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For the first time, rutin-rich extracts from black elderberry waste (BEW) were encapsulated using the particles from gas-saturated solutions (PGSS) method to improve the preservation of rutin. The extracts used in this study were obtained using five different extraction techniques under optimal conditions, as follows: conventional solid–liquid extraction (SLE) and four non-conventional techniques—ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), enhanced solvent extraction (ESE), and supercritical CO2 pretreatment—followed by ESE (SFE-CO2 + ESE). The PGSS process of the obtained extracts was performed using two amphiphilic carriers, glycerol monostearate (GlyMS) and gelucire (Gel), in a mass ratio of 1:6, in favor of the carrier. The efficiency of the PGSS process was evaluated based on the encapsulation yield (EnY), encapsulation efficiency (EE), and physical properties of the encapsulated extracts. The results showed that the SLE extract encapsulated with GlyMS had the highest EnY (92.47%). The Gel only in combination with the ESE extract exceeded the 50% efficacy threshold, with an EnY of 55.18%. The encapsulated SLE extract with Gel showed excellent flow properties and the highest EE (98.91%). These results emphasize the advantages of the PGSS process, including its efficiency and adaptability to produce encapsulated rutin-enriched BEW extracts for pharmaceutical, nutraceutical, and cosmetic applications.

Background: Cystic fibrosis is a hereditary disease, which causes the accumulation of dense mucus in the lungs accompanied by frequent local inflammation. The non-steroidal anti-inflammatory drug ibuprofen (IBU) and the mucolytic mannitol (MAN) can treat these symptoms. Compared to per os administration, a lower dose of these drugs is sufficient to achieve the desired effect by delivering them in a pulmonary manner. However, it is still a challenge to administer high drug doses to the lungs. We aim to develop two inhaled powder formulations, a single-drug product of MAN and a combined formulation containing IBU and MAN. Methods: MAN was dissolved in an aqueous solution of Poloxamer-188 (POL). In the case of the combined formulation, a suspension was first prepared in a planetary mill via wet milling in POL medium. After the addition of leucine (LEU), the formulations were spray-dried. The prepared DPI samples were analyzed by using laser diffraction, scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, density tests, in vitro aerodynamic studies (Andersen Cascade Impactor, Spraytec® device), in vitro dissolution tests in artificial lung fluid, and in silico tests with stochastic lung model. Results: The DPIs showed suitability for inhalation with low-density spherical particles of appropriate size. The LEU-containing systems were characterized by high lung deposition and adequate aerodynamic diameter. The amorphization during the procedures resulted in rapid drug release. Conclusions: We have successfully produced a single-drug formulation and an innovative combination formulation, which could provide complex treatment for patients with cystic fibrosis to improve their quality of life.

Background/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery—expressly in the lung—seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of γ-cyclodextrin (γCD) and potassium cations (K+) were employed to encapsulate the poorly water-soluble model drug Ibuprofen (IBU) for the treatment of cystic fibrosis (CF). Methods: Using the LeanQbD® software (v2022), we designed the experiments based on the Quality by Design (QbD) concept. According to QbD, we identified the three most critical factors, which were the molar ratio of the IBU to the γCD, incubation time, and the percentage of the organic solvent. light-, scanning electron microscope (SEM) and laser diffraction were utilized to observe the morphology and particle size of the samples. In addition, the products were characterized by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). Results: Based on characterizations, we concluded that a γCD-MOF/IBU complex was also formed using the freeze-drying method. Using formulations with optimal aerodynamic properties, we achieved 38.10 ± 5.06 and 47.18 ± 4.18 Fine Particle Fraction% (FPF%) based on the Andersen Cascade Impactor measurement. With these formulations, we achieved a fast dissolution profile and increased IBU solubility. Conclusions: This research successfully demonstrates the innovative use of freeze-drying to produce γCD-MOFs for inhalable IBU delivery. The method enabled to modify the particle size, which was crucial for successful pulmonary intake, emphasizing the need for further investigation of these formulations as effective delivery systems.

Intravascular catheter-associated infections pose a significant threat to the health of patients because of biofilm formation. Hence, it is imperative to exploit cost-effective approaches to improve patient compliance. With this aim, our present study reported the potential of an antimicrobial polymeric gel coating of chitosan (CS) and chlorhexidine (CHX) on the marketed urinary catheters to minimize the risk of biofilm formation. The study involved the implementation of the Quality by Design (QbD) approach by identifying the critical parameters that can affect the coating of the catheter’s surface in any possible way. Later, design of experiments (DoE) analysis affirmed the lack of linearity in the model for the studied responses in a holistic manner. Moreover, in vitro studies were conducted for the evaluation of various parameters followed by the antibiofilm study. The coating exhibited promising release of CHX in the artificial urinary media together with retention of the coating on the catheter’s surface. Therefore, this study aims to emphasize the importance of a systematic and quality-focused approach by contributing to the development of a safe, effective, and reliable catheter coating to enhance intravascular catheter safety.

