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The selection of appropriate functional co-processed excipient (CPE) is a crucial stage in orodispersible minitablets (ODMTs) development. This paper aimed to identify the most important morphological attributes influencing the flowability and homogeneity of powder mixtures and minitablets final quality. Our research included the use of the laser diffraction method, the microscopic automated imaging technique and a flowability tester. All powder parameters examined were divided into two groups: those affecting mixture homogeneity or flowability. A Pearson's correlation matrix revealed a strong relationship between both, especially in terms of solidity-circularity and convexity-circularity pairs (r = −0.71, p = 0.010 and r = 0.93, p = 0.000 respectively). An analysis of model mixtures confirmed that high solidity values of the CPE support final mixture homogeneity and accordingly high circularity values support its flowability. In conclusion, solidity and circularity were indicated as the most critical morphological parameters, which have to be analyzed to define the best possible ODMTs formulation.

The widespread role of titanium (IV) oxide (TiO2) in many industries makes this substance of broad scientific interest. TiO2 can act as both a photoprotector and photocatalyst, and the potential for its role in both applications increases when present in nanometer-sized crystals. Its sunlight-scattering properties are used extensively in sunscreens. Furthermore, attempts have been made to incorporate TiO2 into dermal formulations of photolabile drugs. However, the propensity to generate reactive oxygen species (ROS) rendering this material potentially cytotoxic limits its role. Therefore, modifications of TiO2 nanoparticles (e.g., its polymorphic form, size, shape, and surface modifications) are used in an effort to reduce its photocatalytic effects. This review provides an overview of the potential risks arising from and opportunities presented by the use of TiO2 in skin care formulations.

Recently, minitablets have been given extensive coverage in literature, as they are perfectly matched to the current therapy individualization trend. Within this scope, special attention is paid to minitablets that enable convenient drug intake for patients with swallowing problem. However, the packaging system, dispensing the necessary amount of drug units and safe administration still remain unsolved problems or are partially overlooked. Although there are many different approaches towards dosing tablets, only a few seem to be tailored to particularly small tablets. Moreover, none of these approaches meets all the user's expectations. This paper comprehensively elaborates and critically discusses the available dosing options like sachets, blisters, home electronic dispensing systems and minitablets manual dispensers. Additional tests have been also conducted to simulate the handling and dosing procedure with 2 mm diameter placebo minitablets. Despite many advantageous inventions, it has been revealed that further efforts are necessary to identify the optimal design that would allow to eliminate the shaking procedure, adjust cavities diameter or provide better protection against humidity. Nevertheless, the current trend may lead to individual therapy becoming more convenient, safe and reliable, especially in pediatric and geriatric patients.

Two novel self-emulsifying drug delivery systems (SEDDS) with atorvastatin calcium, an anti-hyperlipidemic drug, were obtained and adsorbed on different solid inorganic carriers. In order to determine the parameters affecting the drug release process, different physicochemical analyses were performed. Liquid SEDDS were investigated for water solubilization capacity, viscosity and surface tension. In the case of solid materials, differential scanning calorimetry and scanning electron microscopy were conducted in order to check the samples for the presence of drug crystals. The interactions between the components of the materials were analyzed with inverse gas chromatography and Flory-Huggins parameters were calculated. The drug release experiments performed for all investigated formulations revealed that after the initial quick release the drug concentration in the dissolution medium decreased slightly which might be related to the crystallization process. However, the level of the released active ingredient was maintained at 80% for most formulations. It was also shown that the results of drug dissolution studies were independent of the measured physicochemical parameters, even though some clear differences have been observed between the analyzed materials.

In this paper, we present results on the sorption and wettability of tablets containing mucoadhesive (Carbopol 974P NF, HEC) and film-forming (Kollidon VA 64) polymers, with fluconazole as a model active pharmaceutical ingredient (API), important from the point of view of designing new mucoadhesive drug delivery systems for potential use for development of mucoadhesive vaginal or buccal dosage forms. Preliminary studies of the powdered polymer mixture with API and the tablets containing the same components in simulated saliva and vaginal fluids were conducted. Wetting properties of the tablets were determined by contact angle measurements using the sessile drop method. On the basis of the measured contact angles, the surface free energy (SFE) was determined according to the Owens-Wendt-Rabel-Kaelble (OWRK) approach. The sorption properties of the powders were evaluated by the liquid penetration method. Moreover, in vitro fluconazole release studies were performed using USP 4 apparatus. The composition of the formulation as well as pH of the model fluids were found to significantly influence the surface properties of the tested systems, but simultaneously, composition revealed a weak effect of the above parameters on the rate of drug release from the polymer matrix was observed. It was found that the fluconazole release kinetics for most of the tested tablets can be described by the anomalous or super case II transport mechanism.

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [μg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80–125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations. Electronic supplementary material The online version of this article (10.1208/s12249-020-01662-8) contains supplementary material, which is available to authorized users.

