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Grape pomace is a by-product of winemaking characterized by a rich chemical composition from which phenolics stand out. Phenolics are health-promoting agents, and their beneficial effects depend on their bioaccessibility, which is influenced by gastrointestinal digestion. The effect of encapsulating phenol-rich grape pomace extract (PRE) with sodium alginate (SA), a mixture of SA with gelatin (SA-GEL), and SA with chitosan (SA-CHIT) on the bioaccessibility index (BI) of phenolics during simulated digestion in vitro was studied. A total of 27 individual phenolic compounds (IPCs) were quantified by UHPLC. The addition of a second coating to SA improved the encapsulation efficiency (EE), and the highest EE was obtained for SA-CHIT microbeads (56.25%). Encapsulation affected the physicochemical properties (size, shape and texture, morphology, crystallinity) of the produced microbeads, which influenced the delivery of phenolics to the intestine and their BI. Thus, SA-GEL microbeads had the largest size parameters, as confirmed by scanning electron microscopy (SEM), and the highest BI for total phenolic compounds and IPCs (gallic acid, 3,4-dihydroxybenzoic acid and o-coumaric acid, epicatechin, and gallocatechin gallate) ranged from 96.20 to 1011.3%. The results suggest that encapsulated PRE has great potential to be used as a functional ingredient in products for oral administration.

Oil spills pose a significant threat to marine life and finding cost-effective and environmentally friendly solutions is crucial. In this study, pulsed laser ablation (PLA) was applied to produce polymer-based magnetic nanocomposites for oil spill remediation. The selected polymers (polyvinylpyrrolidone, chitosan, and methyl cellulose) are known for their adsorptive removal of polluting residues from various oil species. PLA was performed on pressed tablets containing magnetite nanoparticles (NPs) and polymers, and the generated particles were collected using an external magnetic field. The chemical composition of the ablated products was analyzed using Fourier-transform infrared (FTIR) and Raman spectroscopy, while particle sizes were measured using Leica Image Processing and Analysis System. The study demonstrated that PLA is a single-step, green, and efficient technique for preparing magnetic nanocomposites for oil spill treatment. The average particle size of the composites was in the 1.5–4 µm range, considerably smaller than the initial size of the corresponding polymer. The oil/water separation process using these composites was demonstrated, with separation occurring ~ 1 s after applying the magnetic field. These findings suggest that PLA-generated magnetic nanocomposites have significant potential for oil spill remediation applications.

The increasing prevalence of water insoluble or poorly soluble drugs calls for the development of new formulation methods. Common approaches include the reduction of particle size and degree of crystallinity. Pulsed laser ablation is a chemical-free technique for producing sub-micrometre sized drug particles and has the potential to induce amorphization. We studied the effect of femtosecond pulsed laser ablation (ELI ALPS THz pump laser system: λc = 781 nm, τ = 135 fs) on meloxicam in distilled water and in air. The ablated particles were characterized chemically, morphologically, in terms of size, crystallinity and thermal behaviour. Furthermore, we analyzed changes in the solubility as compared to the original material. We demonstrated that femtosecond laser ablation in both distilled water and air can be an effective particle size reduction technique, resulting in an increased saturation concentration of the drug. The mostly sub-micrometre sized particles showed signs of melting and decreased crystallinity. In case of femtosecond pulsed laser ablation in air meloxicam spheres were produced without the use of excipients. We aimed to describe the abalation processes in both unvestigated media.

Antihistamines such as levocetirizine dihydrochloride (LC) are commercially used in oral tablets and oral drops to reduce allergic symptoms. In this study, LC was nano-spray-dried using three mucoadhesive polymers and four cyclodextrin species to form composite powders for nasal administration. The product was composed of hydroxypropyl methylcellulose polymer, including LC as a zwitterion, after neutralization by NaOH, and XRD investigations verified its amorphous state. This and a sulfobutylated-beta-cyclodextrin sodium salt-containing sample showed crystal peaks due to NaCl content as products of the neutralization reaction in the solutions before drying. The average particle size of the spherical microparticles was between 2.42 and 3.44 µm, except for those containing a polyvinyl alcohol excipient, which were characterized by a medium diameter of 29.80 µm. The drug was completely and immediately liberated from all the samples at pH 5.6 and 32 °C; i.e., the carriers did not change the good dissolution behavior of LC. A permeability test was carried out by dipping the synthetic cellulose ester membrane in isopropyl myristate using modified horizontal diffusion cells. The spray-dried powder with β-cyclodextrin showed the highest permeability (188.37 µg/cm2/h), as this additive was the least hydrophilic. Products prepared with other cyclodextrins (randomly methylated-beta-cyclodextrin, sulfobutylated-beta-cyclodextrin sodium salt and (hydroxypropyl)-beta-cyclodextrin) showed similar or slightly higher penetration abilities than LC. Other polymer excipients resulted in lower penetration of the active agent than the pure LC.