In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.

The phenols from grape pomace have remarkable beneficial effects on health prevention due to their biological activity, but these are often limited by their bioaccessibility in the gastrointestinal tract. Encapsulation could protect the phenolics during digestion and influence the controlled release in such an intestine where their potential absorption occurs. The influence of freeze-drying encapsulation with sodium alginate (SA) and its combination with gum Arabic (SA-GA) and gelatin (SA-GEL) on the encapsulation efficiency (EE) of phenol-rich grape pomace extract and the bioaccessibility index (BI) of phenolics during simulated digestion in vitro was investigated. The addition of a second coating to SA improved the EE, and the highest EE was obtained with SA-GEL (97.02–98.30%). The release of phenolics followed Fick’s law of diffusion and the Korsmeyer–Peppas model best fitted the experimental data. The highest BI was found for the total phenolics (66.2–123.2%) and individual phenolics (epicatechin gallate 958.9%, gallocatechin gallate 987.3%) using the SA-GEL coating were used. This study shows that freeze-dried encapsulated extracts have the potential to be used for the preparation of various formulations containing natural phenolic compounds with the aim of increasing their bioaccessibility compared to formulations containing non-encapsulated extracts.

Most infectious diseases of the gastrointestinal tract can easily be treated by exploiting the already available antibiotics with the change in administration approach and delivery system. Ciprofloxacin (CIP) is used as a drug of choice for many bacterial infections; however, long-term therapy and off-site drug accumulation lead to an increased risk of tendinitis and peripheral neuropathy. To overcome this issue, nanotechnology is being exploited to encapsulate antibiotics within polymeric structures, which not only facilitates dose maintenance at the infection site but also limits off-site side effects. Here, sodium alginate (SA) and thiol-anchored chitosan (TC) were used to encapsulate CIP via a calcium chloride (CaCl2) cross-linker. For this purpose, the B-390 encapsulator was employed in the preparation of nanobeads using a simple technique. The hydrogel-like sample was then freeze-dried, using trehalose or mannitol as a lyoprotectant, to obtain a fine dry powder. Design of Experiment (DoE) was utilized to optimize the nanobead production, in which the influence of different independent variables was studied for their outcome on the polydispersity index (PDI), particle size, zeta potential, and percentage encapsulation efficiency (% EE). In vitro dissolution studies were performed in simulated saliva fluid, simulated gastric fluid, and simulated intestinal fluid. Antibacterial and anti-inflammatory studies were also performed along with cytotoxicity profiling. By and large, the study presented positive outcomes, proving the advantage of using nanotechnology in fabricating new delivery approaches using already available antibiotics.

Both grape pomace and whey are waste products from the food industry that are rich in valuable ingredients. The utilization of these two by-products is becoming increasingly possible as consumer awareness of upcycling increases. The biological activities of grape pomace extract (GPE) are diverse and depend on its bioavailability, which is influenced by processes in the digestive system. In this work, goat whey protein (GW) was used as the primary coating to protect the phenolic compounds of GPE during the spray drying process. In addition, trehalose (T), sucrose (S), xylose (X), and maltodextrin (MD) were added to the goat whey proteins as co-coatings and protein stabilizers. All spray drying experiments resulted in microcapsules (MC) with a high encapsulation efficiency (77.6–95.5%) and yield (91.5–99.0%) and almost 100% recovery of phenolic compounds during the release test. For o-coumaric acid, the GW-coated microcapsules (MC) showed a bioavailability index of up to 731.23%. A semi-crystalline structure and hydrophilicity were characteristics of the MC coated with 10% T, S, X, or 5% MD. GW alone or in combination with T, S, MD, or X proved to be a promising carrier for polyphenols from grape pomace extract and ensured good bioavailability of these natural antioxidants.

