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Journal Cover European Journal of Pharmaceutical Sciences
  [SJR: 1.176]   [H-I: 98]   [112 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0928-0987
   Published by Elsevier Homepage  [3043 journals]
  • Overview of PAT process analysers applicable in monitoring of film coating
           unit operations for manufacturing of solid oral dosage forms
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Klemen Korasa, Franc Vrečer
      Over the last two decades, regulatory agencies have demanded better understanding of pharmaceutical products and processes by implementing new technological approaches, such as process analytical technology (PAT). Process analysers present a key PAT tool, which enables effective process monitoring, and thus improved process control of medicinal product manufacturing. Process analysers applicable in pharmaceutical coating unit operations are comprehensibly described in the present article. The review is focused on monitoring of solid oral dosage forms during film coating in two most commonly used coating systems, i.e. pan and fluid bed coaters. Brief theoretical background and critical overview of process analysers used for real-time or near real-time (in-, on-, at- line) monitoring of critical quality attributes of film coated dosage forms are presented. Besides well recognized spectroscopic methods (NIR and Raman spectroscopy), other techniques, which have made a significant breakthrough in recent years, are discussed (terahertz pulsed imaging (TPI), chord length distribution (CLD) analysis, and image analysis). Last part of the review is dedicated to novel techniques with high potential to become valuable PAT tools in the future (optical coherence tomography (OCT), acoustic emission (AE), microwave resonance (MR), and laser induced breakdown spectroscopy (LIBS)).
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      PubDate: 2017-10-14T06:17:05Z
       
  • Atovaquone oral bioavailability enhancement using electrospraying
           technology
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Aditya Darade, Sulabha Pathak, Shobhona Sharma, Vandana Patravale
      Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose and poor bioavailability are the main hurdles associated with atovaquone oral therapy. The present study reports development of atovaquone nanoparticles, using in house designed and fabricated electrospraying equipment, and the assessment of bioavailability and therapeutic efficacy of the nanoparticles after oral administration. Solid nanoparticles of atovaquone were successfully produced by electrospraying and were characterized for particle size and flow properties. Differential Scanning Calorimetry, X-ray Diffraction, Fourier Transform Infrared Spectroscopy studies were also carried out. Atovaquone nanoparticles along with proguanil hydrochloride and a suitable wetting agent were filled in size 2 hard gelatin capsules. The formulation was compared with Malarone® tablets (GSK) and Mepron® suspension (GSK) in terms of in vitro release profile and in vivo pharmacokinetic studies. It showed 2.9-fold and 1.8-fold improved bioavailability in rats compared to Malarone® tablets and Mepron® suspension respectively. Therapeutic efficacy of the formulation was determined using modified Peter's 4-day suppressive tests and clinical simulation studies using Plasmodium berghei ANKA infected Swiss mice and compared to Malarone®. The developed formulation showed a 128-fold dose reduction in the modified Peter's 4-day suppressive tests and 32-fold dose reduction in clinical simulation studies. Given that only one capsule a day of developed formulation is required to be administered orally compared to 4 Malarone® tablets once a day and that too at a significantly reduced dose, this nanoparticle formulation will definitely reduce the side-effects of the treatment and is also likely to increase patient compliance.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Improvement in the water solubility of drugs with a solid dispersion
           system by spray drying and hot-melt extrusion with using the amphiphilic
           polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft
           copolymer and d-mannitol
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Noriko Ogawa, Tomoki Hiramatsu, Ryohei Suzuki, Ryohei Okamoto, Kohei Shibagaki, Kosuke Fujita, Chisato Takahashi, Yoshiaki Kawashima, Hiromitsu Yamamoto
      The aim of this study was to prepare and characterize solid dispersion particles with a novel amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, as a water-soluble carrier. Solid dispersion particles were prepared by hot-melt extrusion and spray drying. Indomethacin (IMC) was used as a model comprising drugs with low solubility in water and d-mannitol (MAN) was used as an excipient. The physicochemical properties of prepared particles were characterized by scanning electron microscopy, thermal analysis, powder X-ray diffraction (PXRD) analysis, FTIR spectra analysis, and drug release studies. Stability studies were also conducted under stress conditions at 40°C, 75% relative humidity. We found that dissolution behavior of the original drug crystal could be improved by solid dispersion with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The PXRD pattern and thermal analysis indicated that the solid dispersion prepared with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC was in an amorphous state. FTIR spectra analysis indicated that the interaction manner between the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC may differ with the preparation method and formulation of solid dispersions. Stability studies proved that the amorphous state of IMC in solid dispersion particles was preserved under stress conditions for more than two weeks.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Binding affinity toward human prion protein of some anti-prion compounds
           — Assessment based on QSAR modeling, molecular docking and
           non-parametric ranking
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Strahinja Kovačević, Milica Karadžić, Sanja Podunavac-Kuzmanović, Lidija Jevrić
