Nanogels Based on N,N-Dimethylacrylamide and ß-Cyclodextrin Triacrylate for Enhanced Solubility and Therapeutic Efficacy of Aripiprazole.

Aripiprazole (ARZ) is a medication used for the treatment of various diseases such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Despite its therapeutic benefits, ARZ is characterized by a poor water solubility which provoked the development of various delivery systems in order to enhance its solubility. In the present work, a nanoscale drug delivery system based on N,N-dimethylacrylamide (DMAA) and ß-cyclodextrin triacrylate (ß-CD-Ac3) as potential aripiprazole delivery vehicles was developed. The nanogels were synthesized by free radical polymerization of DMAA in the presence of ß-CD-Ac3 as a crosslinking agent and then loaded with ARZ via host-guest inclusion complexation. The blank- and drug-loaded nanogels were evaluated using different methods. Fourier transform infrared (FTIR) spectroscopy was employed to confirm the incorporation of ß-CD moieties into the polymer network. Dynamic light scattering (DLS) was used to study the size of the developed systems. The samples exhibited a monomodal particle size distribution and a relatively narrow dispersity index. The hydrodynamic diameter (Dh) of the gels varied between 107 and 129 nm, with a tendency for slightly larger particles as the ß-CD-Ac3 fraction increased. Loading the drug into the nanocarrier resulted in slightly larger particles than the blank gels, but their size was still in the nanoscopic range (166 to 169 nm). The release profiles in PBS were studied and a sustained release pattern with no significant burst effect was observed. A cytotoxicity assessment was also conducted to demonstrate the non-toxicity and biocompatibility of the studied polymers.

Off-Label Prescribing in Pediatric Population-Literature Review for 2012-2022.

Off-label prescribing is widespread among pediatricians, and it is unlikely that this trend will soon be bound by a uniform legal framework. This is necessitated by the fact that there are four variables: the patient's health condition, the physician's experience and knowledge, the legislative measures (laws, directives, guidelines, and recommendations), and finally, the pharmaceutical industry. There is considerable concern worldwide about the use of off-label medicines in children. We may call it an enormous global problem that is much talked about and written about; however, we should not forget that the goal around which everyone should unite is the patient's life. For healthcare providers, the most important thing will always be the health and preservation of the patient's life, particularly when it comes to children with life-threatening conditions in neonatal and pediatric intensive care units (NICU and PICU). The study aimed to examine the prevalence of off-label drug use in pediatrics. Literature research was conducted, and we included studies from 2012 to 2022 that evaluated off-label drug prevalence in various pediatric patient populations.

Development, Characterization and Pharmacological Evaluation of Cannabidiol-Loaded Long Circulating Niosomes.

Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming these limitations. The present study is focused on exploring the feasibility of copolymer-modified niosomes as platforms for systemic delivery of CBD. To confer steric stabilization, the niosomal membranes were grafted with newly synthesized amphiphilic linear or star-shaped 3- and 4-arm star-shaped copolymers based on polyglycidol (PG) and poly(ε-caprolactone) (PCL) blocks. The niosomes were prepared by film hydration method and were characterized by DLS, cryo-TEM, encapsulation efficacy, and in vitro release. Free and formulated cannabidiol were further investigated for cytotoxicity and pro-apoptotic and anti-inflammatory activities in vitro in three human tumor cell lines. The optimal formulation, based on Tween 60:Span60:Chol (3.5:3.5:3 molar ration) modified with 2.5 mol% star-shaped 3-arm copolymer, is characterized by a size of 235 nm, high encapsulation of CBD (94%), and controlled release properties. Niosomal cannabidiol retained the antineoplastic activity of the free agent, but noteworthy superior apoptogenic and inflammatory biomarker-modulating effects were established at equieffective exposure vs. the free drug. Specific alterations in key signaling molecules, implicated in programmed cell death, cancer cell biology, and inflammation, were recorded with the niosomal formulations.

Study and Characterization of Polyvinyl Alcohol-Based Formulations for 3D Printlets Obtained via Fused Deposition Modeling.