Grape pomace is a byproduct of wineries and a rich source of phenolic compounds that can exert multiple pharmacological effects when consumed and enter the intestine where they can then be absorbed. Phenolic compounds are susceptible to degradation and interaction with other food constituents during digestion, and encapsulation may be a useful technique for protecting phenolic bioactivity and controlling its release. Therefore, the behavior of phenolic-rich grape pomace extracts encapsulated by the ionic gelation method, using a natural coating (sodium alginate, gum arabic, gelatin, and chitosan), was observed during simulated digestion in vitro. The best encapsulation efficiency (69.27%) was obtained with alginate hydrogels. The physicochemical properties of the microbeads were influenced by the coatings used. Scanning electron microscopy showed that drying had the least effect on the surface area of the chitosan-coated microbeads. A structural analysis showed that the structure of the extract changed from crystalline to amorphous after encapsulation. The phenolic compounds were released from the microbeads by Fickian diffusion, which is best described by the Korsmeyer–Peppas model among the four models tested. The obtained results can be used as a predictive tool for the preparation of microbeads containing natural bioactive compounds that could be useful for the development of food supplements.

Pulmonary drug delivery (PDD) has potential for both local and systemic therapy. Our research group is focus- ing on the development of dry powder inhalation (DPI) systems for PDD due to their beneficial properties. Although there is not yet a marketed inhalation product for non-steroidal anti-inflammatory drugs (NSAIDs), their therapeutic use in sev- eral lung diseases is well established and successful DPI developments have been performed with them. Sodium stearate (NaSt) is a promising excipient for DPI development, but its role in NSAIDs has not yet been investigated. Thus, the aim was to study DPI samples produced by co-spray-drying, applying meloxicam potassium (MXP) as an NSAID drug, and different concentrations (0-2 w/w%) of NaSt. Physicochemical investigations, in vitro lung deposition, and in vitro drug release measurements were performed. It can be stated that co-spray-drying of MXP with NaSt resulted in remarkable morphological differences by increasing the concentration of NaSt, which had a positive effect on cohesive work. Further- more, applying of NaSt accelerates the dissolution in simulated lung fluid (SLF). NaSt as excipient has a future for the formulation of the DPI systems because there are in the development focus the attaintment of the higher FPF values and improvement of dissolution in SLF.

The study aimed to prepare ciprofloxacin-loaded polyvinylpyrrolidone electrospun nanofibers for oral drug delivery, using a conventional nozzle-based and a lab-built nozzle-free electrospinning equipment. To produce nanofibers, electrospinning is the process most often used. However, from the industry’s point of view, conventional electrospinning does not have sufficiently high productivity. By omitting the nozzle, productivity can be increased, and so the development of nozzle-free processes is worthwhile. In this study, a solution of ciprofloxacin and polyvinylpyrrolidone was electrospun under similar conditions, using both single-nozzle and nozzle-free methods. The two electrospinning methods were compared by investigating the morphological and physicochemical properties, homogeneity, in vitro drug release, and cytotoxicity. The stability of the nanofibers was monitored from different aspects in a 26 month stability study. The results showed that the use of the nozzle-free electrospinning was preferable due to a higher throughput, improved homogeneity, and the enhanced stability of nanofiber mats, compared to the nozzle-based method. Nevertheless, fast dissolving nanofibers loaded with poorly water-soluble ciprofloxacin were produced by both electrospinning methods. The beneficial properties of these nanofibers can be exploited in innovative drug development; e.g., nanofibers can be formulated into orodispersible films or per os tablets.

Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre–few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations.

The use of oral antibiotic therapy for the treatment of respiratory diseases as tuberculosis has promoted the appearance of side effects as well as resistance to these treatments. The low solubility, high metabolism, and degradation of drugs as rifabutin, have led to the use of combined and prolonged therapies, which difficult patient compliance. In this work, we develop inhalable formulations from biomaterials such as protamine to improve the therapeutic effect. Rifabutin-loaded protamine nanocapsules (NCs) were prepared by solvent displacement method and were physico-chemically characterized and evaluated for their dissolution, permeability, stability, cytotoxicity, hemocompatibility, internalization, and aerodynamic characteristics after a spray-drying procedure. Protamine NCs presented a size of around 200 nm, positive surface charge, and drug association up to 54%. They were stable as suspension under storage, as well as in biological media and as a dry powder after lyophilization in the presence of mannitol. Nanocapsules showed a good safety profile and cellular uptake with no tolerogenic effect on macrophages and showed good compatibility with red blood cells. Moreover, the aerodynamic evaluation showed a fine particle fraction deposition up to 30% and a mass median aerodynamic diameter of about 5 µm, suitable for the pulmonary delivery of therapeutics This research was funded by Ministerio de Ciencia e Innovacion RETOS - PID2019-107500RB-I00, Ministry of Human Capacities, Hungary grant TKP2021-EGA-32 and the Erasmus+ program of the European Union SI