Currently marketed drug-eluting stents are non-selective in their anti-restenotic action. New active substance introduction to polymeric stents and vascular grafts can promote early re-endothelialization, crucial in preventing implant restenosis. Additionally, managing material hydrophobicity by blending synthetic polymers limits adverse effects on bulk properties and controls active substance release. However, the influence of hydrophilic synthetic polymer on human cells in the cardiovascular system remains to be determined. In this report, effects of both poly(e-caprolactone) (PCL) fibers hydrophilization with Pluronic P123 (P123) and cilostazol (CIL) loading were studied. Physicochemical and mechanical properties of electrospun tubular structures produced from PCL and PCL/P123 fibers with and without CIL were investigated and compared. Release profiles studies and in vitro cell proliferation assays of electrospun materials were conducted. It was found that P123 located near the surface of electrospun fibers increased the rate of CIL release. PCL formulation sustained human umbilical vein endothelial cells (HUVEC) growth for 48 h. Despite improved hydrophilicity, PCL/P123 formulations were found to reduce HUVEC viability. Both PCL and PCL/P123 materials reduced primary aortic smooth muscle cells (PASM) viability after 48 h. In PCL formulations containing CIL, drug release caused a decrease in PASM viability. P123 blending with PCL was found to be as a useful pre-fabrication technique for modulating surface hydrophobicity of electrospun materials and the release profile of incorporated active substance. The cytotoxicity of P123 was evaluated to improve the design of drug-loaded vascular grafts for cardiovascular applications.

International audience; Water-dispersible 1-thioglycerol (TG)-capped Mn-doped ZnS quantum dots were prepared in aqueous solution using the nucleation-doping strategy. Using 4% Mn relative to Zn and a Zn(OAc)2/Na2S ratio of 0.9, Mn:ZnS nanocrystals with an average diameter of 3.9 ± 0.5 nm, with pure Mn2+-related photoluminescence (PL) at 585 nm, and with a PL quantum yield of 13.2% were obtained. Transmission electron microscopy, X-ray powder diffraction, electron spin resonance, X-ray photoelectron spectroscopy, UV-visible spectroscopy and spectrofluorometry have been used to characterize the crystal structure, the doping status, and the optical properties of the doped-dots. Folic acid (FA) was linked to TG-capped Mn:ZnS nanocrystals to produce Mn:ZnS@TG-FA nanobioconjugates that were used for targeted in vitro delivery to a human cancer cell line. Folate receptor mediated cellular uptake of FA-functionalized dots is proven via confocal and two-photon imaging.

Open Research Biopharmaceutical Internships Support (ORBIS) is an international, Horizon 2020 project funded by Maria Skłodowska-Curie Actions, Research and Innovation Staff Exchange (RISE) programme. Six academic institutions and four pharmaceutical companies from seven countries cooperate with the aim to improve the preclinical pathway of medicine development through increased Research and Development (R&D) productivity, especially focusing on processes and technologies which address the challenge of poor drug bioavailability. The RISE scheme supports secondments, meaning that early stage and experienced researchers are sent to consortium partner institutions to advance studies on pharmaceutical preformulation, dosage forms and drug delivery systems and methods of biopharmaceutical evaluation. The ORBIS project enables secondees to gain news skills and develop their competences in an international and intersectoral environment, strengthening the human capital and knowledge synergy in the European pharmaceutical R&D sector.

Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles’ size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension’s stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.

In the mucoadhesive drug delivery systems the controlling mechanism is initiated by the wetting and swelling of the polymer matrix. In view of the above, the aim of our study was to analyze the effect of model saliva and gastric fluids on the wetting properties and sorption of selected mucoadhesive (Carbopol 974P NF, HEC) and film-forming (Kollidon VA 64) polymers as well as their blends. We considered two types of examined materials: individual polymers and their blends in the form of powders as well as in the form of compressed discs (blanc tablets). The contact angle measurements for powders were performed according to the Washburn method, using the capillary rise technique, whereas the sessile drop method was applied to the compressed discs of mucoadhesive polymers. The surface energy was determined by the OWRK method. The influence of composition of the polymer blends and pH of model fluids on the wetting properties and sorption of the polymer formulations was evaluated. Moreover, significant differences in the morphology, surface roughness and surface properties of mucoadhesion polymers considered were discussed.

An ordered mesoporous silica material, SBA-15, with a hexagonally arranged structure of pores, was applied as a potential nanocarrier for a poorly soluble calcium channel blocker, nifedipine. Nifedipine-loaded samples were analyzed both before and after chemical washing and compared to bulk nifedipine reference. The physicochemical properties were defined by a number of experimental techniques, including differential thermal analysis (DTA), X-ray powder diffraction (PXRD) and Fourier-transform infrared spectroscopy (FT-IR). Analysis of the dissolution profiles revealed that the release rate of the encapsulated nifedipine is at least two orders of magnitude higher than the dissolution rate of the thermodynamically-stable crystalline form. Further employment of 13 C and 1 H solid-state NMR techniques provides a comparison of the molecular dynamics of nifedipine in both bulk and confined states. Such a comparison revealed that nifedipine adsorbed in pores is in an amorphous state and has additional degrees of rotational freedom with respect to the crystalline state. The higher mobility of nifedipine molecules confined in silica matrix can explain its higher release rate with respect to the bulk form.