Non-steroidal anti-inflammatory piroxicam (PRX) is a poorly water-soluble drug that provides relief in different arthritides. Reducing the particle size of PRX increases its bioavailability. For pediatric, geriatric, and dysphagic patients, oral dispersible systems ease administration. Moreover, fast disintegration followed by drug release and absorption through the oral mucosa can induce rapid systemic effects. We aimed to produce an orodispersible lyophilizate (OL) consisting of nanosized PRX. PRX was solved in ethyl acetate and then sonicated into a poloxamer-188 solution to perform spray-ultrasound-assisted solvent diffusion-based nanoprecipitation. The solid form was formulated via freeze drying in blister sockets. Mannitol and sodium alginate were applied as excipients. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to determine the particle size. The morphology was characterized by scanning electron microscopy (SEM). To establish the crystallinity, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used. A disintegration and in vitro dissolution test were performed. DLS and NTA presented a nanosized PRX diameter. The SEM pictures showed a porous structure. PRX became amorphous according to the XRPD and DSC curves. The disintegration time was less than 1 min and the dissolution profile improved. The final product was an innovative anti-inflammatory drug delivery system.

Chitosan, being a biocompatible and mucoadhesive polysaccharide, is one of the most preferred hydrogel-forming materials for drug delivery. The objectives of the present study are to obtain spray-dried microparticles based on low-molecular-weight chitosan and study their potential application as cargo systems for the orally active drug benzydamine hydrochloride. Three types of particles are obtained: raw chitosan particles (at three different concentrations), cross-linked with sodium tripolyphosphate (NaTPP) particles (at three different chitosan:NaTPP ratios), and particles coated with mannitol (at three different chitosan:mannitol ratios), all of them in the size range between 1 and 10 µm. Based on the loading efficiency and the yields of the formulated hydrogel particles, one model of each type is chosen for further investigation of the effect of the cross-linker or the excipient on the properties of the gel structures. The morphology of both empty and benzydamine hydrochloride-loaded chitosan particles was examined by scanning electron microscopy, and it was quite regular and spherical. Interactions and composition in the samples are investigated by Fourier-transformed infrared spectroscopy. The thermal stability and phase state of the drug and drug-containing polymer matrixes were tested by differential scanning calorimetry and X-ray powdered diffraction, revealing that the drug underwent a phase transition. A drug release kinetics study of the chosen gel-based structures in simulated saliva buffer (pH = 6.8) and mathematical modeling of the process were performed, indicating the Weibull model as the most appropriate one.

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4–4.5 µm), fine particle fraction (56–71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.

Grape pomace is a byproduct of wineries and a sustainable source of bioactive phenolic compounds. Encapsulation of phenolics with a well-chosen coating may be a promising means of delivering them to the intestine, where they can then be absorbed and exert their health-promoting properties, including antioxidant, anti-inflammatory, anticancer, cardioprotective, and antimicrobial effects. Ionic gelation of grape pomace extract with natural coatings (sodium alginate and its combination with maltodextrins, gelatin, chitosan, gums Tragacanth and Arabic) was performed, and the resulting hydrogel microbeads were then air-, vacuum-, and freeze-dried to prevent spoilage. Freeze-drying showed advantages in preserving the geometrical parameters and morphology of the microbeads compared to other drying techniques. A good relationship was found between the physicochemical properties of the dried microbeads and the in vitro release of phenolics. Freeze-dried microbeads showed the highest cumulative release of phenols in the intestinal phase (23.65–43.27 mgGAE/gMB), while the most suitable release dynamics in vitro were observed for alginate-based microbeads in combination with gelatin, gum Arabic, and 1.5% (w/v) chitosan. The results highlight the importance of developing encapsulated formulations containing a natural source of bioactive compounds that can be used in various functional foods and pharmaceutical products.

Bovine serum albumin (BSA) has been used extensively as a suitable carrier system for alternative drug delivery routes, such as nasal administration. However, the optimization of BSA nanoparticles with respect to their nasal applicability has not been widely studied. The present study focuses on the characterization of BSA nanoparticles prepared using the desolvation method, followed by a gelation process to facilitate intranasal drug delivery. The results demonstrated that the ratio of BSA and the desolvating agent, ethanol, played a critical role in the nanoparticle characteristics of the BSA nanogel matrices (BSA-NGs). Based on the gelling properties, the formulations of BSA-NG 2, BSA-NG 4, and BSA-NG 6 were selected for further investigation. The Raman spectra confirmed that there were no specific changes to the secondary structures of the BSA. The mucoadhesion studies revealed moderately high mucoadhesive properties, with a mucin binding efficiency (MBE) value of around 67%, allowing the dose to avoid elimination due to rapid mucociliary clearance of the nasal passage. Via studying the nexus of the carrier system, BSA-NGs loaded with dexamethasone as a model drug were prepared and evaluated by differential scanning calorimetry (DSC) and thermal gravimetry (TG), ascertaining that no ethanol remained in the samples after the freeze-drying process. Furthermore, the viscosity measurements exhibited moderate viscosity, which is suitable for nasal liquid preparations. The in vitro release studies performed with a simulated nasal electrolyte solution (SNES) medium showed 88.15–95.47% drug release within 4 h. In conclusion, BSA nanoparticle gelling matrices can offer potential, value-added drug delivery carriers for improved nasal drug administration.