In this study, the aerogel technology was used to prepare pulmonary drug carriers consisting of alginate and alginate-hyaluronic acid by an emulsion gelation technique and supercritical CO2 drying. During the preparation process, the emulsification rate and inner phase viscosity were varied to control the diameter of aerogel microspheres. Results showed that the aerogel microspheres were highly porous (porosity > 98%) with low densities in the range between 0.0087 and 0.0634 g/cm3 as well as high surface areas between 354 and 759 m2/g. The obtained microspheres showed aerodynamic diameter below 5 µm making them suitable for pulmonary drug delivery. An in vitro drug release study with the model drug sodium naproxen was conducted and a non-Fickian drug release mechanism was observed, with no significant difference between the release profiles of alginate and alginate-hyaluronic acid microspheres. During the emulsion gelation step, the feasibility of using the capillary number to estimate the largest stable droplet size in the emulsions was also studied and it was found that using this number, the droplet size in the emulsions may well be predicted.

The development of suitable formulations for the pediatric population remains a challenging field with great advances reported every year in terms of excipients and technology. When developing pediatric formulations, the acceptability of medicines represents a key element to consider. For this reason, milk can be a widely accepted excipient with taste-masking properties and supplementary advantages for drug solubility. In recent years, the orodispersible dosage forms have come onto the market as child-friendly formulations. The current study aimed to develop freeze-dried orodispersible dosage forms containing bovine milk or infant formulae as the main component. In the first stage, an exploratory study evaluated the mechanical properties of placebo milk formulations and the suitability of milk as a matrix-forming agent. As the appropriate mechanical strength to withstand manipulation was demonstrated, milk oral lyophilizates were loaded with a poorly soluble model API, loratadine. Hence, a D-optimal design was conducted to prepare milk lyophilizates with loratadine and to evaluate the effects of three factors (dose of loratadine, the lyophilizate size, and the type of milk) and their interactions. Finally, three formulations were prepared to confront the predictions of the DoE and further studied to thoroughly understand the observed effects. The experimental results showed the potential of milk in the development of oral lyophilizates loaded with different doses of suspended API.

Solvent-free preparation types for cyclodextrin complexation, such as co-grinding, are technologies desired by the industry. However, in-depth analytical evaluation of the process and detailed characterization of intermediate states of the complexes are still lacking in areas. In our work, we aimed to apply the co-grinding technology and characterize the process. Fenofibrate was used as a model drug and dimethyl-β-cyclodextrin as a complexation excipient. The physical mixture of the two substances was ground for 60 min; meanwhile, samples were taken. A solvent product of the same composition was also prepared. The intermediate samples and the final products were characterized with instrumental analytical tools. The XRPD measurements showed a decrease in the crystallinity of the drug and the DSC results showed the appearance of a new crystal form. Correlation analysis of FTIR spectra suggests a three-step complexation process. In vitro dissolution studies were performed to compare the dissolution properties of the pure drug to the products. Using a solvent-free production method, we succeeded in producing a two-component system with superior solubility properties compared to both the active ingredient and the product prepared by the solvent method. The intermolecular description of complexation was achieved with a detailed analysis of FTIR spectra.

Existing therapies yield low drug encapsulation or accumulation in the lungs, hence the site-specific drug delivery remains the challenge for tuberculosis. Lately, dry powder inhalers (DPIs) are showing promising drug deposition in the deeper lung tissues. Biocompatible polymers with the ability to naturally recognize and bind to the surface receptors of alveolar macrophages, the reservoir of the causative organism, were selected. DPIs comprised of chitosan (CS)/thiolated chitosan (TC) in conjugation with Hyaluronic acid (HA) were synthesized loaded with isoniazid (INH) by using the Design of Experiment (DoE) approach. Nanosuspensions were prepared by ionic gelation method using cross-linker, sodium-tripolyphosphate (TPP) and were optimized by using Box-Behnken 3-level screening design and later freeze-dried to obtain nanopowders. Physico-chemical compatibility of nanoplex systems was investigated using in-vitro characterization techniques. In-vitro release and permeation studies were correlated in terms of the pattern of drug content dissolved over time. In addition, the cytotoxicity studies on A549 cells demonstrated the safety profile of the nanoplexes. Moreover, in-silico studies and aerodynamic profiles verify the suitability of DPIs for further in-vivo tuberculosis therapeutics. DoE analyses affirmed the lack of linearity in the model for the certain response of studied parameters in a holistic way, which was not possible else ways.

