Fibrous matrices facilitate pleurocidin killing of wound associated bacterial pathogens.

Conventional wound infection treatments neither actively promote wound healing nor address the growing problem of antibacterial resistance. Antimicrobial peptides (AMPs) are natural defense molecules, released from host cells, which may be rapidly bactericidal, modulate host-immune responses, and/or act as endogenous mediators for wound healing. However, their routine clinical use has hitherto been hindered due to their instability in the wound environment. Here we describe an electrospun carrier system for topical application of pleurocidin, demonstrating sufficient AMP release from matrices to kill wound-associated pathogens including Acinetobacter baumannii and Pseudomonas aeruginosa. Pleurocidin can be incorporated into polyvinyl alcohol (PVA) fiber matrices, using coaxial electrospinning, without major drug loss with a peptide content of 0.7% w/w predicted sufficient to kill most wound associated species. Pleurocidin retains its activity on release from the electrospun fiber matrix and completely inhibits growth of two strains of A. baumannii (AYE; ATCC 17978) and other ESKAPE pathogens. Inhibition of P. aeruginosa strains (PAO1; NCTC 13437) is, however, matrix weight per volume dependent, with only larger/thicker matrices maintaining complete inhibition. The resulting estimation of pleurocidin release from the matrix reveals high efficiency, facilitating a greater AMP potency. Wound matrices are often applied in parallel or sequentially with the use of standard wound care with biocides, therefore the presence and effect of biocides on pleurocidin potency was tested. It was revealed that combinations displayed additive or modestly synergistic effects depending on the biocide and pathogens which should be considered during the therapy. Taken together, we show that electrospun, pleurocidin-loaded wound matrices have potential to be investigated for wound infection treatment.

Solid oral medications' suitability for use in enteral feeding tubes.

BACKGROUND: There is a lack of specific data about the efficacy and safety of medications administered via feeding tubes, although there is a general awareness that not all drug formulations are suitable. AIMS AND OBJECTIVES: To overview the current situation with solid medications administered through feeding tubes in the Tartu University Hospital intensive care units. To evaluate the availability of information on the suitability of drug formulations for administration via feeding tubes. DESIGN: This was a descriptive retrospective document analysis study. METHODS: During visits to the intensive care units, medication data for current patients were collected from paper medical charts and nurses. In addition, package information leaflets, summaries of product characteristics, and two practical handbooks were used for evaluating the medicines' suitability for administration via feeding tubes. A request for information was also sent to manufacturers or marketing authorization holders. RESULTS: In 3 months, data were collected from 113 intensive care patients' medical charts. A total of 306 medication administrations via feeding tubes were documented and analysed, 67% of which were solid oral dosage forms. Exactly 91.2% of these were conventional tablets. After the analysis of information availability, 88% of the medications were classified as suitable for administration via feeding tubes, but only 48% had the manufacturer-provided information. CONCLUSION: This study showed that the information about the suitability of formulations administration through a feeding tube is not readily available for almost half of the medications. The manufacturers seem to have the relevant information, but it is not always added to their medications' official information, putting these patients at higher risk for errors. RELEVANCE TO CLINICAL PRACTICE: This study shows that if there is no clear statement about administration through feeding tubes on official manufacturers' information, this should be sought directly from manufacturers or marketing authorization holders, and the data could be incorporated into local guidelines.

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.

Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.

Electrospun Amphiphilic Nanofibers as Templates for In Situ Preparation of Chloramphenicol-Loaded Liposomes.