Three-dimensional (3D) printing has emerged as a new promising technique for the production of personalized dosage forms and medical devices. Polyvinyl alcohol is prominently used as a source material to produce 3D-printed medicines via fused deposition modeling (FDM)-a technology that combines hot melt extrusion and 3D printing. A preliminary screening of three grades of PVA indicated that partially hydrolyzed PVA with a molecular weight (MW) of 31,000-50,000 and plasticized with sorbitol was most suitable for 3D printing. Paracetamol was used as a model drug. The materials and the produced filaments were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The complex viscosity (η*) of the polymer melts was determined as a function of the angular frequency (ω) at the printing temperature to assess their printability. Three-dimensional printlets with a 40% infill exhibited an immediate release of the API, while tablets with a higher infill were prone to a prolonged release regardless of the filament drug loading. A factorial design was used to give more insight into the influence of the drug-loading of the filaments and the tablet infill as independent variables on the production of 3D printlets. The Pareto chart confirmed that the infill had a statistically significant effect on the dissolution rate after 45 min, which was chosen as the response variable.

Conceptualization and Investigation of Multicomponent Polymer Networks as Prospective Corticosteroid Carriers.

Dexamethasone (DXM) is a highly potent and long-acting synthetic glucocorticoid with anti-inflammatory, anti-allergic, and immunosuppressive effects. However, the systemic application of DXM can cause undesirable side effects: sleep disorders, nervousness, heart rhythm disorders, heart attack, and others. In the present study, multicomponent polymer networks were developed as potential new platforms for the dermal application of dexamethasone sodium phosphate (DSP). First, a copolymer network (CPN) comprising hydrophilic segments of different chemical structures was synthesized by applying redox polymerization of dimethyl acrylamide onto poly(ethylene glycol) in the presence of poly(ethylene glycol) diacrylate (PEGDA) as a crosslinker. On this basis, an interpenetrating polymer network structure (IPN) was obtained by introducing a second network of PEGDA-crosslinked poly(N-isopropylacrylamide). Multicomponent networks obtained were characterized by FTIR, TGA, and swelling kinetics in different solvents. Both CPN and IPN showed a high swelling degree in aqueous media (up to 1800 and 1200%, respectively), reaching the equilibrium swelling within 24 h. Additionally, IPN showed temperature-responsive swelling in an aqueous solution as the equilibrium swelling degree decreased considerably with an increase in the temperature. In order to evaluate the networks' potential as drug carriers, swelling in DSP aqueous solutions of varied concentration was investigated. It was established that the amount of encapsulated DSP could be easily controlled by the concentration of drug aqueous solution. In vitro DSP release was studied in buffer solution (BS) with pH 7.4 at 37 °C. The results obtained during DSP loading and release experiments proved the feasibility of the developed multicomponent hydrophilic polymer networks as effective platforms for potential dermal application.

Chitosan-Based Nanoparticles for Targeted Nasal Galantamine Delivery as a Promising Tool in Alzheimer's Disease Therapy.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer's dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan-alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C.

Polyacrylamide/poly(2-(dimethylamino) Ethyl Methacrylate) Interpenetrating Polymer Networks as Drug Delivery Systems for Diclofenac Sodium.

Nowadays, modern pharmaceutical investigations are directed toward the design and production of drug delivery systems for achieving prolonged and controlled drug delivery. In this respect, the use of interpenetrating polymer networks (IPNs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of novel poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) and polyacrylamide (PAAm)-based IPNs with different compositions and their application as diclofenac sodium delivery systems. The prepared IPNs were shown to possess phase-separated structures at the nano level, as revealed by SEM and TM-DSC. The IPNs' composition was shown to determine the swelling behavior of these novel materials, and the inclusion of the charged IPN component (PDMAEMA) has changed the water molecules type diffusion from Fickian to non-Fickian, as revealed by the swelling kinetics study. Loading efficiency of diclofenac sodium and diclofenac sodium content in the polymer network was evaluated, and in vitro drug release experiments were carried out in order to estimate the ability of the obtained IPNs to control the release of the water-soluble drug.

Design and Concept of Polyzwitterionic Copolymer Microgel Drug Delivery Systems In Situ Loaded with Non-steroidal Anti-inflammatory Ibuprofen.

Nowadays, the modern pharmaceutical investigations are directed toward obtaining of new polymer micro- and nano-sized drug delivery carriers. In this respect, the use of hydrogel carriers based on polyzwitterions (PZIs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of micro-structured p(VA-co-DMAPS) systems with different compositions in situ loaded with Ibuprofen by emulsifier-free emulsion copolymerization (EEC) in water. The mean size of the prepared microparticles was measured by SEM and particles have been visualized by AFM. The inclusion of Ibuprofen in the polyzwitterionic copolymer microgel systems was established by using DSC. In vitro drug release experiments were carried out in order to estimate the ability of the obtained microgels to modify the release of water-insoluble Ibuprofen.

pH-Sensitive cationic copolymers of different macromolecular architecture as potential dexamethasone sodium phosphate delivery systems.