The surface properties play a particularly important role in the mucoadhesive drug delivery systems. In these formulations, the adsorption of polymer matrix to mucous membrane is limited by the wetting and swelling process of the polymer structure. Hence, the performance of mucoadhesive drug delivery systems made of polymeric materials depends on multiple factors, such as contact angle, surface free energy and water absorption rate. The aim of our study was to analyze the effect of model saliva and vaginal fluids on the wetting properties of selected mucoadhesive (Carbopol 974P NF, Noveon AA-1, HEC) and film-forming (Kollidon VA 64) polymers as well as their blends at the weight ratio 1:1 and 1:1:1, prepared in the form of discs. Surface properties of the discs were determined by measurements of advancing contact angle on the surface of polymers and their blends using the sessile drop method. The surface energy was determined by the OWRK method. Additionally, the mass swelling factor and hydration percentage of examined polymers and their blends in simulated biological fluids were evaluated.

Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product’s bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound’s intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid. Electronic supplementary material The online version of this article (10.1208/s12249-019-1600-z) contains supplementary material, which is available to authorized users.

A liquid chromatography-tandem mass spectrometry analytical method was developed for the simultaneous determination of five parabens and four bisphenols in human breast milk samples in both free forms and as the total concentration, which included also conjugated compounds. The samples for the determination of free forms were extracted directly using the QuEChERS method, while the determination of the total content included a preliminary enzymatic hydrolysis step. Breast milk was sampled 3-6 weeks and 3 months after delivery. Methylparaben was the most abundant paraben with an average total concentration in the two sampling points 1.02 and 1.52 ng mL-1, respectively. Bisphenol A was the most abundant bisphenol with an average total concentration in the two sampling points 1.91 and 1.41 ng mL-1, respectively. For the first time, the hazard quotients were calculated for these compounds in the breast milk samples demonstrating that bisphenol A contributed the most to the hazard caused by the tested compounds. However, the hazard index calculated for the cumulative impact indicates that the milk samples were safe for the children.

This work reviews the examples of the application of lyophilization and its cryogenic modifications as the production method of solid dispersions and drug nanocrystals, two formulation approaches aimed at increasing the solubility, dissolution rate and oral bioavailability of poorly water soluble drugs. A brief recapitulation of freeze-drying basics is presented and the review is organized according to application and product type, with the consideration of different cryogenic techniques, e.g. spray freezing into liquid, as well as the combinations of lyophilization with other nanonization methods in pharmaceutical technology. The review focuses on freeze-drying as a particle engineering tool for the size reduction and surface area enhancement in the generation of nanosized drug particles, both as simple nanocrystals and as their dispersions within water soluble micro- or nanoparticulate matrices, instead of the use of lyophilization as a mere drying or solidification method. Therefore, attention is given to the relationships between formulation and process parameters (e.g. freezing rate), and the properties of the obtained material: particle size, porosity, surface area, morphology, polymorphism and dissolution behavior.

The review discusses the progress in the design and synthesis of bioactive agents incorporated into vascular grafts obtained by the electrospinning process. Electrospun fibers can be applied as an artificial extracellular matrix for tissue engineering and drug delivery, improving tissue regeneration and therapeutic outcomes. A large number of active substances are loaded into the fibers, such as growth factors, heparin, NO donors, statins, antibiotics or anti-inflammatory agents. There are various methods for bioactive substance incorporation including direct blending, emulsion, and coaxial electrospinning as well as covalent and non-covalent binding of the bioactive molecules to the fiber surface. The release mechanism of the drug depends on the synthesis route, active substance properties, and polymer matrix nature. The electrospun materials represent a very promising building block for the fabrication of effective vascular prosthesis in the near future.

Interactions occurring between components in the quaternary powder mixtures consisting of perindopril tert-butylamine, indapamide (active pharmaceutical ingredients), carrier substance and hydrophobic colloidal silica were examined. Two grades of lactose monohydrate: Spherolac(®) 100 and Granulac(®) 200 and two types of microcrystalline cellulose: M101D+ and Vivapur(®) 102 were used as carriers. We determined the size distribution (laser diffraction method), morphology (scanning electron microscopy) and a specific surface area of the powder particles (by nitrogen adsorption-desorption). For the determination of the surface energy of powder mixtures the method of inverse gas chromatography was applied. Investigated mixtures were characterized by surface parameters (dispersive component of surface energy, specific interactions parameters, specific surface area), work of adhesion and cohesion as well as Flory-Huggins parameter χ23('). Results obtained for all quaternary powder mixtures indicate existence of interactions between components. The strongest interactions occur for both blends with different types of microcrystalline cellulose (PM-1 and PM-4) while much weaker ones for powder mixtures with various types of lactose (PM-2 and PM-3).