The hydration of phospholipids, electrospun into polymeric nanofibers and used as templates for liposome formation, offers pharmaceutical advantages as it avoids the storage of liposomes as aqueous dispersions. The objective of the present study was to electrospin and characterize amphiphilic nanofibers as templates for the preparation of antibiotic-loaded liposomes and compare this method with the conventional film-hydration method followed by extrusion. The comparison was based on particle size, encapsulation efficiency and drug-release behavior. Chloramphenicol (CAM) was used at different concentrations as a model antibacterial drug. Phosphatidylcoline (PC) with polyvinylpyrrolidone (PVP), using ethanol as a solvent, was found to be successful in fabricating the amphiphilic composite drug-loaded nanofibers as well as liposomes with both methods. The characterization of the nanofiber templates revealed that fiber diameter did not affect the liposome size. According to the optical microscopy results, the immediate hydration of phospholipids deposited on the amphiphilic nanofibers occurred within a few seconds, resulting in the formation of liposomes in water dispersions. The liposomes appeared to aggregate more readily in the concentrated than in the diluted solutions. The drug encapsulation efficiency for the fiber-hydrated liposomes varied between 14.9 and 28.1% and, for film-hydrated liposomes, between 22.0 and 77.1%, depending on the CAM concentrations and additional extrusion steps. The nanofiber hydration method was faster, as less steps were required for the in-situ liposome preparation than in the film-hydration method. The liposomes obtained using nanofiber hydration were smaller and more homogeneous than the conventional liposomes, but less drug was encapsulated.

Preformulation Study of Electrospun Haemanthamine-Loaded Amphiphilic Nanofibers Intended for a Solid Template for Self-Assembled Liposomes.

Haemanthamine (HAE) has been proven as a potential anticancer agent. However, the therapeutic use of this plant-origin alkaloid to date is limited due to the chemical instability and poorly water-soluble characteristics of the agent. To overcome these challenges, we developed novel amphiphilic electrospun nanofibers (NFs) loaded with HAE, phosphatidylcholine (PC) and polyvinylpyrrolidone (PVP), and intended for a stabilizing platform (template) of self-assembled liposomes of the active agent. The NFs were fabricated with a solvent-based electrospinning method. The chemical structure of HAE and the geometric properties, molecular interactions and physical solid-state properties of the NFs were investigated using nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM), photon correlation spectroscopy (PCS), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), respectively. An in-house dialysis-based dissolution method was used to investigate the drug release in vitro. The HAE-loaded fibers showed a nanoscale size ranging from 197 nm to 534 nm. The liposomes with a diameter between 63 nm and 401 nm were spontaneously formed as the NFs were exposed to water. HAE dispersed inside liposomes showed a tri-modal dissolution behavior. In conclusion, the present amphiphilic NFs loaded with HAE are an alternative approach for the formulation of a liposomal drug delivery system and stabilization of the liposomes of the present alkaloid.

Monitoring of Antimicrobial Drug Chloramphenicol Release from Electrospun Nano- and Microfiber Mats Using UV Imaging and Bacterial Bioreporters.

New strategies are continuously sought for the treatment of skin and wound infections due to increased problems with non-healing wounds. Electrospun nanofiber mats with antibacterial agents as drug delivery systems provide opportunities for the eradication of bacterial infections as well as wound healing. Antibacterial activities of such mats are directly linked with their drug release behavior. Traditional pharmacopoeial drug release testing settings are not always suitable for analyzing the release behavior of fiber mats intended for the local drug delivery. We tested and compared different drug release model systems for the previously characterized electrospun chloramphenicol (CAM)-loaded nanofiber (polycaprolactone (PCL)) and microfiber (PCL in combination with polyethylene oxide) mats with different drug release profiles. Drug release into buffer solution and hydrogel was investigated and drug concentration was determined using either high-performance liquid chromatography, ultraviolet-visible spectrophotometry, or ultraviolet (UV) imaging. The CAM release and its antibacterial effects in disc diffusion assay were assessed by bacterial bioreporters. All tested model systems enabled to study the drug release from electrospun mats. It was found that the release into buffer solution showed larger differences in the drug release rate between differently designed mats compared to the hydrogel release tests. The UV imaging method provided an insight into the interactions with an agarose hydrogel mimicking wound tissue, thus giving us information about early drug release from the mat. Bacterial bioreporters showed clear correlations between the drug release into gel and antibacterial activity of the electrospun CAM-loaded mats.