We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ1 = 532 nm/λ2 = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30–80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration.

Nanocapsules (NCs) have become one of the most researched nanostructured drug delivery systems due to their advantageous properties and versatility. NCs can enhance the bioavailabiliy of hydrophobic drugs by impoving their solubility and permeability. Also, they can protect these active pharmaceutical agents (APIs) from the physiological environment with preventing e.g. the enzymatic degradation. NCs can be used for many administration routes: e.g. oral, dermal, nasal and ocular formulations are exisiting in liquid and solid forms. The nose is one of the most interesting alternative drug administration route, because local, systemic and direct central nervous system (CNS) delivery can be achived; this could be utilized in the therapy of CNS diseases. Therefore, the goal of this study was to design, prepare and investigate a novel, lamotrigin containing NC formulation for nasal administration. The determination of micrometric parameters (particle size, polydispersity index, surface charge), in vitro (drug loading capacity, release and permeability investigations) and in vivo characterization of the formulations were performed in the study. The results indicate that the formulation could be a promising alternative of lamotrigine (LAM) as the NCs were around 305 nm size with high encapsulation efficiency (58.44%). Moreover, the LAM showed rapid and high release from the NCs in vitro and considerable penetration to the brain tissues was observed during the in vivo study.

Drug administration through the nose offers great possibilities which have been discovered in the past few decades. Besides the most known local effect, systemic and central nervous system effect is also available, the administration is non-painful and the degradation effect of the gastrointestinal tract can be avoided. Amongst the nasal formulations, powders have become more popular as their stability is favorable compared to the liquid formulations and a higher dose can be administered in powder form. The quality insurance and stability of the products in the pharmaceutical field have gained considerable attention in the last decades. Due to this fact, the aim was to execute a long-term stability study of a previously developed, nanosized lamotrigine (LAM) containing nasal powder (NP) formulation. The results of the stability test showed that the NP formulation preserved its key properties (particle size, morphology, structure and in vitro drug release) after 6 months of storage.

Pulmonary drug administration provides a platform for the effective local treatment of various respiratory diseases. Application of nano-sized active ingredients results in higher bioavailability because of their large specific surface area. Extra-fine dry powder inhalers reach the smaller airways, further improving therapeutic efficiency. Poorly water-soluble meloxicam was the selected active ingredient. We aimed to decrease the particle size into the nano range by wet milling and producing extra-fine inhalable particles via nano spray-drying. The diameter of the drug was reduced to 138 nm. The particle size of the dry products was between 1.1 and 1.5 µm, and the dispersed diameter was between 500 and 800 nm. Owing to the excipients (poly-vinyl-alcohol, leucine), the spray-dried particles presented nearly spherical morphology. The drug became partially amorphous. Thanks to the improved surface area, the solubility and the released and the diffused amount of the meloxicam increased in artificial lung media. The in vitro aerodynamic measurements showed that the leucine-containing formulations had outstanding fine particle fraction (FPF) deposition with 1.3 µm mass median aerodynamic diameter (MMAD). The aerodynamic particle counter test also proved the extra-fine aerodynamic particle size. The in vitro cell line experiments revealed the non-cytotoxicity of the products and the suppression of the interleukin concentration. Overall, the powders are suitable for deep pulmonary delivery and the local treatment of lung inflammations.

Molecular complexation with cyclodextrins (CDs) has long been a known process for modifying the physicochemical properties of problematic active pharmaceutical ingredients with poor water solubility. In current times, the focus has been on the solvent-free co-grinding process, which is an industrially feasible process qualifying as a green technology. In this study, terbinafine hydrochloride (TER), a low solubility antifungal drug was used as a model drug. This study aimed to prepare co-ground products and follow through the preparation process of the co-grinding method in the case of TER and two amorphous CD derivatives: (2-hydroxypropyl)-β-cyclodextrin (HPBCD); heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB). For this evaluation, the following analytical tools and methods were used: phase solubility studies, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), hot-stage X-ray powder diffractometry (HOT-XRPD), Fourier-transform infrared (FT-IR), Raman spectroscopy, and Scanning Electron Microscopy (SEM). Furthermore, in vitro characterization (dissolution and diffusion studies) was performed in two kinds of dissolution medium without enzymes. In the XRPD and SEM studies, it was found that the co-grinding of the components resulted in amorphous products. FT-IR and Raman spectroscopies confirmed the formation of an inclusion complex through the unsaturated aliphatic chain of TER and CDs. In vitro characterization suggested better dissolution properties for both CDs and decreased diffusion at higher pH levels in the case of HPBCD.