SBA-16 and two modified SBA-16 type ordered mesoporous silica were used as the carriers for ibuprofen (anti-inflammatory drug) and furosemide (loop diuretic drug). Modification of the solid carrier was prepared with chitosan or N-3[(amino(poly-propylenoxy)]aminopropyltrimethoxysilane. The samples of carriers and carrier-drug loaded materials were characterized by X-ray diffraction, N2 adsorption, Fourier-transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. The release profiles of active pharmaceutical ingredients were performed in media with different pH in the USP 2 apparatus as well as in two biorelevant media (fasted state simulated gastric fluid and fasted state small intestinal fluid) in USP 4 apparatus. The loading of active substances into mesoporous materials was performed with modified immersion method. The maximum content of deposited drug in mesoporous material was close to 12.0 and 2.2 wt.% for ibuprofen and furosemide, respectively. After drug adsorption, the reduction of BET surface area, pore volume and pore diameter of non-modified and modified SBA-16 was observed, while the cubic arrays of siliceous matrix were well preserved. The release profiles of ibuprofen and furosemide loaded in mesoporous materials in media with different pH and biorelevant fasted state simulated gastric fluid and fasted state small intestinal fluid showed that the new SBA-16 type materials modify the release profiles of furosemide, increasing the dissolution rate of these substances in the medium at pH 1.2. The cytotoxicity of the materials and permeability of drugs after their loading on SBA-16 materials were evaluated on Caco-2 model. The results of our study showed that mesoporous materials did not exert cytotoxic effects and did not influence on the permeability of both active pharmaceutical ingredients in relation to pure substances.

The commercially available coated tablets containing either racemic form of ofloxacin (Tarivid 200 mg, OfloHexal 200 mg and Ofloxacin-Ratiopharm 200 mg) or only levofloxacin S-(-)-isomer (Tavanic 250 mg) were examined. The aim of our study was to establish the kinetics of dissolution rate process of ofloxacin optical isomers (S-(-) and R-(+)-ofloxacin) from solid oral dosage forms using flow-through cell method (USP 4 method). The concentrations of analytes (racemic ofloxacin and its enantiomers) in the samples of tablet extracts as well as in dissolution media (0.1 M/L HCl and phosphate buffer pH 6.8) were determined by validated high performance capillary electrophoresis method. The fraction of the average dose of the individual optical isomers of ofloxacin released from the examined tablets was calculated. In the case of the OfloHexal, Ofloxacin-Ratiopharm and Tavanic it was found to be around 100% for both S-(-) and R-(+)-ofloxacin in 0.1 M/L HCI after 30 min of dissolution test. The fraction of the average dose for the Tarivid tablets was approximately 50% at the same time. A similar results were observed for the Ofloxacin-Ratiopharm and Tavanic tablets examined in phosphate buffer (average fraction about 100% after 30 min), while in the case of Tarivid and OfloHexal the averige fraction of the dose determined in a buffer pH 6.8 was 14% and 44%, respectively. There were not found any differences in the kinetics of dissolution of the S-(-)-ofloxacin and R-(+)-ofloxacin isomers within the same formulation. However, statistically significant differences were found in the dissolution of ofloxacin enantiomers between different preparations.

This work describes the synthesis of SBA-16 modified with amine groups and chitosan. The synthesized materials were characterized by small angle XRD (SXRD), wide angle XRD (WXRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Fourier-transformed Infra-red (FTIR) spectroscopy and nitrogen adsorption/desorption techniques. The characterization results revealed that the new materials show highly ordered mesostructure with large surface area and pore diameter, suitable for further applications. FTIR, WXRD, TGA data and elemental analyses proved that amine groups/chitosan were uniformly dispersed on SBA-16 surface. The materials obtained can be considered as safe, on the basis of insignificant cytotoxic effect against a human colon cancer cell line Caco-2. The preliminary tests have shown that the SBA-16 materials are able to modify the release profile of furosemide (FUR), a poorly soluble active substance of Class IV of the Biopharmaceutics Classification System (BCS).

The aim of our study was to examine the irritation potential of new eye drops containing 2% choline salicylate (CS) as an active pharmaceutical ingredient (API) and various polymers increasing eye drop viscosity (hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone). The standard method for assessing the potential of irritating substances has been the Draize rabbit eye test. However the European Centre for Validation of Alternative Methods and the Coordinating Committee for Validation of Alternative Methods recommend, short time exposure (STE) in vitro tests as an alternative method for assessing eye irritation. The eye irritation potential was determined using cytotoxicity test methods for rabbit corneal cell line (SIRC) after 5min exposure. The viability of cells was determined using two cytotoxicity assays: MTT and Neutral Red Uptake. According to the irritation rankings for the short time exposure test, all tested eye drops are classified as non-irritating (cell viability >70%).