In this present formulation study, vinpocetine-loaded nano-spray-dried polymeric micelles were developed via nano-spray-drying. Three different mucoadhesive excipients were applied in the studies, namely chitosan, hyaluronic acid and hydroxypropyl methylcellulose. In all cases, the formulations had a proper particle size and drug content after drying with spherical morphology and amorphous structure. After rapid dissolution in water, the polymeric micelles had a particle size around 100–130 nm, in monodisperse size distribution. The high encapsulation efficiency (>80%) and high solubilization (approx. 300-fold increase in thermodynamic solubility) contributed to rapid drug release (>80% in the first 15 min) and fast passive diffusion at simulated nasal conditions. The formulated prototype preparations fulfilled the demands of a low-viscosity, moderately mucoadhesive nasal drug delivery system, which may be capable of increasing the overall bioavailability of drugs administered via the auspicious nasal drug delivery route.

The aim of this study was to develop, for the first time, anthocyanin-enriched fractions from black raspberry pomace (BRP) using ultrasound-assisted extraction (UAE) via sonotrode and the Particles from Gas-Saturated Solutions (PGSS) process. UAEs with different amplitudes and sonication times were evaluated and showed relevant effects on the yields of target analytes. The raspberry pomace extracts were formulated in a powder form by PGSS using glyceryl monostearate as a carrier at different extract-to-carrier ratios of 1:11, 1:5, and 1:3. The effects of all variables were evaluated in terms of extraction yield, total phenolic content, and encapsulation yield. UAE was strongly affected by amplitude, and the highest amplitude (100%) provided the best results for extraction yield and total phenolics. HPLC of UAE extracts and powders was utilized for quantification of polyphenol compounds, showing cyanidin-3-rutinoside as a main compound, followed by cyanidin-3-glucoside, rutin, ellagic acid, and gallic acid. These results show that these time-efficient and high-performance techniques enable the production of natural fractions from industrial BRP with acceptable characteristics to be used for the development of nutraceuticals and different food formulations.

As a well-known plant flavanol, quercetin possesses a diverse range of biological properties. These include its ability to act as an antioxidant, reduce inflammation, and exhibit anticancer effects. Consequently, it finds extensive application in numerous models related to wound healing. However, the poor physicochemical characteristics of the molecule (which include low solubility, stability, and permeability) eventually reduce its bioavailability at the targeted sites. A variety of nano formulations with great therapeutic potential have been created in order to get around these obstacles on the way to successful therapy. The current investigation aims to examine the properties of nano- and micro-sized casein/chitosan gel polyelectrolyte complexes (PECs) with respect to their potential for quercetin loading and release. Four different types of hydrogel particles at pH 6 and different casein/chitosan charge ratios were synthesized; namely, 1:1, 2:1, 4:1, and 6:1 in excesses of casein. The attractive electrostatic interactions between the oppositely charged polyelectrolytes were proved by FT-IR spectroscopy. The process yield increased from 37.5% to 72.5% in excesses of casein. The gel particle’s size varied between 377 nm and 5.72 µm depending on the casein/chitosan stoichiometry. The morphology of the obtained gel polyelectrolyte complexes was found to be spherical, based on scanning electron microscopy and atomic force microscopy analysis. The quercetin loading efficiency was above 95% for all investigated hydrogel complexes. Investigation of the physical state of the loaded polyphenol by the differential scanning calorimetry and X-ray powdered diffraction technique suggested the occurrence of partial recrystallization phenomena. The quercetin release test was performed in phosphate buffer (pH 5.5) at 32 °C and permanent stirring at 50 rpm. A zero-order model was used to describe in the best way the release kinetics. The reported casein/chitosan complexes loaded with quercetin may find application in wound healing as a concomitant treatment.

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.

Pulmonary drug transport has numerous benefits. Large surface areas for absorption and limited drug degradation of the gastrointestinal system are provided through the respiratory tract. The administration is painless and easy for the patient. Due to their better stability when compared to liquid formulations, powders have gained popularity among pulmonary formulations. In the pharmaceutical sector, quality assurance and product stability have drawn a lot of attention. Due to this, it was decided to perform a long-term stability study on a previously developed, nanosized dry powder inhaler (DPI) formulation that contained meloxicam. Wet milling was implemented to reduce the particle size, and nano spray-drying was used to produce the extra-fine inhalable particles. The particle diameter was determined using dynamic light scattering and laser diffraction. Scanning electron microscopy was utilized to describe the morphology. X-ray powder diffraction and differential scanning calorimetry were applied to determine the crystallinity. In an artificial lung medium, the in vitro dissolution was studied. The Andersen Cascade Impactor was used to investigate the in vitro aerodynamic characteristics. The stability test results demonstrated that the DPI formulation maintained its essential qualities after 6 and 12 months of storage. Consequently, the product might be promising for further studies and development.