In this study, the effect of Cremophor® RH 40 (CR 40) classic micelles and Soluplus® (SP) polymeric micelles were investigated on a novel granule-type drug-delivery system containing megestrolacetate (MGA). Using a risk assessment-based approach on the formulation via melt technology resulted in the formation of these granules, presented as the dosage, with proper particle size and flow characteristics. Due to the application of a eutectic carrier base composition, gentle process conditions were reached, retaining the crystalline structure of the carrier system and allowing for the proper distribution of MGA in the granules. The increased water solubility (0.111 mg/mL to 2.154 mg/mL), and the decreased nano particle size (102.27 nm) with uniform distribution (polydispersity index of 0.259) and colloid stability (zeta potential of −12.99 mV) resulted in SP polymeric micelles prevailing over CR 40 micelles in this gastric dissolution study, performed in biorelevant fasted and fed state drug-release media. Mathematical characterization and kinetic model fitting supported the fast drug-release mechanism of polymeric micelles over micelles. The value-added polymeric micelle-containing formulation developed can be successfully administered perorally and the enhanced drug release offers the possibility of greater drug absorption in the gastrointestinal tract.

A two-component injectable hydrogel was suitably prepared for the encapsulation and prolonged release of tilorone which is an antimuscular atrophy drug. The rapid (7–45 s, depending on the polymer concentration) in situ solidifications of the hydrogel were evoked by the evolving Schiff-base bonds between the aldehyde groups of modified PVA (4-formyl benzoate PVA, PVA-CHO, 5.9 mol% functionalization degree) and the amino groups of 3-mercaptopropionate chitosan (CHIT-SH). The successful modification of the initial polymers was confirmed by both FTIR and NMR measurements; moreover, a new peak appeared in the FTIR spectrum of the 10% w/v PVA-CHO/CHIT-SH hydrogel at 1647 cm−1, indicating the formation of a Schiff base (–CH=N–) and confirming the interaction between the NH2 groups of CHIT–SH and the CHO groups of PVA-CHO for the formation of the dynamic hydrogel. The reaction between the NH2 and CHO groups of the modified biopolymers resulted in a significant increase in the hydrogel’s viscosity which was more than one thousand times greater (9800 mPa·s) than that of the used polymer solutions, which have a viscosity of only 4.6 and 5.8 mPa·s, respectively. Furthermore, the initial chitosan was modified with mercaptopropionic acid (thiol content = 201.85 ± 12 µmol/g) to increase the mucoadhesive properties of the hydrogel. The thiolated chitosan showed a significant increase (~600 mN/mm) in adhesion to the pig intestinal membrane compared to the initial one (~300 mN/mm). The in vitro release of tilorone from the hydrogel was controlled with the crosslinking density/concentration of the hydrogel; the 10% w/v PVA-CHO/CHIT-SH hydrogel had the slowest releasing (21.7 h−1/2) rate, while the 2% w/v PVA-CHO/CHIT-SH hydrogel had the fastest releasing rate (34.6 h−1/2). Due to the characteristics of these hydrogels, their future uses include tissue regeneration scaffolds, wound dressings for skin injuries, and injectable or in situ forming drug delivery systems. Eventually, we hope that the developed hydrogel will be useful in the local treatment of muscle atrophy, such as laryngotracheal atrophy.

Marketed dosage forms fail to deliver anti-tubercular drugs directly to the lungs in pulmonary Tuberculosis (TB). Therefore, nanomediated isoniazid (INH)-loaded dry powder for inhalation (Nano-DPI) was developed for macrophage-targeted delivery in TB. Mannosylated chitosan (MC) and hyaluronic acid (HA) with an affinity for the surface mannose and CD44 receptors of macrophages were used in conjugation to prepare hybrid nanosuspension by ionic gelation method using cross-linker, sodium tri-polyphosphate (TPP) followed by freeze-drying to obtain a dry powder composed of nanoparticles (INH-MC/HA NPs). Nanoformulations were evaluated for aerodynamic characteristics, cytotoxicity, hemocompatibility, macrophage phenotype analysis, and immune regulation. Cellular uptake imaging was also conducted to evaluate the uptake of NPs. The nanopowders did not pose any significant toxicity to the cells, along with good compatibility with red blood cells (RBCs). The pro-inflammatory costimulatory markers were upregulated, demonstrating the activation of T-cell response. Moreover, the NPs did not show any tolerogenic effect on the macrophages. Furthermore, confocal imaging exhibited the translocation of NPs in the cells. Altogether, the findings present that nano-DPI was found to be a promising vehicle for targeting macrophages.