Fabrication of scaffolds loaded with nitric oxide (NO) donors (S-nitrosoglutathione, GSNO, and isosorbide mononitrate, ISMN) with suitable cell compatibility and optimized properties for tissue-engineering applications is reported using “in situ” technique. Based on FDA-approved polymer, solvent and dosage forms, this gentle process allowed the incorporation of the GSNO labile drug into scaffolds made of either poly(lactide-co-glycolide) (PLGA) or PLGA/poly(ɛ-caprolactone) (PCL) blend. During scaffolds manufacturing process including washing cycles, NO donors were leached from scaffolds. However, GSNO and ISMN concentrations in the last washing medium (10−7 M and 10−4 M, respectively) were in the range of cell suitability for tissue engineering. Further morphological analyses indicated that smoother surfaces with fewer but bigger pores (compatible with cell penetration and ingrowth) were obtained with PLGA in comparison with PLGA/PCL scaffolds. Among all tested matrices, only unloaded PLGA and GSNO-loaded PLGA/PCL exhibited intermediate cell anchorage, with mitochondrial activity close to the control and an increase in protein content, a prognostic for scaffold cell colonization, defining them as promising candidates. Deeper analyses of these two scaffolds looking at intracellular redox balance through reactive oxygen species production, glutathione, S-nitrosothiols, and nitrite ions content exhibited GSNO-loaded PLGA/PCL as the best of all tested 3D scaffolds for tissue engineering.

International audience; A one-pot synthetic approach was developed to prepare water-dispersible core/shell CdTexS1-x/ZnS QDs using CdCl2, Zn(OAc)2, NaHTe and 3-mercaptopropionic acid (MPA) as starting materials. Sulfide S2- ions produced from the partial decomposition of MPA associate to CdTe nuclei to form an alloyed CdTexS1-x core before reacting with Zn2+ ions to generate the ZnS shell. The photoluminescence (PL) of CdTexS1-x/ZnS QDs QDs can be adjusted from the green to the near-infrared region by varying the ratio of precursors or the reaction time. The formation of core/shell CdTexS1-x/ZnS structure was confirmed by high resolution transmission electron microscopy and X-ray diffraction studies. The highly luminescent QDs (PL quantum yields up to 35%) exhibit good stability in aqueous solution and low cytotoxicity towards Kluyveromyces bulgaricus cells. Bioconjugation of CdTexS1-x/ZnS QDs with (D)-(+)-galactose was successfully applied for the fluorescent imaging of the yeast cells.

Purpose The study discusses the value of electrospun cilostazol-loaded (CIL) polymer structures for potential vascular implant applications. Methods Biodegradable polycaprolactone (PCL) fibers were produced by electrospinning on a rotating drum collector. Three different concentrations of CIL: 6.25%, 12.50% and 18.75% based on the amount of polymer, were incorporated into the fibers. The fibers were characterized by their size, shape and orientation. Materials characterization was carried out by Fourier Transformed Infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vitro drug release study was conducted using flow-through cell apparatus (USP 4). Results Three-dimensional structures characterized by fibers diameter ranging from 0.81 to 2.48 μm were in the range required for cardiovascular application. DSC and XRD confirmed the presence of CIL in the electrospun fibers. FTIR and Raman spectra confirmed CIL polymorphic form. Elastic modulus values for PCL and the CIL-loaded PCL fibers were in the range from 0.6 to 1.1 GPa. The in vitro release studies were conducted and revealed drug dissolution in combination with diffusion and polymer relaxation as mechanisms for CIL release from the polymer matrix. Conclusions The release profile of CIL and nanomechanical properties of all formulations of PCL fibers demonstrate that the cilostazol loaded PCL fibers are an efficient delivery system for vascular implant application. Electronic supplementary material The online version of this article (10.1007/s11095-017-2314-0) contains supplementary material, which is available to authorized users.

The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett-Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.

The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets' critical quality attributes (CQA).The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues.In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU.Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading.The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API's content and uniformity when compared to industrial gravitational transfer.

International audience; Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) activates signaling pathways responsible for smooth muscle cell relaxation, leading to vasodilation and thus plays an important role in controlling vascular homeostasis, thrombosis and inflammation.Recent studies indicate that S-nitrosothiols produced in vivo as well as synthetic ones might be important reservoirs of NO. Based on a broad range of NO functions within the living organisms, this review highlights the impact of S-nitrosothiols on cardiovascular cell cycle. The cell membrane transport and the decomposition patterns responsible of S-nitrosothiols actions are presented. The effects of NO delivery through S-nitrosothiols have a significant potential in cardiovascular diseases with various underlying causes. The challenges related to their application in the pharmacotherapy of patients with various cardiovascular diseases are also discussed.