      The present study is based on the quantitative structure-activity relationship (QSAR) analysis of binding affinity toward human prion protein (huPrPC ) of quinacrine, pyridine dicarbonitrile, diphenylthiazole and diphenyloxazole analogs applying different linear and non-linear chemometric regression techniques, including univariate linear regression, multiple linear regression, partial least squares regression and artificial neural networks. The QSAR analysis distinguished molecular lipophilicity as an important factor that contributes to the binding affinity. Principal component analysis was used in order to reveal similarities or dissimilarities among the studied compounds. The analysis of in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters was conducted. The ranking of the studied analogs on the basis of their ADMET parameters was done applying the sum of ranking differences, as a relatively new chemometric method. The main aim of the study was to reveal the most important molecular features whose changes lead to the changes in the binding affinities of the studied compounds. Another point of view on the binding affinity of the most promising analogs was established by application of molecular docking analysis. The results of the molecular docking were proven to be in agreement with the experimental outcome.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Insight into lipophilicity of deoxyribonucleoside‑boron cluster
           conjugates
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Aneta Dąbrowska, Michał Matuszewski, Krzysztof Zwoliński, Anna Ignaczak, Agnieszka B. Olejniczak
      Lipophilicity was investigated for 20 2′-deoxyribonucleoside derivatives modified with electron-neutral 1,2-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, 7,8-dicarba-nido-undecaborate anion, and metallacarborane containing Co, Fe, or Cr. The partition coefficient (P) for neutral conjugates and the distribution coefficient (D 7.4) for ionic compounds were determined as a lipophilicity descriptor using a shake-flask method. All modified nucleosides had P/D 7.4 values higher than those of an appropriate unmodified 2′-closo-dodecaborane and metallacarborane was found to be three orders of magnitude higher than that of its unmodified counterpart. The lowest impact on the P/D 7.4 values of the conjugates was observed for the 7,8-dicarba-nido-undecaborate anion. A preliminary molecular modeling study of a thymidine-carborane conjugate with β-cyclodextrin confirmed the ability of the components to form an inclusion complex.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Tuning the rheological properties of an ammonium methacrylate copolymer
           for the design of adhesives suitable for transdermal patches
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Gaia M.G. Quaroni, Chiara G.M. Gennari, Francesco Cilurzo, Guylaine Ducouret, Costantino Creton, Paola Minghetti
      Eudragit® RL (EuRL) matrices have been proposed to release a drug to the skin. However, no information is available on both viscoelastic and adhesive properties of such compositions. This work focuses on the evaluation of both rheological and texture properties of EuRL differently plasticized with tributyl citrate (TBC) or triacetin (TRI) in order to design a pressure sensitive adhesive suitable for transdermal patch preparation. The patch adhesive properties (i.e. tack, peel adhesion and shear adhesion) as well as its in vitro biopharmaceutical performances were determined after loading ibuprofen, ketoprofen or flurbiprofen. The addition of 40–60% w/w TBC or 40–50% w/w TRI to EuRL permitted to obtain matrices with the desired adhesive properties. Moreover, the increase of plasticizer content and loading of the drug reduced the relaxation time (τR). Consequently, the shear adhesion values decreased and the in vitro drug release constants (k) increased. Indeed, the k values from patches containing TBC were lower than the corresponding with TRI because of the lower fluidity of such matrices. In conclusion, the 60/40 EuRL/TBC binary blend is suitable for the design of transdermal patches since the in vitro permeability of the three selected drugs appeared comparable to those described in literature for marketed products.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Statistical investigation of the full concentration range of fasted and
           fed simulated intestinal fluid on the equilibrium solubility of oral drugs
           
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Jeremy Perrier, Zhou Zhou, Claire Dunn, Ibrahim Khadra, Clive G. Wilson, Gavin Halbert
      Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Comparative evaluation of electrospraying and lyophilization techniques on
           solid state properties of Erlotinib nanocrystals: Assessment of In-vitro
           cytotoxicity
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Shreya Thakkar, Dilip Sharma, Manju Misra
      Introduction Erlotinib is a well known FDA approved drug from category of tyrosine kinase inhibitors; used for the treatment of lung cancer. However its use is limited because of its poor water solubility. Objective The aim of present work was to improve solubility by developing a stable nanocrystal based drug delivery system of ERL with the aid of sodium lauryl sulfate as potential stabilizer and to carry out comparative evaluation of electrospraying and lyophilization as solidification techniques on its solid state properties. Experimental Nanocrystal formulation was developed with antisolvent precipitation method having particle size, polydispersity index and zetapotential of 232.4±4.3nm, 0.162 and −9.82mV respectively. Further comparative evaluation of lyophilization and electrospraying was commenced as potential solidification techniques and solid powder matrix obtained from both the solidification techniques were compared in terms of size after re-dispersion (260±4.8 and 329±5.2nm respectively), particle morphology, surface area (0.984±0.11 and 0.341±0.05m2/g respectively), pore volume (0.0014 and 0.0009cc/g respectively), solid state of drug present and % drug release (~100% and ~78% respectively in 600min). In vitro cytotoxicity studies shared that obtained formulation was having reduced IC50 values in comparison to drug. Further intracellular reactive oxygen species production was found to be higher for formulation treated cells when compared to free drug. Overall developed formulation was found to be potential drug delivery system for lung cancer therapy.