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.

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.

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.

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.

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.

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.

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.

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.

Nanocrystal is widely applied to improve the dissolution of poorly water-soluble drugs. We aimed to prepare meloxicam (MLX) nanocrystals using the bead mill method, followed by high-pressure homogenization (HPH). Simple drying at room temperature (RD), vacuum-drying (VD), and freeze-drying (FD) using mannitol or trehalose as a cryoprotectant were applied to obtain dry nanocrystals. The nanocrystals were fully characterized. The MLX nanosuspension containing 5% w/v MLX and 1% w/v of Pluronic F68 showing a mean particle size (MPS) of 242 nm and a polydispersity index (PDI) of 0.36 was prepared after 40 min of premilling and 30 min of HPH. The dried nanocrystals were spherical within the nano range. DSC and XRPD confirmed the absence of MLX amorphization. The smartcrystals showed enhanced MLX release. Approximately 100% release was achieved with phosphate buffer (PB), pH 5.6, and 80% was released with PB, pH 7.4, from the freeze-dried samples. The results revealed the effects of the drying method and cryoprotectant type on the properties of dry nanocrystals. The freeze-dried samples showed the smallest particle size, in particular trehalose-based samples. On the other hand, mannitol-based dried samples showed the highest crystallinity index among all nanocrystals (77.8%), whereas trehalose showed the lowest (59.2%). These factors explained the dissolution differences among the samples.

Nasal drug delivery has many beneficial properties, such as avoiding the first pass metabolism and rapid onset of action. However, the limited residence time on the mucosa and limited absorption of certain molecules make the use of various excipients necessary to achieve high bioavailability. The application of mucoadhesive polymers can increase the contact time with the nasal mucosa, and permeation enhancers can enhance the absorption of the drug. We aimed to produce nanoparticles containing meloxicam potassium (MEL-P) by spray drying intended for nasal application. Various cyclodextrins (hydroxypropyl-β-cyclodextrin, α-cyclodextrin) and biocompatible polymers (hyaluronic acid, poly(vinylalcohol)) were used as excipients to increase the permeation of the drug and to prepare mucoadhesive products. Physico-chemical, in vitro and ex vivo biopharmaceutical characterization of the formulations were performed. As a result of spray drying, mucoadhesive nanospheres (average particle size 2) and ex vivo (1.47 μg/mm2) as well. After further optimization, the resulting formulations may be promising for eliciting a rapid analgesic effect through the nasal route.

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.

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 < 0.05) with increasing hydrophobicity. The products with controlled release can reduce the off period frequency.

Nowadays, the intranasal route has become a reliable alternative route for drug administration to the systemic circulation or central nervous system. However, there are no official in vitro diffusion and dissolution tests especially for the investigation of nasal formulations. Our main goal was to study and compare a well-known and a lesser-known in vitro permeability investigation method, in order to ascertain which was suitable for the determination of drug permeability through the nasal mucosa from different formulations. The vertical diffusion cell (Franz cell) was compared with the horizontal diffusion model (Side-Bi-Side). Raw and nanonized meloxicam containing nasal dosage forms (spray, gel and powder) were tested and compared. It was found that the Side-Bi-Side cell was suitable for the investigation of spray and powder forms. In contrast, the gel was not measurable on the Side-Bi-Side cell; due to its high viscosity, a uniform distribution of the active substance could not be ensured in the donor phase. The Franz cell, designed for the analysis of semi-solid formulations, was desirable for the investigation of nasal gels. It can be concluded that the application of a horizontal cell is recommended for liquid and solid nasal preparations, while the vertical one should be used for semi-solid formulations.

Three-dimensional printing (3DP) by fused deposition modeling (FDM) has gained momentum as a promising pharmaceutical manufacturing method due to encouraging forward-looking perspectives in personalized medicine preparation. The current challenges the technology has for applicability in the fabrication of solid dosage forms include the limited range of suitable pharmaceutical grade thermoplastic materials. Hence, it is important to investigate the implications of variable properties of the polymeric carrier on the preparation steps and the final output, as versatile products could be obtained by using the same material. In this study, we highlighted the influence of polyvinyl alcohol (PVA) particle size on the residence time of the mixtures in the extruder during the drug-loaded filament preparation step and the consequent impact on drug release from the 3D printed dosage form. We enhanced filament printability by exploiting the plasticizing potential of the active pharmaceutical ingredient (API) and we explored a channeled tablet model as a design strategy for dissolution facilitating purposes. Our findings disclosed a new perspective regarding material considerations for the preparation of PVA-based solid dosage forms by coupling hot melt extrusion (HME) and FDM-3DP.