Resistance to an anti-platelet agent clopidogrel (CLP) and the growing number of products with the drug cause the need for comparison of their quality to assure patients safe and effective treatment. Therefore, the aim of the study was to compare in vitro dissolution kinetics of CLP immediate-release tablets, commonly used in anti-platelet therapy in Poland. For analysis of CLP in samples obtained from dissolution test a capillary zone electrophoresis (CZE) method was elaborated and validated. Separation of CLP and ticlopidine, used as an internal standard, was performed in silica capillary filled with phosphate buffer of pH 2.5, at the applied voltage of 20 kV. The CZE method fulfilled the validation requirements for determination of drugs in pharmaceutical matrices and was successfully applied for analysis of CLP dissolved from the tablets. Dissolution profiles were prepared for each product and mean dose fractions of CLP dissolved from tablets at 30 min were calculated. Kinetic parameters of the CLP dissolution from the studied products were compared. Analysis of variance (ANOVA) did not reveal differences between CLP fractions dissolved at 30 min time point from the tested drug products. However, ANOVA with Tukey multiple comparison test revealed significant differences in first-order dissolution rate constants and t₀.₅ values (times at which 50% of drug is dissolved) of CLP among tested tablets. It was concluded that the studied CLP products met the acceptance criteria regarding dissolution test but differed with each other in dissolution kinetics.

International audience; 3-Mercaptopropionic acid-capped core/shell ZnS:Cu/ZnS and ZnS:Mn/ZnS doped quantum dots (QDs) prepared through hydrothermal methods exhibit high photoluminescence intensity as well as good photostability. These water-dispersible nanoparticles exhibit high fluorescence sensitivity to folic acid due to the high affinity of the carboxylate groups and nitrogen atoms of folic acid towards the Zn surface atoms of the doped dots. Quenching of the fluorescence intensity of the QDs allows the detection of folic acid concentrations as low as 11 mu M, thus affording a very sensitive system for the sensing of this biologically active molecule in aqueous solution. The possible quenching mechanism is discussed.

Polychlorinated biphenyls (PCBs) are present in the environment as complex mixtures, which make it challenging to identify PCB congeners that may be subject to active transport processes. Here we employ a transgenic mouse model in combination with multivariate analyses to investigate if chiral PCBs 91, 95, 132, 136, 149, 174, 176 and 183 are subject to active (enantioselective) transport by multidrug resistance (MDR) transporters. A synthetic PCB mixture containing these congeners was administered orally to female FVB or mdr1a/1b knockout mice. Due to the short half-life of chiral PCB congeners, mice were euthanized after 24h and PCB concentrations and enantiomeric fractions were determined in selected tissues and excreta. Principal component analysis did not reveal differences between wild-type and mdr1a/1b knockout mice. However, Hotelling T2-test revealed significantly lower PCB concentrations and a more pronounced enantiomeric enrichment in the adipose tissue of mdr1a/1b knockout mice. These differences are due to higher body weights and higher fecal fat contents of mdr1a/1b knockout mice. Analysis of the enantiomeric fractions of PCBs 91, 95, 136, 149 and 174 showed a significant enantiomeric enrichment for all five congeners in wild-type and mdr1a/1b knockout mice. Overall, by studying a PCB mixture in a transgenic mouse model in combination with a multivariate data reduction approach, PCBs 91, 95, 136, 149 and 174 could be excluded as substrates of multidrug resistance transporters 1a/b. Keywords: Polychlorinated biphenyls, Enantiomeric fraction, Atropisomers, Fecal fat content, Multivariate analysis, Chemometrics, Principal component analysis, Hotelling T2-test, Transgenic mice, Active transport, Multidrug resistance transporters

Principal component analysis (PCA) was applied to a data set containing the levels of indicator polychlorinated biphenyls (PCBs) in human milk of mothers living in the Wielkopolska region, Poland, in order to investigate the information captured in the PCB patterns and to elucidate the relationship between PCB concentrations in milk and donor characteristics. According to the obtained PCA results milk fat content was the most influential factor affecting the PCB levels in milk of the Wielkopolska cohort. The lifestyle data collected from the questionnaire completed by the donors appeared to have no influence on PCB concentrations in breast milk. The score plots revealed the PCB contents of milk were quite low and uniform with a few outliers, without discrimination observed either between the primipareous and secundipareous females or between donors from the urban and rural areas. Comparison of the PCB levels and profiles of human milk from the Wielkopolska region and from various European and Asian locations made by PCA reflected a generally low background exposure and indicated the possible reasons for the outlying of some samples. In order to enhance the chances of observing the relationship between donor habits and PCB levels in breast milk it was suggested that the questionnaire be redesigned to gather information about vegetable product consumption and indoor air exposure. Keywords: PCB, Human milk, Principal component analysis

Signaling pathways in living cells which regulate cell cycle and activate defense mechanisms against environmental stresses are mainly controlled through cell redox potential status. The main cellular redox buffer is constituted by oxidized/reduced glutathione system (GSSG/2GSH). Physiological functions and pathological situations resulting from oxidative stress are driven by glutathione homeostasis and its dysfunction, respectively. Many methodologies devoted to the investigation of cellular redox potential relying on the determination of reduced and oxidized glutathione concentrations measured in various cellular compartments, tissues and organs have been reported. Most of them are till now based on separative and non-separative techniques and include extractive step from biological samples. They are time-consuming and tedious in order to preserve reduced to oxidized glutathione ratio, thus introducing bias in its evaluation. New trends are focused on in situ evaluation of redox state especially through the monitoring of glutathione pool. This review reports recent developments in fluorescence imaging of cellular redox state, especially those involving nanotechnologies.