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      PubDate: 2017-10-14T06:17:05Z
       
  • Studying of drug solubility in water and alcohols using drug-ammonium
           ionic liquid-compounds
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Mohammad Halayqa, Aneta Pobudkowska, Urszula Domańska, Maciej Zawadzki
      Synthesis of three mefenamic acid (MEF) derivatives - ionic liquid compounds composed of MEF in an anionic form and ammonium cation (choline, MEF1), or {di(2-hydroxyethyl)dimethyl ammonium (MEF2)}, or {tri(2-hydroxyethyl)methyl ammonium compound (MEF3)} is presented. The basic thermal properties of pure compounds i.e. fusion temperatures, and the enthalpy of fusion of these compounds have been measured with differential scanning microcalorimetry technique (DSC). Molar volumes have been calculated with the Barton group contribution method. The solubilities of MEF1, MEF2 and MEF3 using the dynamic method were measured at constant pH in a range of temperature from (290 to 370) K in three solvents: water, ethanol and 1-octanol. The experimental solubility data have been correlated by means of three commonly known G E equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here present simple eutectic behaviour. The activity coefficients of pharmaceuticals at saturated solutions in each binary mixture were calculated from the experimental data. The formation of MEF-ionic liquid compounds greatly increases the solubility in water in comparison with pure MEF or complexes with 2-hydroxypropyl-β-cyclodextrin. The development of these compounds formulations will assist in medication taking into account oral solid or gel medicines.
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      PubDate: 2017-10-14T06:17:05Z
       
  • A comparison study between lycobetaine-loaded nanoemulsion and liposome
           using nRGD as therapeutic adjuvant for lung cancer therapy
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Tijia Chen, Ting Gong, Ting Zhao, Yao Fu, Zhirong Zhang, Tao Gong
      To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.
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      PubDate: 2017-10-14T06:17:05Z
       
  • The Global Bioequivalence Harmonization Initiative: Summary report for
           EUFEPS international conference
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Mei-Ling Chen, Henning Blume, Gerald Beuerle, Barbara Davit, Mehul Mehta, Henrike Potthast, Barbara Schug, Yu Chung Tsang, Ralph-Steven Wedemeyer, Werner Weitschies, Jan Welink
      Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studies and minimize drug exposure to humans. Harmonization around the globe may be achieved by a better understanding of scientific principles and expectations from different regulatory authorities. To facilitate global harmonization, the Network on Bioavailability and Biopharmaceutics (BABP) under the European Federation for Pharmaceutical Sciences (EUFEPS) launched a Global Bioequivalence Harmonization Initiative (GBHI) several years ago. This international conference was the first in a series of workshops organized by EUFEPS/BABP under GBHI. The workshop provided a forum for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on selected BE issues in the hope of identifying common ground and arriving at a harmonized view on these topics.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Mucoadhesive nanostructured polyelectrolytes complexes modulate the
           intestinal permeability of methotrexate
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Fernanda Isadora Boni, Andreia Almeida, Anna Lechanteur, Bruno Sarmento, Beatriz Stringhetti Ferreira Cury, Maria Palmira Daflon Gremião