This paper describes the synthesis and characterization of cationic copolymers with different macromolecular architecture and drug delivery properties of the corresponding dexamethasone sodium phosphate (DSP)-loaded systems. Copolyelectrolytes comprising poly[2-(acryloyloxy)ethyl] trimethylammonium chloride (PAETMAC) and poly(ethylene glycol) blocks as well as a tri-arm star-shaped PAETMAC were synthesized using cerium(IV) ion-mediated polymerization method. The obtained copolyelectrolytes and corresponding ionic associates with DSP have been characterized by (1)H NMR, Fourier Transform Infrared spectroscopy, and differential scanning calorimetry. The average diameter, size distribution, and ζ-potential of the copolymers and DSP-copolymer ionic associates were determined by dynamic light scattering, and particles were visualized by scanning electron microscopy and transmission electron microscopy. The biocompatibility and cytotoxicity of obtained copolymers were determined. In vitro drug release experiments were carried out to estimate the ability of the obtained nanoparticles for sustained release of DSP for a period of 24 h.

Image processing and lattice determination for three-dimensional nanocrystals.

Three-dimensional nanocrystals can be studied by electron diffraction using transmission cryo-electron microscopy. For molecular structure determination of proteins, such nanosized crystalline samples are out of reach for traditional single-crystal X-ray crystallography. For the study of materials that are not sensitive to the electron beam, software has been developed for determining the crystal lattice and orientation parameters. These methods require radiation-hard materials that survive careful orienting of the crystals and measuring diffraction of one and the same crystal from different, but known directions. However, as such methods can only deal with well-oriented crystalline samples, a problem exists for three-dimensional (3D) crystals of proteins and other radiation sensitive materials that do not survive careful rotational alignment in the electron microscope. Here, we discuss our newly released software AMP that can deal with nonoriented diffraction patterns, and we discuss the progress of our new preprocessing program that uses autocorrelation patterns of diffraction images for lattice determination and indexing of 3D nanocrystals.

A novel approximation method of CTF amplitude correction for 3D single particle reconstruction.

The typical resolution of three-dimensional reconstruction by cryo-EM single particle analysis is now being pushed up to and beyond the nanometer scale. Correction of the contrast transfer function (CTF) of electron microscopic images is essential for achieving such a high resolution. Various correction methods exist and are employed in popular reconstruction software packages. Here, we present a novel approximation method that corrects the amplitude modulation introduced by the contrast transfer function by convoluting the images with a piecewise continuous function. Our new approach can easily be implemented and incorporated into other packages. The implemented method yielded higher resolution reconstructions with data sets from both highly symmetric and asymmetric structures. It is an efficient alternative correction method that allows quick convergence of the 3D reconstruction and has a high tolerance for noisy images, thus easing a bottleneck in practical reconstruction of macromolecules.

Unit-cell determination from randomly oriented electron-diffraction patterns.

Unit-cell determination is the first step towards the structure solution of an unknown crystal form. Standard procedures for unit-cell determination cannot cope with data collections that consist of single diffraction patterns of multiple crystals, each with an unknown orientation. However, for beam-sensitive nanocrystals these are often the only data that can be obtained. An algorithm for unit-cell determination that uses randomly oriented electron-diffraction patterns with unknown angular relationships is presented here. The algorithm determined the unit cells of mineral, pharmaceutical and protein nanocrystals in orthorhombic high- and low-symmetry space groups, allowing (well oriented) patterns to be indexed.

Heterogeneous nucleation of three-dimensional protein nanocrystals.

Nucleation is the rate-limiting step in protein crystallization. Introducing heterogeneous substrates may in some cases lower the energy barrier for nucleation and thereby facilitate crystal growth. To date, the mechanism of heterogeneous protein nucleation remains poorly understood. In this study, the nucleating properties of fragments of human hair in crystallization experiments have been investigated. The four proteins that were tested, lysozyme, glucose isomerase, a polysaccharide-specific Fab fragment and potato serine protease inhibitor, nucleated preferentially on the hair surface. Macrocrystals and showers of tiny crystals of a few hundred nanometres thickness were obtained also under conditions that did not produce crystals in the absence of the nucleating agent. Cryo-electron diffraction showed that the nanocrystals diffracted to at least 4 A resolution. The mechanism of heterogeneous nucleation was studied using confocal fluorescent microscopy which demonstrated that the protein is concentrated on the nucleating surface. A substantial accumulation of protein was observed on the sharp edges of the hair's cuticles, explaining the strong nucleating activity of the surface.