This work describes some results of identification and determination of bisphenol A (BPA) in powdered milk by applying the gas chromatography. To determine BPA contents in the milk and to reduce the matrix interference associated with the constituents of the powdered milk, we performed the following activities. First, we ultra-centrifuged the dissolved milk solutions. Next, we preconcentrated the analyte in the supernatant using a C(18) and new sorbent with chemically bonded ketoimine group solid phase extraction column. Finally, we used gas chromatography for the determination of BPA in the samples under study. A recovery of bisphenol A from spiked milk samples was also performed, with recovery result located at 91% +/- 3%/94% +/- 2%.

Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model.The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms.Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described.There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of "from powder to tablet" is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible.A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production.

The levels of organochlorinated pesticides (OCPs): p,p′-DDT and its metabolites, hexachlorobenzene (HCB), hexachlorocyclohexane isomers (HCHs), chlordanes and their metabolites, and 18 polychlorinated biphenyl (PCB) congeners were measured in maternal serum, umbilical cord serum and human milk collected from 22 mothers living in the Wielkopolska region, Poland. Additionally, 11 polybrominated diphenyl ether (PBDE) congeners were measured in the human milk samples. p,p′-DDT and its major metabolite, p,p′-DDE, together with HCB, were found in all milk and serum samples. Median concentrations of p,p′-DDE in maternal serum, umbilical cord serum and milk were 343, 329 and 634 ng/g lipid weight (lw). PCB congeners 138, 153 and 180 were the major congeners measured in all serum samples, while CB 170 was detected in 74% and 100% of umbilical cord and maternal serum, respectively. Except for CBs 74, 101 and 105, which had a detection frequency of 77%, 23% and 82%, respectively, all investigated PCB congeners were measured in all human milk samples. The median concentrations of sum PCBs in maternal serum, umbilical cord serum and milk were 79, 60 and 133 ng/g lw, respectively. A good correlation (Spearman RS > 0.75, p < 0.001) was found for major PCBs, p,p′-DDT and p,p′-DDE, between maternal and umbilical cord serum, while the correlation was weaker between milk and serum. The median of sum PBDEs in human milk was 2.0 ng/g lw (range 0.8 to 8.4), with BDE 47 being always the most abundant PBDE congener and, together with BDE 153, being present in all samples. In general, results found in the investigated group are at the low end of the concentration range measured in Europe.

Selective fluorogenic probes for the labelling of intracellular reduced glutathione (GSH), i.e. ortho-phthaldialdehyde (OPA) and naphthalene-2,3-dicarboxaldehyde (NDA), have been encapsulated in polymeric nanoparticles (NPs) and the ability of the NPs to enhance uptake of the probe by microbial cells has been evaluated. Preparation of the probe-loaded NPs composed of Eudragit(®) E was based on an oil-in-water emulsification solvent evaporation method using an ultrasonic probe and polyvinyl alcohol as the surfactant. The encapsulation efficiency of the probes in lyophilized NPs was determined using high performance liquid chromatography (HPLC). A higher encapsulation rate of NDA than OPA was found: 47.6 ± 9.9 (n = 6) and 2.1 ± 0.2% (n = 3), respectively. The NDA-loaded particle diameter and zeta potential were 224.6 ± 14.7 nm and +40.9 ± 6.5 mV, respectively. After 20 min incubation of cultured Candida albicans yeast cells with either free NDA or NDA-loaded NPs (final NDA concentration 100 µM), cells were harvested and corresponding lysates were analysed using HPLC coupled with spectrofluorimetric detection. Incubation of cells with NDA-loaded NPs increased intracellular levels of NDA-GSH adduct by about nine-fold in comparison with the free probe. Adhesion on the cells and the penetration behaviour of NPs loaded with either NDA or fluorescent label (Nile Red) were characterized qualitatively by confocal laser scanning microscopy.

The database of the relative retention times (RRTs) of polychlorinated biphenyls (PCBs) reported in literature was used to calculate the retention indices (RIs) of all 209 PCB congeners on temperature programmed capillary column Rtx-5. Calculation of retention indices was based on reference series of seven congeners (PCB IUPAC Nos. 18, 52, 101, 143, 185, 203 and 206) that exhibit linear relative retention time behaviour as a function of chlorine number. The calculated indices were compared to those determined in our laboratory as well as to those obtained by other authors. The proposed indices system was applied for identification individual congeners in mixture of Aroclors 1242:1254:1260, using only reference series of PCBs.