The development of in vitro investigation models could be important using sensitive and fast methods during formulation. Intranasal applied drugs (meloxicam, lamotrigine, and levodopa) avoid the gastrointestinal tract and can achieve higher bioavailability, therefore a penetration extent is a key property. In this study, the in vitro adaptability of a modified horizontal diffusion cell was tested by using these model active pharmaceutical ingredients (APIs). The special factors consisted of the volume of the chambers, the arrangement of the stirrers, the design of probe input for real-time analysis and decreased membrane area. Membranes were impregnated by isopropyl myristate and by using phosphate buffer to evaluate the effect of API hydrophilicity on the diffusion properties. The lipophilicity of the API was proportional to the penetration extent through isopropyl myristate-impregnated membranes compared with buffer-soaked membranes. After evaluating the arithmetic mean of standard relative deviations and the penetrated extent of APIs at 15 min, Metricel® could be suggested for levodopa and meloxicam, and Whatman™ for lamotrigine. The modified model is suitable for inline, real-time detection, at nasal conditions, using small volumes of phases, impregnated membrane, to monitor the diffusion of the drug and to determine its concentration in the acceptor and donor phases.

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the ICH guideline in the above-mentioned three capsule types. The results of the novel combined formulated microcomposite were more favorable than those of the carrier-free formulation for all capsule types. The use of HPMC capsules results in the greatest stability and thus the best in vitro aerodynamic results for both DPI powders after six months. This can be explained by the fact that the residual solvent content (RSC) of the capsules differs. Under the applied conditions the RSC of the HPMC capsule decreased the least and remained within the optimal range, thus becoming less fragmented, which was reflected in the RSC, structure and morphology of the particles, as well as in the in vitro aerodynamic results (there was a difference of approximately 10% in the lung deposition results). During pharmaceutical dosage form developments, emphasis should be placed in the case of DPIs on determining which capsule type will be used for specific formulations.

In pharmaceutical development, more and more drugs are classified as poorly water-soluble or insoluble. Particle size reduction is a common way to fight this trend by improving dissolution rate, transport characteristics and bioavailability. Pulsed laser ablation is a ground-breaking technique of drug particle generation in the nano- and micrometer size range. Meloxicam, a commonly used nonsteroidal anti-inflammatory drug with poor water solubility, was chosen as the model drug. The pastille pressed meloxicam targets were irradiated by a Ti:sapphire laser (τ = 135 fs, λc = 800 nm) in air and in distilled water. Fourier transform infrared and Raman spectroscopies were used for chemical characterization and scanning electron microscopy to determine morphology and size. Additional particle size studies were performed using a scanning mobility particle sizer. Our experiments demonstrated that significant particle size reduction can be achieved with laser ablation both in air and in distilled water without any chemical change of meloxicam. The size of the ablated particles (~50 nm to a few microns) is approximately at least one-tenth of the size (~10–50 micron) of commercially available meloxicam crystals. Furthermore, nanoaggregate formation was described during pulsed laser ablation in air, which was scarcely studied for drug/organic molecules before.

The absorption of non-steroidal anti-inflammatory drugs (NSAIDs) through the nasal epithelium offers an innovative opportunity in the field of pain therapy. Thanks to the bonding of chitosan to the nasal mucosa and its permeability-enhancing effect, it is an excellent choice to formulate microspheres for the increase of drug bioavailability. The aim of our work includes the preparation of spray-dried cross-linked and non-cross-linked chitosan-based drug delivery systems for intranasal application, the optimization of spray-drying process parameters (inlet air temperature, pump rate), and the composition of samples. Cross-linked products were prepared by using different amounts of sodium tripolyphosphate. On top of these, the micrometric properties, the structural characteristics, the in vitro drug release, and the in vitro permeability of the products were studied. Spray-drying resulted in micronized chitosan particles (2–4 μm) regardless of the process parameters. The meloxicam (MEL)-containing microspheres showed nearly spherical habit, while MEL was present in a molecularly dispersed state. The highest dissolved (>90%) and permeated (~45 µg/cm2) MEL amount was detected from the non-cross-linked sample. Our results indicate that spray-dried MEL-containing chitosan microparticles may be recommended for the development of a novel drug delivery system to decrease acute pain or enhance analgesia by intranasal application.