      Nanostructured polyelectrolytes complexes (nano PECs) loaded with methotrexate (MTX) were obtained by the polyelectrolyte complexation of chitosan (CS) and hyaluronic acid (HA), further incorporating hypromellose phthalate (HP). The mean diameter of nano PECs ranged from 325 to 458nm, with a narrow size distribution. Zeta potential was close to +30mV, decreasing to +21mV after the incorporation of HP, a range of values that favour the physical stability of system as the interaction with cationic biological membranes. The electrostatic interactions between the different components were indicated by the FTIR data. The mucoadhesiveness of nano PECs was demonstrated and MTX and HP influenced this property. The cell viability assays showed the biosafety of the isolated polymers and nano PECs in intestinal HT29-MTX and Caco-2 cell lines at 4h of test. The permeability values of MTX loaded in CS/HA nano PECs were 7.6 and 4-fold higher than those of CS/HA/HP nano PECS and free drug, respectively, in the Caco-2 monoculture. In mucus secreting co-culture cell model these values were 3 and 6.5 fold, respectively. Such features indicate that nano PECs developed in this work can be promising carriers for MTX in the treatment of local or systemic diseases.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Mucoadhesive maleimide-functionalised liposomes for drug delivery to
           urinary bladder
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Daulet B. Kaldybekov, Prasopchai Tonglairoum, Praneet Opanasopit, Vitaliy V. Khutoryanskiy
      Intravesical drug administration is used to deliver chemotherapeutic agents via a catheter to treat bladder cancer. The major limitation of this treatment is poor retention of the drug in the bladder due to periodic urine voiding. In this work, maleimide-functionalised PEGylated liposomes (PEG-Mal) were explored as mucoadhesive vehicles for drug delivery to the urinary bladder. The retention of these liposomes on freshly excised porcine bladder mucosa in vitro was compared with conventional liposomes, PEGylated liposomes, two controls (dextran and chitosan), and evaluated through Wash Out50 (WO50) values. PEG-Mal liposomes exhibited greater retention on mucosal surfaces compared to other liposomes. The penetration abilities of conventional, PEG-Mal-functionalised and PEGylated liposomal dispersions with encapsulated fluorescein sodium into the bladder mucosa ex vivo were assessed using a fluorescence microscopy technique. PEGylated liposomes were found to be more mucosa-penetrating compared to other liposomes. All liposomes were loaded with fluorescein sodium salt as a model drug and the in vitro release kinetics was evaluated. Longer drug release was observed from PEG-Mal liposomes.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Evaluation of the digestibility of solid lipid nanoparticles of glyceryl
           dibehenate produced by two techniques: Ultrasonication and spray-flash
           evaporation
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Vincent Jannin, Lucia Blas, Stéphanie Chevrier, Cédric Miolane, Frédéric Demarne, Denis Spitzer
      Objective To evaluate the digestibility of Solid Lipid Nanoparticles (SLN) of glyceryl dibehenate prepared either with surfactants by ultrasonication or without surfactant by spray-flash evaporation. Methods SLN of glyceryl dibehenate (Compritol® 888 ATO) were produced by two processes: (i) high-shear homogenization with a solution of water-soluble surfactants followed by ultrasonication (ii) and Spray-Flash Evaporation (SFE) of the pure lipid. The digestibility of these nanoparticles was then tested by in vitro lipolysis using a pH-stat apparatus and the assay of glycerides by gel phase chromatography. Results SLN of glyceryl dibehenate prepared by ultrasonication exhibited a mean particle size of 180nm and showed a limited digestion of the lipid excipient. SLN comprising only glyceryl dibehenate produced by SFE have a mean particle size between 235 and 411nm depending on process parameters. These nanoparticles were not digested by lipases. The presence of surfactant at the lipid/water interface of the SLN seems to be mandatory to allow the adsorption of the lipase and degradation of glyceryl behenate. Conclusions Glyceryl dibehenate as a solid particle – even as a SLN – is not digested by pancreatin during in vitro lipolysis test.