A method for determination of trace concentrations of individual PCB congeners in human milk was validated. The analytical procedure included the following steps: acetone : hexane extraction, clean-up of extracts with concentrated sulfuric acid and solid phase extraction (SPE) on Florisil. The identification and quantification of analytes in purified extracts were carried out by high-resolution gas chromatography (HRGC) with electron capture detection (ECD) and/or with low-resolution mass spectrometry (LRMS). Recoveries of 14 PCB congeners from spiked cow milk samples, based on HRGC-ECD were between 87.3 and 93.6%. The precision of analyte determination was established as close to or less than 10%. The detection limits ranged between 0.14 and 0.26 ng/g fat and the quantification limits between 0.57 and 0.86 ng/g fat. The method was linear and characterized by good correlation coefficients (>0.99) for most of the compounds studied. The quality of the method under validation was verified by the analysis of ...

Fabrication of scaffolds loaded with nitric oxide (NO) donors (S-nitrosoglutathione, GSNO, and isosorbide mononitrate, ISMN) with suitable cell compatibility and optimized properties for tissue-engineering applications is reported using "in situ" technique. Based on FDA-approved polymer, solvent and dosage forms, this gentle process allowed the incorporation of the GSNO labile drug into scaffolds made of either poly(lactide-co-glycolide) (PLGA) or PLGA/poly(ɛ-caprolactone) (PCL) blend. During scaffolds manufacturing process including washing cycles, NO donors were leached from scaffolds. However, GSNO and ISMN concentrations in the last washing medium (10(-7) M and 10(-4) M, respectively) were in the range of cell suitability for tissue engineering. Further morphological analyses indicated that smoother surfaces with fewer but bigger pores (compatible with cell penetration and ingrowth) were obtained with PLGA in comparison with PLGA/PCL scaffolds. Among all tested matrices, only unloaded PLGA and GSNO-loaded PLGA/PCL exhibited intermediate cell anchorage, with mitochondrial activity close to the control and an increase in protein content, a prognostic for scaffold cell colonization, defining them as promising candidates. Deeper analyses of these two scaffolds looking at intracellular redox balance through reactive oxygen species production, glutathione, S-nitrosothiols, and nitrite ions content exhibited GSNO-loaded PLGA/PCL as the best of all tested 3D scaffolds for tissue engineering.

The ability of organic–inorganic hybrid materials to act as drug release-modifying agents was examined. In this study, ibuprofen, a non-steroidal anti-inflammatory drug was used as a model active pharmaceutical ingredient. The physicochemical properties of individual components of the hybrids, as well as these for two- and three-component systems were examined by inverse gas chromatography. The dispersive component of the free surface energy ( γ S D ), K A and K D parameters describing acidity and basicity of hybrid materials, respectively, as well as Flory–Huggins parameters were determined. χ 12 ∞ and χ ′ 23 parameters characterize the interactions between the hybrids and a test solute, or interactions between the drug and inorganic–organic materials, respectively. Additionally, Brunauer–Emmett–Teller (BET) method was used to characterize adsorption activity of the studied materials. The prepared hybrid materials were also characterized by Fourier transform infra-red (FTIR) spectroscopy. The release profiles of ibuprofen for the created hybrid materials were determined. Relationship between the physicochemical activity of hybrid materials and ibuprofen release was presented and discussed.

International audience; The interaction of thiols (glutathione, cysteine, and cysteamine) with yellow-emitting siloxane-capped ZnO QDs was studied. A gradual enlargement of the PL emission band resulting in white-light emission was observed upon reaction with thiols, while the diameter (ca. 4 nm) and the crystallinity of the dots were not affected. The appearance of broad white-emission was accompanied by a decrease of the photoluminescence quantum yield from 16% to 5-6%. Generation of surface defect states through interaction of the thiols with Zn surface atoms of the dots provoking shrunk of the siloxane capping may be responsible of that broadband emission throughout most of the light spectrum.

International audience; This work presents a novel approach to producing water soluble manganese-doped core/shell ZnS/ZnS quantum dots (ZnS:Mn/ZnS). The Mn-doped ZnS core was prepared through a nucleation doping strategy and a ZnS shell was grown on ZnS:Mn d-dots by decomposition of Zn2+-3-mercaptopropionic acid (MPA) complexes at 100 degrees C. It was found that the Mn2+ T-4(1) -> (6)A(1) fluorescence emission at similar to 590 nm significantly increased after growth of the shell when the Mn2+ doping content was 4.0 at.%. A photoluminescence quantum yield of similar to 22% was obtained for core/shell nanocrystals. The nanoparticles were structurally and compositionally characterized by transmission electron microscopy. X-ray diffraction, X-ray photoelectron spectroscopy, and dynamic light scattering. The surface MPA molecules favor the dispersion of ZnS:Mn/ZnS QDs in aqueous media and make possible conjugation with targeting folic acid molecules. The folate receptor-mediated delivery of folic acid-conjugated ZnS:Mn/ZnS QDs was demonstrated using confocal microscopy with biphotonic excitation. Bare and folate-conjugated QDs exhibit only weak cytotoxicity towards folate receptor-positive T47D cancer cells and MCF-7 cells, used as a reference, at high concentrations (mmolar range) after 72 h incubation