A fatal hereditary condition, cystic fibrosis (CF) causes severe lung problems. Ibuprofen (IBU), a non-steroidal anti-inflammatory drug, slows the progression of disease without causing significant side effects. Considering the poor water-solubility of the drug, IBU nanoparticles are beneficial for local pulmonary administration. We aimed to formulate a carrier-free dry powder inhaler containing nanosized IBU. We combined high-performance ultra-sonication and nano spray-drying. IBU was dissolved in ethyl acetate; after that, it was sonicated into a polyvinyl alcohol solution, where it precipitated as nanoparticles. Mannitol and leucine were added when producing dry particles using nano-spray drying. The following investigations were implemented: dynamic light scattering, laser diffraction, surface tension measurement, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, in vitro dissolution test, and in vitro aerodynamic assessment (Andersen Cascade Impactor). The particle diameter of the IBU was in the nano range. The spray-dried particles showed a spherical morphology. The drug release was rapid in artificial lung media. The products represented large fine particle fractions and proper aerodynamic diameters. We successfully created an inhalable powder, containing nano-sized IBU. Along with the exceptional aerodynamic performance, the ideal particle size, shape, and drug-release profile might offer a ground-breaking local therapy for CF.

Electrospinning is the simplest and most widely used technology for producing ultra-thin fibers. During electrospinning, the high voltage causes a thin jet to be launched from the liquid polymer and then deposited onto the grounded collector. Depending on the type of the fluid, solution and melt electrospinning are distinguished. The morphology and physicochemical properties of the produced fibers depend on many factors, which can be categorized into three groups: process parameters, material properties, and ambient parameters. In the biomedical field, electrospun nanofibers have a wide variety of applications ranging from medication delivery systems to tissue engineering scaffolds and soft electronics. Many of these showed promising results for potential use as medical devices in the future. Medical devices are used to cure, prevent, or diagnose diseases without the presence of any active pharmaceutical ingredients. The regulation of conventional medical devices is strict and carefully controlled; however, it is not yet properly defined in the case of nanotechnology-made devices. This review is divided into two parts. The first part provides an overview on electrospinning through several examples, while the second part focuses on developments in the field of electrospun medical devices. Additionally, the relevant regulatory framework is summarized at the end of this paper.

Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution. In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements.

The brain insulin metabolism alteration has been addressed as a pathophysiological factor underlying Alzheimer’s disease (AD). Insulin can be beneficial in AD, but its macro-polypeptide nature negatively influences the chances of reaching the brain. The intranasal (IN) administration of therapeutics in AD suggests improved brain-targeting. Solid lipid nanoparticles (SLNs) and poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are promising carriers to deliver the IN-administered insulin to the brain due to the enhancement of the drug permeability, which can even be improved by chitosan-coating. In the present study, uncoated and chitosan-coated insulin-loaded SLNs and PLGA NPs were formulated and characterized. The obtained NPs showed desirable physicochemical properties supporting IN applicability. The in vitro investigations revealed increased mucoadhesion, nasal diffusion, and drug release rate of both insulin-loaded nanocarriers over native insulin with the superiority of chitosan-coated SLNs. Cell-line studies on human nasal epithelial and brain endothelial cells proved the safety IN applicability of nanoparticles. Insulin-loaded nanoparticles showed improved insulin permeability through the nasal mucosa, which was promoted by chitosan-coating. However, native insulin exceeded the blood-brain barrier (BBB) permeation compared with nanoparticulate formulations. Encapsulating insulin into chitosan-coated NPs can be beneficial for ensuring structural stability, enhancing nasal absorption, followed by sustained drug release.

The therapeutic application of nasal powders requires the development of novel mucoadhesive excipients. Thiolated polymers exhibit significant potential for this purpose based on their increased mucoadhesion attributable to the formation of disulfide bonds between the polymer and mucus surface. A chitosan–cysteine (chit-cyst) conjugate was synthesized using 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide in aqueous solution. The synthetic yield and synthesis conditions were optimized, and the efficiency of the reaction was evaluated. Rheological measurements revealed that the polymer derivative exhibited increased mucoadhesive properties in comparison to chitosan powder. To characterize the polymer, a novel purity investigation method was developed and verified to investigate the residual l-cysteine content. The results revealed that l- cysteine was not detectable in the resultant polymer matrix. Based on the cytotoxicity studies, chit-cyst was found to be safe for nasal application. Thereafter, nasal powder formulations were prepared using the polymer and the antiparkinsonian drug levodopa methyl ester hydrochloride by freeze-drying to investigate their nasal applicability. Based on the in vitro studies, these powders might be suitable for reducing the off periods of Parkinson’s disease because of their expected higher in vivo mucoadhesion.

