loading dye transfer assay for the identification of non-genotoxic tumor-promoting potential. The reduction in expression and plasma membrane localization of Cx43 was detected following SiO₂NP treatment. Particularly, SiO₂NP treatment increased Cx43 phosphorylation state, which was significantly attenuated by inhibitors of extracellular signal-regulated kinases 1/2 (ERK1/2) and threonine and tyrosine kinase (MEK), but not by protein kinase C (PKC) inhibitor. Taken together, in addition to a significant increase in DNA breakage, SiO₂NP treatment resulted in GJIC dysregulation involved in Cx43 phosphorylation through the activation of mitogen-activated protein kinase (MAPK) signaling. Overall findings of the genotoxic and non-genotoxic carcinogenic potential of SiO₂NPs provide useful toxicological information for clinical application at an appropriate dose. Full article

Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro Plasmodium falciparum cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL). This led to the selection of five chemically modified heparins according to the parameters explored, i.e., chain length, sulfation degree and position, and glycol-split, and whose in vivo toxicity indicated their safety for mice up to an intravenous dose of 320 mg/kg. The in vivo antimalarial activity of the selected formulations was poor as a consequence of their short blood half-life. The covalent crosslinking of heparin onto the surface of polyethylene glycol-containing liposomes did not affect its antimalarial activity in vitro and provided higher initial plasma concentrations, although it did not increase mean circulation time. Finding a suitable nanocarrier to impart long blood residence times to the modified heparins described here will be the next step toward new heparin-based antimalarial strategies. Full article

Shikimic acid, a critical starting material for the semi-total synthesis of oseltamivir to treat and prevent influenza, exerts many pharmacological effects. However, the optimal bioanalytical method has not been adequately defined. We used liquid chromatography-tandem mass spectrometry to quantitate shikimic acid in rat plasma and studied its pharmacokinetics after intragastric and intravenous administration. Plasma was spiked with an internal standard, and the proteins were precipitated with acetonitrile, followed by solvent evaporation and reconstitution of the mobile phase. Shikimic acid was separated on a hydrophilic reverse-phase column and showed a mass transition ([M-H]⁻) at m/z 173.4→136.6. Shikimic acid exhibited bi-exponential decay after intravenous dosing, with a rapid distribution (5.57 h⁻¹) up to 1 h followed by slow elimination (0.78 h⁻¹). The steady state distribution and clearance volumes were 5.17 and 1.79 L/h/kg, respectively. After intragastric administration, the shikimic acid level peaked at about 3 h, and the material then disappeared mono-exponentially with a half-life of 1.3 h. A double peak phenomenon was observed. The absolute oral bioavailability was about 10% in rats. We explored the relationship between the pharmacokinetics and pharmacodynamics of shikimic acid. Full article

Bone morphogenetic protein-2 (BMP-2) is a known key mediator of physiological bone regeneration and is clinically approved for selected musculoskeletal interventions. Yet, broad usage of this growth factor is impeded due to side effects that are majorly evoked by high dosages and burst release kinetics. In this study, mesoporous bioactive glass microspheres (MBGs), produced by an aerosol-assisted spray-drying scalable process, were loaded with BMP-2 resulting in prolonged, low-dose BMP-2 release without affecting the material characteristics. In vitro, MBGs were found to be cytocompatible and to induce a pro-osteogenic response in primary human mesenchymal stromal cells (MSCs). In a pre-clinical rodent model, BMP-2 loaded MBGs significantly enhanced bone formation and influenced the microarchitecture of newly formed bone. The MBG carriers alone performed equal to the untreated (empty) control in most parameters tested, while additionally exerting mild pro-angiogenic effects. Using MBGs as a biocompatible, pro-regenerative carrier for local and sustained low dose BMP-2 release could limit side effects, thus enabling a safer usage of BMP-2 as a potent pro-osteogenic growth factor. Full article

Silver nanoparticles (AgNPs) have recently become very attractive for the scientific community due to their broad spectrum of applications in the biomedical field. The main advantages of AgNPs include a simple method of synthesis, a simple way to change their morphology and high surface area to volume ratio. Much research has been carried out over the years to evaluate their possible effectivity against microbial organisms. The most important factors which influence the effectivity of AgNPs against microorganisms are the method of their preparation and the type of application. When incorporated into fabric wound dressings and other textiles, AgNPs have shown significant antibacterial activity against both Gram-positive and Gram-negative bacteria and inhibited biofilm formation. In this review, the different routes of synthesizing AgNPs with controlled size and geometry including chemical, green, irradiation and thermal synthesis, as well as the different types of application of AgNPs for wound dressings such as membrane immobilization, topical application, preparation of nanofibers and hydrogels, and the mechanism behind their antimicrobial activity, have been discussed elaborately. Full article

The increasing demand for product and process understanding as an active pursuit in the quality guideline Q8 and, more recently, on the draft guideline on quality and equivalence of topical products, has unveiled the tremendous potential of rheology methods as a tool for microstructure characterization of topical semisolid dosage forms. Accordingly, procedure standardization is a dire need. This work aimed at developing and validating a methodology tutorial for rheology analysis. A 1% hydrocortisone cream was used as model cream formulation. Through a risk assessment analysis, the impact of selected critical method variables (geometry, temperature and application mode) was estimated in a broad range of rheological critical analytical attributes—zero-shear viscosity, upper-shear thinning viscosity, lower-shear thinning viscosity, infinite-shear viscosity, rotational yield point, thixotropic relative area, linear viscoelastic region, oscillatory yield point, storage modulus, loss modulus, and loss tangent. The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition. The thixotropic relative area, oscillatory yield point, flow point and viscosity related endpoints proved to be highly sensitive and discriminatory parameters. This rationale provided a standard framework for the development of a reliable and robust rheology profile acquisition. Full article