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      PubDate: 2017-10-08T06:07:43Z
       
  • The quest for exceptional drug solubilization in diluted surfactant
           solutions and consideration of residual solid state
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Wiebke Saal, Nicole Wyttenbach, Jochem Alsenz, Martin Kuentz
      Solubility screening in different surfactant solutions is an important part of pharmaceutical profiling. A particular interest is in low surfactant concentrations that mimic the dilution of an oral dosage form. Despite of intensive previous research on solubilization in micelles, there is only limited data available at low surfactant concentrations and generally missing is a physical state analysis of the residual solid. The present work therefore studied 13 model drugs in 6 different oral surfactant solutions (0.5%, w/w) by concomitant X-ray diffraction (XRPD) analysis to consider effects on solvent-mediated phase transformations. A particular aspect was potential occurrence of exceptionally high drug solubilization. As a result, general solubilization correlations were observed especially between surfactants that share chemical similarity. Exceptional solubility enhancement of several hundred-fold was evidenced in case of sodium dodecyl sulfate solutions with dipyridamole and progesterone. Furthermore, carbamazepine and testosterone showed surfactant-type dependent hydrate formation. The present results are of practical relevance for an optimization of surfactant screenings in preformulation and early development and provide a basis for mechanistic modeling of surfactant effects on solubilization and solid state modifications.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Vincristine-loaded liposomes prepared by ion-paring techniques: Effect of
           lipid, pH and antioxidant on chemical stability
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Yunning Yang, Yuting Guo, Xinyi Tan, Haibing He, Yu Zhang, Tian Yin, Hui Xu, Xing Tang
      In the present study, vincristine (VCR)-loaded liposomes were designed by ion-pairing techniques and the model could be applied to investigate the effect of lipids on the degradation of vinca alkaloids, and how to weaken their influence by adjusting pH and adding antioxidants. It was found that there was a positive correlation between degree of degradation and the unsaturation extent of the phospholipids. In the phospholipid with the lowest oxidation index, only 6% of VCR was degraded in 6days at 37°C, whereas for the phospholipids with highest oxidation index, the degradation reached above 95% over the same time. At pH6.8 and 7.4, the degradation rate of VCR in the lipid membrane was significantly faster than that in aqueous solution, instead, at pH5.0. After the addition of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, ascorbate and tocopherol with ascorbate, the residual content of VCR after 6days was 79.9%, 78.1%, 7.1%, 89.6% and 94.6% respectively. It was speculated that VCR could be oxidized by hydrated peroxyl radicals, which formed from lipid peroxidation as well as nucleophilic substitution with peroxyl radicals in the dry state. Also, the antioxidants were shown to have different eliminating capacity on the peroxyl radicals whether hydrated or not, and the phenoxyl radicals generated from fat-soluble antioxidants may be potentially destabilizing to VCR. Therefore, for these two crucial reasons, the degradation of VCR was quite different when used with a combination of water and fat-soluble antioxidants, and thus provides the best protection for VCR.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Preparation and characterization of intravaginal vardenafil suppositories
           targeting a complementary treatment to boost in vitro fertilization
           process
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Eman Gomaa, Amr S. Abu Lila, Azza A. Hasan, Fakhr-eldin S. Ghazy
      Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher Cmax (32 times) and AUC0–4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Evaluation of critical parameters for in vitro skin permeation and
           penetration studies using animal skin models
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Fabíola Silva Garcia Praça, Wanessa Silva Garcia Medina, Josimar O. Eloy, Raquel Petrilli, Patrícia Mazureki Campos, Andreia Ascenso, Maria Vitória L.B. Bentley
      In vitro skin permeation/penetration studies may be affected by many sources of variation. Herein, we aimed to investigate the major critical procedures of in vitro skin delivery studies. These experiments were performed with model drugs according to official guidelines. The influence of skin source on penetration studies was studied as well as the use of a cryopreservation agent on skin freezing evaluated by transepidermal water loss, electrical resistance, permeation/penetration profiles and histological changes of the skin. The best condition for tape stripping procedure was validated through the evaluation of the distribution of corneocytes, mass of stratum corneum (SC) removed and amount of protein removed using finger pressure, a 2kg weight and a roller. The interchangeability of the tape stripping procedures followed by the epidermis and dermis homogenate and the micrometric horizontal cryostat skin sectioning methods were also investigated, besides the effect of different formulations. Noteworthy, different skin sources were able to ensure reliable interchangeability for in vitro permeation studies. Furthermore, an increased penetration was obtained for stored frozen skin compared to fresh skin, even with the addition of a cryoprotectant agent. The best method for tape stripping was the finger pressure followed by the addition of a propylene glycol solvent leading to better SC removal. Finally, no significant difference was found in skin penetration studies performed by different methods suggesting their possible interchangeability.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Nanocapsules improve indole-3-carbinol photostability and prolong its