Background Cystic fibrosis (CF) is a life-threatening multiorgan genetic disease, particularly affecting the lungs, where recurrent infections are the main cause of reduced life expectancy. In CF, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein impair transepithelial electrolyte and water transport, resulting in airway dehydration, and a thickening of the mucus associated with abnormal viscoelastic properties. Our aim was to develop a rheological method to assess the effects of hypertonic saline (NaCl) and NaHCO3 on CF sputum viscoelasticity in vitro, and to identify the critical steps in sample preparation and in the rheological measurements. Methods Sputum samples were mixed with hypertonic salt solutions in vitro in a ratio of either 10:4 or 10:1. Distilled water was applied as a reference treatment. The rheological properties of sputum from CF patients, and the effects of these in vitro treatments, were studied with a rheometer at constant frequency and strain, followed by frequency sweep tests, where storage modulus (G′), loss modulus (G″) and loss factor were determined. Results We identified three distinct categories of sputum: (i) highly elastic (G′ > 100,000 Pa), (ii) elastic (100,000 Pa > G′ > 1000 Pa), and (iii) viscoelastic (G′ 3 (p 3, but not with NaCl. For the viscoelastic samples, the additives did not cause significant changes in the parameters. When the lower additive ratio (10:1) was used, the mean values of the rheological parameters usually decreased, but the changes were not statistically significant. Conclusion Based on the rheological properties of the initial sputum samples, we can predict with some confidence the treatment efficacy of each of the alternative additives. The marked differences between the three categories suggest that it is advisable to evaluate each sample individually using a rheological approach such as that described here.

Background: The drug release of antiparkinsonian drugs is an important issue during the formulation process because proper release kinetics can help to reduce the off periods of Parkinson’s disease. A 2-factor, 3-level (32) full-factorial design was conducted to evaluate statistically the influence of the hydrophobicity of mesoporous silica on drug release. Methods: Hydrophobization was evaluated by different methods, such as contact angle measurement, infrared spectroscopy and charge titration. After loading the drug (levodopa methyl ester hydrochloride, melevodopa hydrochloride, LDME) into the mesopores, drug content, particle size, specific surface area and homogeneity of the products were also analyzed. The amorphous state of LDME was verified by X-ray diffractometry and differential scanning calorimetry. Results: Drug release was characterized by a model-independent method using the so-called initial release rate parameter, as detailed in the article. The adaptability of this method was verified, the model fitted closely to the actual release results according to the similarity factor, independently of the release kinetics. Conclusions: The API was successfully loaded into the silica, resulting in a reduced surface area. The release studies indicated that the release rate significantly decreased (p &lt, 0.05) with increasing hydrophobicity. The products with controlled release can reduce the off period frequency.

The objective of the present study was to develop n-propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design approach and central composite design. The in vitro mucoadhesion, scavenging activity, drug release, permeation studies of PG from PG-SLNs-loaded HG were evaluated under simulated nasal conditions. Compared with in vitro release behavior of PG from SLNs, the drug release from the PG-SLNs-loaded HG showed a lower burst effect and sustained release profile. The cumulative permeation of PG from PG-SLNs-loaded HG with TC-P was 600 μg/cm2 within 60 min, which is 3–60-fold higher than PG-SLNs and native PG, respectively. Raman mapping showed that the distribution of PG-SLNs was more concentrated in HG having lower concentrations of hyaluronic acid. The scavenging assay demonstrated increased antioxidant activity at higher concentrations of HG. Due to enhanced stability and mucoadhesive properties, the developed HG-based SLNs can improve nasal absorption by increasing residence time on nasal mucosa. This study provides in vitro proof of the potential of combining the advantages of SLNs and HG for the intranasal delivery of antioxidants.

We studied the applicability of Pulsed Laser Deposition (PLD) as a particle engineering method in the field of drug preformulation. Improving the dissolution and thereby the bioavailability of poorly water-soluble compounds is still a challenging task in pharmaceutical formulation. It was shown earlier that particle size reduction or the development of stable amorphous forms may both facilitate drug absorption. Using ibuprofen as a model drug, we studied the ablated particles obtained by pulsed-laser-beam irradiation of ibuprofen tablets. Nanosecond and femtosecond laser pulses (KrF excimer laser, λ = 248 nm, FWHM = 18 ns; 600 fs) were applied at various ambient pressures (10−4 mbar to 1 bar). The ablated particles were deposited for further analysis by FTIR, Raman Spectroscopy, XRPD, DSC and SEM. We found that all deposits prepared in vacuum by ns-pulses were chemically identical with ibuprofen, but their morphology varied depending on the applied pressure. At higher pressures (10 mbar to 10−1 mbar) the deposits exhibited similar crystalline morphology as the initial ibuprofen, while at lower pressures (10−2 mbar to 10−3 mbar), the deposits were rather amorphous. Using fs-pulses, molecular decomposition occurred at all background pressures. We have established that PLD with ns-pulses is a promising technique in the field of drug preformulation.