Nanofibers of the poorly water-soluble antibiotic ciprofloxacin (CIP) were fabricated in the form of an amorphous solid dispersion by using poly(vinyl pyrrolidone) as a polymer matrix, by the low-cost electrospinning method. The solubility of the nanofibers as well as their in vitro diffusion were remarkably higher than those of the CIP powder or the physical mixture of the two components. The fiber size and morphology were optimized, and it was found that the addition of the CIP to the electrospinning solution decreased the nanofiber diameter, leading to an increased specific surface area. Structural characterization confirmed the interactions between the drug and the polymer and the amorphous state of CIP inside the nanofibers. Since the solubility of CIP is pH-dependent, the in vitro solubility and dissolution studies were executed at different pH levels. The nanofiber sample with the finest morphology demonstrated a significant increase in solubility both in water and pH 7.4 buffer. Single medium and two-stage biorelevant dissolution studies were performed, and the release mechanism was described by mathematical models. Besides, in vitro diffusion from pH 6.8 to pH 7.4 notably increased when compared with the pure drug and physical mixture. Ciprofloxacin-loaded poly(vinyl pyrrolidone) (PVP) nanofibers can be considered as fast-dissolving formulations with improved physicochemical properties.

Pulmonary delivery has high bioavailability, a large surface area for absorption, and limited drug degradation. Particle engineering is important to develop inhalable formulations to improve the therapeutic effect. In our work, the poorly water-soluble meloxicam (MX) was used as an active ingredient, which could be useful for the treatment of non-small cell lung cancer, cystic fibrosis, and chronic obstructive pulmonary disease. We aimed to produce inhalable “nano-in-micro” dry powder inhalers (DPIs) containing MX and additives (poly-vinyl-alcohol, leucine). We targeted the respiratory zone with the microcomposites and reached a higher drug concentration with the nanonized active ingredient. We did the following investigations: particle size analysis, morphology, density, interparticular interactions, crystallinity, in vitro dissolution, in vitro permeability, in vitro aerodynamics (Andersen cascade impactor), and in silico aerodynamics (stochastic lung model). We worked out a preparation method by combining wet milling and spray-drying. We produced spherical, 3–4 µm sized particles built up by MX nanoparticles. The increased surface area and amorphization improved the dissolution and diffusion of the MX. The formulations showed appropriate aerodynamical properties: 1.5–2.4 µm MMAD and 72–76% fine particle fraction (FPF) values. The in silico measurements proved the deposition in the deeper airways. The samples were suitable for the treatment of local lung diseases.

Albendazole is a benzimidazole derivative with documented antitumor activity and low toxicity to healthy cells. The major disadvantage in terms of clinical use is its low aqueous solubility which limits its bioavailability. Albendazole was incorporated into stable and homogeneous polyurethane structures with the aim of obtaining an improved drug delivery system model. Spectral and thermal analysis was used to investigate the encapsulation process and confirmed the presence of albendazole inside the nanoparticles. The in vitro anticancer properties of albendazole encapsulated in polyurethane structures versus the un-encapsulated compound were tested on two breast cancer cell lines, MCF-7 and MDA-MB-231, in terms of cellular viability and apoptosis induction. The study showed that the encapsulation process enhanced the antitumor activity of albendazole on the MCF-7 and MDA-MB-23 breast cancer lines. The cytotoxic activity manifested in a concentration-dependent manner and was accompanied by changes in cell morphology and nuclear fragmentation.

Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, which is an interactive physical blend of a surface-modified carrier and a spray-dried drug with suitable shape and size for pulmonary application. Meloxicam potassium, a nonsteroidal anti-inflammatory drug (NSAID), was used as an active ingredient due to its local anti-inflammatory effect and ability to decrease the progression of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The results of the in vitro and in silico investigations showed high lung deposition in the case of this new formulation, confirming that the interparticle interactions were changed favorably.

Nasal drug delivery has become a popular research field in the last years. This is not surprising since the nose possesses unique anatomical and physical properties. Via the nasal mucosa local, systemic, and directly central nerve systemic (CNS) effect is achievable. Powders have favorable physicochemical properties over liquid formulations. Lamotrigine (LAM) is an antiepileptic agent with a relatively mild side effect spectrum, but only available in tablet form on market. Reducing the particle size to the nano range can affect the bioavailability of pharmaceutical products. The aim of this article was to continue the work started, compare the in vitro properties of a nanonized lamotrigine containing nasal powder (nanoLAMpowder) and its physical mixture (PM) that were prepared by dry milling. Moreover, to study their trans-epithelial absorption to reach the blood and target the brain by axonal transport. Due to the dry milling technique, the particle size of LAM, their surface and also their structure changed that led to higher in vitro dissolution and permeability rate. The results of the in vivo tests showed that the axonal transport of the drug was assumable by both intranasal formulations because the drug was present in the brain within a really short time, but the LAM from the nanoLAMpowder liberated even faster.