           antinociceptive action in acute pain animal models
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Mailine Gehrcke, Marcel Henrique Marcondes Sari, Luana Mota Ferreira, Allanna Valentini Barbieri, Laura Minussi Giuliani, Vinicius Costa Prado, Jessica Mendes Nadal, Paulo Vitor Farago, Cristina Wayne Nogueira, Letícia Cruz
      This study aimed the development of nanocapsules (NCs) for oral indole-3-carbinol (I3C) administration and evaluation of antinociceptive potential of this compound in its two forms, free and nanoencapsulated, using acute pain models. NCs showed adequate physicochemical characteristics and protected the I3C against UVC radiation exposure. It was observed no chemical bond between I3C and polymer by FTIR. Besides, X-ray and DSC analysis suggested that I3C was molecularly dispersed in NCs. The dialysis bag technique showed that almost 100% of the compound was released from NCs at 360min. Mathematical modeling demonstrated that this release occurred in two rates, with an initial burst effect followed by a slower release of I3C. Regarding the in vivo analysis, time-response curve showed that both forms of I3C caused an inhibition in inflammatory phase of nociception induced by formalin and increased the latency response in hot plate test. Interestingly, NCs were able to prolong the I3C effect in both tests. Furthermore, in dose-response curve, only I3C in its nanoencapsulated form presented effect on inflammatory phase of the formalin test. In conclusion, NCs to I3C incorporation presented adequate nanometric characteristics and prolonged its antinociceptive action in acute pain models tested.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Investigation of novel supersaturating drug delivery systems of
           chlorthalidone: The use of polymer-surfactant complex as an effective
           carrier in solid dispersions
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Maria Terezinha França, Rafael Pereira Nicolay, Manoela Klüppel Riekes, Juliana Munari Oliveira Pinto, Hellen Karine Stulzer
      Supersaturating drug delivery systems (SDDS), as solid dispersions (SDs), stand out among strategies to enhance bioavailability of poorly soluble drugs. After oral administration, their dissolution in gastrointestinal fluids often leads to supersaturation, which drives to a rapid and sustained absorption. Polymers and surfactants play important roles in SDs through inhibiting precipitation caused by transitions from amorphous into crystalline form, in supersaturated solutions, and also through improving SDs physical stability. Novel chlorthalidone SDs, a BCS IV drug, were developed using polymeric and non-polymeric carriers, specially a polymer-surfactant complex. SDs drug releases were evaluated using sink and non-sink conditions in water and biorelevant medium. Their physical stability was also monitored under different storage conditions. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL), sodium lauryl sulfate (SLS) and a combination of both showed promising results in apparent solubility studies, and therefore they were selected to compose the spray dried SDs. Dissolution studies demonstrated the SOL-SLS complex potential for providing chlorthalidone fast release (>80% in 15min), producing and maintaining in vitro supersaturation. This formulation comprising high drug loading (75%) reached a high supersaturation degree under non-sink condition (up to 6-fold the equilibrium solubility) once maintained for 6h in biorelevant medium. In addition, this SD presented better physical stability when compared to the chlorthalidone neat amorphous. The SOL-SLS complex impacts positively on chlorthalidone release and physical stability, highlighting its potential as carrier in SDDS of a poorly soluble drug.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Shedding light on surface exposition of poly(ethylene glycol) and folate
           targeting units on nanoparticles of poly(ε-caprolactone) diblock
           copolymers: Beyond a paradigm
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Alessandro Venuta, Francesca Moret, Giovanni Dal Poggetto, Diletta Esposito, Aurore Fraix, Concetta Avitabile, Francesca Ungaro, Mario Malinconico, Salvatore Sortino, Alessandra Romanelli, Paola Laurienzo, Elena Reddi, Fabiana Quaglia
      Polymeric nanoparticles (NPs) of poly(ε-caprolactone) (PCL) covered with a hydrophilic poly(ethylene glycol) (PEG) shell are usually prepared from diblock PEG-PCL copolymers through different techniques. Furthermore PEG, NPs can be decorated with targeting ligands to accumulate in specific cell lines. However, the density and conformation of PEG on the surface and its impact on the exposition of small targeting ligands has been poorly considered so far although this has a huge impact on biological behaviour. Here, we focus on PEG-PCL NPs and their folate-targeted version to encourage accumulation in cancer cells overexpressing folate receptor α. NPs were prepared with mixtures of PEG-PCL with different PEG length (short 1.0kDa, long 2.0kDa,) and a folate-functionalized PEG-PCL (PEG 1.5kDa) by the widely employed solvent displacement method. In depth characterization of NPs surface by 1H NMR, fluorescence and photon correlation spectroscopy evidenced a PEGylation extent below 7% with PEG in a mushroom conformation and the presence of folate more exposed to water pool in the case of copolymer with short PEG. NPs with short PEG adsorbed HSA forming a soft corona without aggregating. Although limited, PEGylation overall reduced NPs uptake in human macrophages. Uptake of NPs exposing folate prepared with short PEG was higher in KB cells (FR+) than in A549 (FR−), occurred via FR-receptor and involved lipid rafts-dependent endocytosis. In conclusion, the present results demonstrate that PEG length critically affects protein interaction and folate exposition with a logical impact on receptor-mediated cell uptake. Our study highlights that the too simplistic view suggesting that PEG-PCL gives PEG-coated NPs needs to be re-examined in the light of actual surface properties, which should always be considered case-by-case.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Ophthalmic administration of a 10-fold-lower dose of conventional