Csaba Bartos,1 Rita Ambrus,1 Gábor Katona,1 Tamás Sovány,1 Róbert Gáspár,2 Árpád Márki,3 Eszter Ducza,4 Anita Ivanov,4 Ferenc Tömösi,5 Tamás Janáky,5 Piroska Szabó-Révész1 1Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary; 2Faculty of Medicine, Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; 3Faculty of Medicine, Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary; 4Faculty of Pharmacy, Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary; 5Interdisciplinary Excellence Centre, Department of Medical Chemistry, University of Szeged, Szeged, HungaryCorrespondence: Piroska Szabó-RévészFaculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös u 6, Szeged H-6720, HungaryTel +36 62 545 5722Fax +36 62 545 571Email revesz@pharm.u-szeged.huPurpose: The aim of this work was to study the influence of solidification of meloxicam (Mel) containing nanosuspension (nanoMel) on the physical stability and drug bioavailability of the products. The nanoMel sample had poly(vinyl alcohol) (PVA) as a protective polymer, but no surfactant as a further stabilizing agent because the final aim was to produce surfactant-free solid phase products as well.Methods: The solidified samples produced by fluidization and lyophilization (fluidMel, lyoMel) were examined for particle size, crystallinity, and in vitro release of Mel compared to similar parameters of nanoMel. The products were subjected to an animal experiment using per oral administration to verify their bioavailability.Results: Mel containing (1%) nanoMel sample was produced by wet milling process using an optimized amount of PVA (0.5%) which resulted in 130 nm as mean particle size and a significant reduction in the degree of crystallinity (13.43%) of Mel. The fluidization technique using microcrystalline cellulose (MCC) as carrier resulted in a quick conversion and no significant change in the critical product parameters. The process of lyophilization required a longer operation time, which resulted in the amorphization of the crystalline carrier (trehalose) and the recrystallization of Mel increased its particle size and crystallinity. The fluidMel and lyoMel samples had nearly five-fold higher relative bioavailability than nanoMel application by oral administration. The correlation between in vitro and in vivo studies showed that the fixed Mel nanoparticles on the surface of solid carriers (MCC, trehalose) in both the artificial gastric juice and the stomach of the animals rapidly reached saturation concentration leading to faster dissolution and rapid absorption.Conclusion: The solidification of the nanosuspension not only increased the stability of the Mel nanoparticles but also allowed the preparation of surfactant-free compositions with excellent bioavailability which may be an important consideration for certain groups of patients to achieve rapid analgesia.Keywords: solidification, fluidization, lyophilization, surfactant-free product, rapid drug absorption, IVIV correlation

The aim of the present study was the preparation of aerogel microspheres based on alginate and hyaluronic acid for the potential application in pulmonary drug delivery. Both polymers are commonly used in the pharmaceutical and medical fields because of their nontoxicity, biodegradability and biocompatibility characteristics. The bio-based microspheres were produced using an emulsion gelation process with a subsequent drying step by supercritical CO2. The microspheres were characterized by FTIR and SEM. Furthermore, their BET surface area, particle size distribution, and their aerodynamic properties were determined. The microspheres showed a low density in the range of 0.035 – 0.063 g/cm3 and a high porosity of 97.6–98.7 %, as well as good in vitro aerodynamic properties with dA values of about 5 μm. The obtained properties of the alginate- hyaluronic acid microspheres suggest that they are potentially suitable as drug carrier for pulmonary delivery.

Levodopa (LEVO) as the gold standard in the treatment of Parkinson’s disease is usually administrated per os but its bioavailability is low. The intranasal administration is a potential alternative route to increase bioavailability of the drug and treat the off period. Our aim was to develop LEVO-containing binary nasal powders with different excipients by dry cogrinding process. The interactions between the components were examined. The optimized cogrinding process parameters (LEVO:excipient ratio and grinding time) resulted in the desired particle size range (5-40 μm). The α-cyclodextrin and poly(vinylpyrrolidone) (PVP) had an intensive crystallinity degree reducing effect on LEVO measured by XRPD, and they functioned as cogrinding agents. Hydroxypropyl methylcellulose, poly (vinyl alcohol) (PVA), and D-mannitol associate around the LEVO crystals preventing its crystalline structure. Hydrogen bonding was detected only for LEVO-PVP and LEVO-D-mannitol used Fourier-transformed infrared spectroscopy. Chemical degradation of LEVO in the products was not detected even after the accelerated stability test. The dissolution profile of the products can be characterized by the first-order kinetic model with different dissolution rate. The dissolution rate of LEVO was increased with α-cyclodextrin and PVP, and the drug release decreased in the case of hydroxypropyl methylcellulose, PVA, and D-mannitol compared to the LEVO powder.

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways – carrier-based, carrier-free, and novel combined formul...