Polymeric oral thin films (OTFs) were prepared by the casting method, combining gellan gum (GG), a water-soluble polysaccharide, and glycerol (Gly) as a plasticizing agent. GG-Gly films were investigated as potential systems for buccal drug delivery using fluconazole (Class I of the Biopharmaceutical Classification System) as a model drug. At a low concentration of Gly drug precipitation occurred while, for higher concentrations of Gly, a significant deterioration of mucoadhesive and mechanical properties was observed. One possible way to overcome all these problems could be the addition of hydroxypropyl-$\mathsf{\beta }$-cyclodextrin (HP-$\mathsf{\beta }$-CD) to the GG-Gly formulation as a drug-precipitation inhibitor. In this work the effect of cyclodextrin addition on the mechanical, mucoadhesive, swelling and release properties of GG-Gly films was investigated. In-vitro drug release studies were carried out using the paddle type dissolution apparatus (USP II) and the millifluidic flow-through device (MFTD). A moving-boundary model for swelling dynamics and release in USP II is proposed to estimate the effective diffusivity of the solvent, HP-$\mathsf{\beta }$-CD, fluconazole and complex fluconazole/HP-$\mathsf{\beta }$-CD in the swelling film. Experimental results, supported by theoretical modeling, confirmed that gellan gum-low glycerol thin films including HP-$\mathsf{\beta }$-CD represent a suitable formulation for fluconazole drug delivery. A sustained release was observed when GG-Gly film is loaded with a preformed complex fluconazole/HP-$\mathsf{\beta }$-CD. Full article

We report on the preparation, characterization, and bioavailability properties of three new crystal forms of ethionamide, an antitubercular agent used in the treatment of drug-resistant tuberculosis. The new adducts were obtained by combining the active pharmaceutical ingredient with three dicarboxylic acids, namely glutaric, malonic and tartaric acid, in equimolar ratios. Crystal structures were obtained for all three adducts and were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. The ethionamide-glutaric acid and the ethionamide-malonic acid adducts were thoroughly characterized by means of solid-state NMR (¹³C and ¹⁵N Cross-Polarization Magic Angle Spinning or CPMAS) to confirm the position of the carboxylic proton, and they were found to be a cocrystal and a salt, respectively; they were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. Ethionamide-tartaric acid was found to be a rare example of kryptoracemic cocrystal. In vitro bioavailability enhancements up to a factor 3 compared to pure ethionamide were assessed for all obtained adducts. Full article

The aim of the study was to develop nicardipine loaded phospholipid extrudates as an alternative for PLA/PLGA-based implants for the prevention of cerebral vasospasms. Extrudates of different mixtures of saturated and unsaturated phosphatidylcholine (PC) were produced and characterized by DSC, microscopy and texture analysis. Single phospholipid components were identified by ELSD-HPLC. Extrudates of 2 mm diameter were obtained by twin screw extrusion temperatures below 50 °C. The ratio of unsaturated and saturated phosphatidylcholine components determines the physicochemical properties of the extrudates as well as the rate of erosion. Nicardipine loaded phospholipids extrudates released the drug over several weeks in vitro. The phospholipid composition of the remaining extrudate changed during the release, the content of unsaturated phospholipids decreased faster compared to the saturated ones. In conclusion, solid phospholipid extrudates are promising materials for the development of new parenteral controlled release systems. Full article

IP₃ receptor-binding protein released with IP₃ (IRBIT) interacts with various ion channels and transporters. An electroneutral type of sodium bicarbonate cotransporter, NBCn1, participates in cell migration, and its enhanced expression is related to cancer metastasis. The effect of IRBIT on NBCn1 and its relation to cancer cell migration remain obscure. We therefore aimed to determine the effect of IRBIT on NBCn1 and the regulation of cancer cell migration due to IRBIT-induced alterations in NBCn1 activity. Overexpression of IRBIT enhanced cancer cell migration and NBC activity. Knockdown of IRBIT or NBCn1 and treatment with an NBC-specific inhibitor, S0859, attenuated cell migration. Stimulation with oncogenic epidermal growth factor enhanced the expression of NBCn1 and migration of cancer cells by recruiting IRBIT. The recruited IRBIT stably maintained the expression of the NBCn1 transporter machinery in the plasma membrane. Combined inhibition of IRBIT and NBCn1 dramatically inhibited the migration of cancer cells. Combined modulation of IRBIT and NBCn1 offers an effective strategy for attenuating cancer metastasis. Full article

Chronic wounds, such as pressure ulcers, diabetic ulcers, venous ulcers and arterial insufficiency ulcers, are lesions that fail to proceed through the normal healing process within a period of 12 weeks. The treatment of skin chronic wounds still represents a great challenge. Wound medical devices (MDs) range from conventional and advanced dressings, up to skin grafts, but none of these are generally recognized as a gold standard. Based on recent developments, this paper reviews nanotechnology-based medical devices intended as skin substitutes. In particular, nanofibrous scaffolds are promising platforms for wound healing, especially due to their similarity to the extracellular matrix (ECM) and their capability to promote cell adhesion and proliferation, and to restore skin integrity, when grafted into the wound site. Nanotechnology-based scaffolds are emphasized here. The discussion will be focused on the definition of critical quality attributes (chemical and physical characterization, stability, particle size, surface properties, release of nanoparticles from MDs, sterility and apyrogenicity), the preclinical evaluation (biocompatibility testing, alternative in vitro tests for irritation and sensitization, wound healing test and animal wound models), the clinical evaluation and the CE (European Conformity) marking of nanotechnology-based MDs. Full article