Effects and efficacy of different sterilization and disinfection methods on electrospun drug delivery systems.

Microbiological quality of a pharmaceutical product is an essential requirement ensuring patient safety, thus effective sterilization/disinfection methods need to be found. The aim of this study was to evaluate the efficacy of different sterilization/disinfection methods on drug-loaded electrospun matrices and the impact of these treatments on the functionality related characteristics of these matrices. The sterilization efficacy of gamma-irradiation, ultraviolet-irradiation, in situ generated chlorine gas and low-pressure argon plasma treatment were evaluated on two different chloramphenicol-loaded electrospun matrices using pristine polycaprolactone (PCL) as a carrier polymer or PCL in combination with polyethylene oxide. Drug stability, solid state properties, morphology, mechanical properties, swelling, biodegradation and drug release kinetics were studied before and after the treatments. It was shown that all tested methods help to reduce bioburden and only plasma treated matrices were not sterile. At the same time drug degradation after the treatment can be considerable and depends not only on the susceptibility of the drug to degradation, but also on matrix properties (e.g. the nature of carrier polymers). Even though no morphological changes were observed, gamma sterilization increased the hardness and elasticity of PCL matrices as a result of increased crystallinity of the polymer. Plasma treatment was able to significantly enhance water absorption to otherwise hydrophobic PCL/CAM matrix and had tremendous impact on its drug release kinetics as the drug was instantly released from otherwise prolonged release formulation.

Interactions between Chloramphenicol, Carrier Polymers, and Bacteria-Implications for Designing Electrospun Drug Delivery Systems Countering Wound Infection.

Antibacterial drug-loaded electrospun nano- and microfibrous dressings are of major interest as novel topical drug delivery systems in wound care. In this study, chloramphenicol (CAM)-loaded polycaprolactone (PCL) and PCL/poly(ethylene oxide) (PEO) fiber mats were electrospun and characterized in terms of morphology, drug distribution, physicochemical properties, drug release, swelling, cytotoxicity, and antibacterial activity. Computational modeling together with physicochemical analysis helped to elucidate possible interactions between the drug and carrier polymers. Strong interactions between PCL and CAM together with hydrophobicity of the system resulted in much slower drug release compared to the hydrophilic ternary system of PCL/PEO/CAM. Cytotoxicity studies confirmed safety of the fiber mats to murine NIH 3T3 cells. Disc diffusion assay demonstrated that both fast and slow release fiber mats reached effective concentrations and had similar antibacterial activity. A biofilm formation assay revealed that both blank matrices are good substrates for the bacterial attachment and formation of biofilm. Importantly, prolonged release of CAM from drug-loaded fibers helps to avoid biofilm formation onto the dressing and hence avoids the treatment failure.

Development of electrosprayed artesunate-loaded core-shell nanoparticles.

OBJECTIVE: Artesunate (ART) is proven to have potential anti-proliferative activities, but its instability and poor aqueous solubility limit its application as an anti-cancer drug. The present study was undertaken to develop coaxial electrospraying as a novel technique for fabricating nanoscale drug delivery systems of ART as the core-shell nanostructures. METHODS: The core-shell nanoparticles (NPs) were fabricated with coaxial electrospraying and the formation mechanisms of NPs were examined. The physical solid state and drug-polymer interactions of NPs were characterized by X-ray powder diffraction (XRPD) and Fourier transform infrared (FTIR) spectroscopy. The effects of materials and electrospraying process on the particle size and surface morphology of NPs were investigated by scanning electron microscopy (SEM). The drug release from NPs was determined in vitro by a dialysis method. RESULTS: The ART/poly(lactic-co-glycolic) acid (PLGA) chitosan (CS) NPs exhibited the mean particle size of 303 ± 93 nm and relatively high entrapment efficiency (80.5%). The release pattern showed an initial rapid release within two hours followed by very slow extended release. The release pattern approached the Korsmeyer-Peppas model. CONCLUSIONS: The present results suggest that the core-shell NPs containing PLGA and CS have a potential as carriers in the anticancer drug therapy of ART.