           nanoliposome formulations caused levels of intraocular pressure similar to
           those induced by marketed eye drops
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): C.M. Arroyo, D. Quinteros, M.J. Cózar-Bernal, S.D. Palma, A.M. Rabasco, M.L. González-Rodríguez
      The purpose of this study was to compare the in vivo efficacy of several timolol (TM)-loaded liposomal formulations with current TM antiglaucoma treatment (aqueous 0.5% w/v eye drops). In this study, conventional liposomes (CL) and deformable liposomes, without (DL1) and with ethanol (DL2) were prepared and characterized. In addition, in vitro release and permeation studies, as well as in vivo lowering intraocular pressure (IOP) and biocompatibility studies were performed. It was found that the quali and quantitative lipid bilayer composition played a significant role in modifying the physical properties of vesicles. The deformability study and electronic microscopy images revealed that membrane elasticity of DL1 and DL2 was much higher than CL. However, in vitro permeation results showed that the flux and permeability coefficient were significantly higher in CL compared to DL. The IOP study revealed that TM-loaded CL showed the best pharmacological activity, in comparison to deformable vesicles. Compared to the eye drops, CL formulation could equally reduce the IOP but using a concentration 10-fold lower, whereas the effective time was significantly longer. In addition, the formulations showed no irritant effects after instillation on the ocular surface.
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      PubDate: 2017-10-08T06:07:43Z
       
  • Advances in paper-analytical methods for pharmaceutical analysis
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Niraj Sharma, Toni Barstis, Basant Giri
      Paper devices have many advantages over other microfluidic devices. The paper substrate, from cellulose to glass fiber, is an inexpensive substrate that can be readily modified to suit a variety of applications. Milli- to micro-scale patterns can be designed to create a fast, cost-effective device that uses small amounts of reagents and samples. Finally, well-established chemical and biological methods can be adapted to paper to yield a portable device that can be used in resource-limited areas (e.g., field work). Altogether, the paper devices have grown into reliable analytical devices for screening low quality pharmaceuticals. This review article presents fabrication processes, detection techniques, and applications of paper microfluidic devices toward pharmaceutical screening.
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      PubDate: 2017-09-29T23:36:09Z
       
  • Optimization of alginate microcapsules containing cells overexpressing
           α-l-iduronidase using Box-Behnken design
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Dirnete Diel, Valeska Lizzi Lagranha, Roselena Silvestri Schuh, Fernanda Bruxel, Ursula Matte, Helder Ferreira Teixeira
      Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by deficiency of α-l-iduronidase (IDUA), which results in the lysosomal accumulation of glycosaminoglycans (GAG) leading to widespread clinical manifestations. The microencapsulation of IDUA overexpressing recombinant cells has been considered as a promising strategy for the treatment of MPS I. This study aimed at the optimization of alginate microcapsules containing recombinant BHK (Baby Hamster Kidney) cells (rBHK) overexpressing IDUA produced by electrostatic extrusion technique. The alginate microcapsule (MC-A) optimization study was carried out by means of an experimental Box-Behnken Design that allowed the simultaneous evaluation of the influence of voltage (kV), alginate/cell suspension flow (mL/h), and alginate concentration (%) on size and IDUA activity. The optimal conditions of voltage (10kV), flow (25mL/h), and alginate concentration (1.3%) made possible to obtain the smallest microcapsules showing the highest IDUA activity. After optimization, the microcapsules were sequentially coated with PLL and alginate (MC-APA) to increase their stability. MC-A and MC-APA presented monodisperse populations (span<1.22) with an average diameter of less than 350μm. The coating increased the mechanical stability of MC-APA by about 6-fold and modulated the permeability to the enzyme. Surface analyzes of MC-APA showed the presence of PLL bands, suggesting that the last alginate layer appears to have only partially coated the PLL. After 30days of subcutaneous implantation of the MC-APA microcapsules containing rBHK cells in a MPS I murine model, a significant increase in IDUA activity was observed in the skin near the implant. Histological analysis revealed an inflammatory infiltrate at the application site, which did not prevent the release of the enzyme under the conditions evaluated. Taken together, the overall results demonstrate the feasibility of MC-APA as a potential alternative for local treatment of MPS I.