The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, −14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable “value-added” product for the treatment of neuroinflammation.

White horehound (Marrubium vulgare L.), is a grey-leaved perennial herb, belonging to Lamiaceae family, distributed in Eurasia and northern Africa. Despite the fact that M. vulgare has been used since ancient times in treating diverse diseases, it is only in the last decade or so that scientists have been able to lay the foundation for its potential pharmacological actions from the results observed through the prism of ethnopharmacological use of this species. The novelty of this study was that subcritical water extraction, acknowledged as a powerful extraction technology to recover phenolic compounds, was coupled with spray drying. The subcritical horehound extract, obtained using optimal process parameters, was used as a liquid feed in spray drying. Maltodextrin was used as a carrier in a concentration of 10%. Thus, two M. vulgare powders, carrier-free and 10% MD, were produced. Comprehensive powders characterization was conducted in order to evaluate their quality. Results confirmed that spray drying can be used as a method of choice for obtaining high quality horehound powders which kept the amorphous structure constant after 6 months.

The aim of this article was to study the trans-epithelial absorption to reach the blood and to target the brain by axonal transport using nasal formulations with nanonized meloxicam (nano MEL spray) and its salt form known as meloxicam potassium monohydrate (MELP spray). The physicochemical properties and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out. These forms were first investigated in “nose-to-brain” relation. It was found that the in vitro study and in vivo study did not show any significant correlation. In vitro experiments demonstrated faster dissolution rate and higher diffusion of MELP from the spray compared with the nano MEL spray. The administration of the nano MEL spray resulted in faster absorption and constant plasma concentration of the drug after five minutes of administration as compared to MELP. The axonal transport of the drug was justified. MEL appeared in the brain tissues after the first five minutes of administration in the case of both spray forms, but its amount was too small in comparison with the total plasma concentration. The application of the nano MEL spray resulted in the same AUC in the brain as the intravenous injection. The “nose-to-blood” results predicted the nasal applicability of MEL and MELP in pain management. The “nose-to-brain” pathway requires further study.

The nasal route receives a great deal of attention as a non-invasive method for the systemic administration of drugs. For nasal delivery, specific formulations containing excipients are used. Because of the sensitive respiratory mucosa, not only the active ingredients, but also additives need to be tested in appropriate models for toxicity. The aim of the study was to measure the cytotoxicity of six pharmaceutical excipients, which could help to reach larger residence time, better permeability, and increased solubility dissolution rate. The following excipients were investigated on RPMI 2650 human nasal septum tumor epithelial cells: β-d-mannitol, sodium hyaluronate, α and β-cyclodextrin, polyvinyl alcohol and methylcellulose. 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye conversion assay and real-time impedance analysis were used to investigate cytotoxicity. No excipient showed toxicity at 0.3% (w/v) concentration or below while 1% concentration a significantly reduced metabolic activity was measured by MTT assay for methylcellulose and cyclodextrins. Using impedance measurements, only β-cyclodextrin (1%) was toxic to cells. Mannitol at 1% concentration had a barrier opening effect on epithelial cells, but caused no cellular damage. Based on the results, all additives at 0.3%, sodium hyaluronate and polyvinyl alcohol at 1% concentrations can be safely used for nasal formulations.

This article reports on the effects of a new combined wet milling technique on the physicochemical properties of meloxicam (MEL). The influence of milling time on the particle size, the crystallinity, the morphology and the dissolution rate of MEL has been studied in the presence and absence of polyvinyl alcohol (PVA) as a stabilizer agent. Micronized MEL particles were produced in aqueous medium which did not contain additive after milling for 10 min. For nanonization an additive and longer milling time were required. After particle size determination the structural and morphological characterization of the wet milled, dried products containing MEL were studied. X-ray powder diffractometry (XRPD) and differential scanning calorimetry (DSC) examinations revealed the change in the crystallinity of MEL. Scanning electron microscopy (SEM) images showed that aggregates of nanosized MEL particles were formed, regardless of the presence of PVA. The nanonized MEL crystals (D50 = 126 nm) exhibited a regular shape and a smooth surface. The increased specific surface area resulted in a high dissolution rate and concentration of free MEL. According to the results, the produced samples could be applied as a basic material (micronized MEL) and intermediate product (micronized and nanonized MEL with PVA) for the design of dosage forms.