Development of Oromucosal Dosage Forms by Combining Electrospinning and Inkjet Printing.

Printing technology has been shown to enable flexible fabrication of solid dosage forms for personalized drug therapy. Several methods can be applied for tailoring the properties of the printed pharmaceuticals. In this study, the use of electrospun fibrous substrates in the fabrication of inkjet-printed dosage forms was investigated. A single-drug formulation with lidocaine hydrochloride (LH) and a combination drug system containing LH and piroxicam (PRX) for oromucosal administration were prepared. The LH was deposited on the electrospun and cross-linked gelatin substrates by inkjet printing, whereas PRX was incorporated within the substrate fibers during electrospinning. The solid state analysis of the electrospun substrates showed that PRX was in an amorphous state within the fibers. Furthermore, the results indicated the entrapment and solidification of the dissolved LH within the fibrous gelatin matrix. The printed drug amount (2-3 mg) was in good correlation with the theoretical dose calculated based on the printing parameters. However, a noticeable degradation of the printed LH was detected after a few months. An immediate release (over 85% drug release after 8 min) of both drugs from the printed dosage forms was observed. In conclusion, the prepared electrospun gelatin scaffolds were shown to be suitable substrates for inkjet printing of oromucosal formulations. The combination of electrospinning and inkjet printing allowed the preparation of a dual drug system.

Pharmacopoieal quality of non-expired and expired nifedipine formulations from Estonian and Russian Federation medicinal products market.

The pharmacopoeial quality of non-expired and expired nifedipine tablets of the same batches purchased from the Estonian and Russian Federation medicinal product markets was evaluated. The IR spectroscopy, HPLC analysis for quantitative content and purity of the active pharmaceutical ingredient (API), and dissolution test techniques were applied. In the experiments with non-expired nifedipine tablets, in all Estonian (n = 8, label claims 10, 20, and 40 mg) and Russian Federation (n = 4, label claim 10 mg) registered formulations the API was identified and quantified as nifedipine in amounts set by the European Pharmacopoeia and without exceeding the tolerance limits for the impurities. The dissolution rate was variable but all 10 and 20 mg non-expired nifedipine tablets released at least 80% of API in 12 h. The expiration of the nifedipine tablets led to somewhat increased dissolution rate while only traces of the nifedipine degradation products were discovered in the dissolution medium. In conclusion, our present study shows that with minor variations the Estonian and Russian Federation registered nifedipine tablets are comparable, the API preserves well beyond the expiration date but the expired nifedipine tablets may release the API faster than the non-expired tablets.

Solid-state dependent dissolution and oral bioavailability of piroxicam in rats.

The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug.

Lead content in pot marigold (Calendula officinalis L.) inflorescences and leaves: impact of precipitations and vicinity of motorway.

Trace metal contamination is a major environmental and health problem virtually in all countries. The present study was aimed to estimate the lead content of pot marigold (Calendula officinalis L.) inflorescences and leaves collected from a nonpolluted test field. The lead content in dry pot marigold inflorescences was 9.34 ± 0.79 µg/g, in dry leaves 11.57 ± 0.47 µg/g, and in soil 0.649 ± 0.012 µg/g. The distance of pot marigold collection beds (30-220 m from the motorway) had no effect on lead content. There was a strong positive correlation between the amount of precipitations and lead content of pot marigold leaves but not inflorescences indicating the soil as primarily the source of increased lead content. In conclusion, no effect of motorway vicinity was found for pot marigold inflorescences or leaves lead content; however, as a precaution, it is not recommended to collect the plants during or just after showers.