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      PubDate: 2017-09-29T23:36:09Z
       
  • p,p′-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules as a
           novel approach to inflammatory pain treatment: Behavioral, biochemistry
           and molecular evidence
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Marcel Henrique Marcondes Sari, Vanessa Angonesi Zborowski, Luana Mota Ferreira, Natália Silva Jardim, Allanna Valentini Barbieri, Letícia Cruz, Cristina Wayne Nogueira
      The current study investigated the effect of organoselenium compound p,p′-methoxyl-diphenyl diselenide [(OMePhSe)2], free or incorporated into nanocapsules, on behavioral, biochemical and molecular alterations in an inflammatory pain model induced by complete Freund's adjuvant (CFA). Male Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h later they were treated via the intragastric route with a single (OMePhSe)2 administration, in its free form (dissolved in canola oil) or (OMePhSe)2 NC. The anti-hypernociceptive time- and dose-response curves were carried out using the von Frey hair test. Biochemical and histological parameters were determined in samples of injected paws and those of cerebral contralateral cortex were collected to determine immuno content of inflammatory proteins. Both (OMePhSe)2 forms reduced the hypernociception induced by CFA as well as attenuated the altered parameters of the inflammatory process in the paw (paw edema, myeloperoxidase and histological). However, the (OMePhSe)2 NC had a more prolonged anti-hypernociceptive action (7h) at a lower dose (10mg/kg) and superior effects on the paw alterations than the free compound form (4h and 25mg/kg). Furthermore, independent of the (OMePhSe)2 form, its administration decreased the MAPKs pathway activation (JNK;ERK1,2; p38) as well as iNOS, COX-2, Nf-κB and IL-1β protein contents in the cerebral contralateral cortex that were increased by paw CFA injection. Therefore, (OMePhSe)2 NC had superior anti-inflammatory action, which possibly occurs by the inflammatory protein content modulation and also attenuates paw biochemical and histological inflammatory alterations induced by CFA injection.
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      PubDate: 2017-09-29T23:36:09Z
       
  • New mesalamine polymeric conjugate for controlled release: Preparation,
           characterization and biodistribution study
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Aina L.A. Cesar, Fernanda A. Abrantes, Luana Farah, Rachel O. Castilho, Valbert Cardoso, Simone O. Fernandes, Ivana D. Araújo, André A.G. Faraco
      Mesalamine (5-ASA) consists of the first-line therapy for the treatment of ulcerative colitis; however, it has low bioavailability, can cause several systemic adverse events, and has low treatment adherence due to the inconvenient dosing scheme. In this work, a new drug delivery system consisting of chondroitin sulfate linked to 5-ASA was synthesized using a carbodiimide as conjugating agent. The system was characterized by spectroscopic techniques (UV, ATR-FTIR, XRD, and NMR 1H) and thermal analysis (TG/DTG and DSC), suggesting the conjugation between the drug and the polymer. The in vitro release and the corresponding kinetics were also evaluated, revealing that approximately 40% of the drug linked was released at pH9 for up to 50h, following Higuchi's model. The conjugate did not show cytotoxicity for the human monocytic cell line at the doses tested, and an in vivo biodistribution study showed that the conjugate remained in the lower GIT for up to 8h with no uptake in the upper GIT. These data corroborate with the radiation found per segment of GIT and in blood. For this last test the conjugate was radiolabeled with Technetium-99m to allow the scintigraphy evaluation and radiation quantification. In conclusion, the polymeric conjugate was successfully synthesized and demonstrated a mucoadhesiveness on the colon as desired, thus supporting its potential use in the treatment of ulcerative colitis.
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      PubDate: 2017-09-29T23:36:09Z
       
  • Improving mechanical properties of desloratadine via multicomponent
           crystal formation
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Ahmad Ainurofiq, Rachmat Mauludin, Diky Mudhakir, Daiki Umeda, Sundani Nurono Soewandhi, Okky Dwichandra Putra, Etsuo Yonemochi
      We report the first multicomponent crystal of desloratadine, an important anti-histamine drug, with a pharmaceutically acceptable coformer of benzoic acid. The single crystal structure analysis revealed that this novel multicomponent crystal is categorized as salt due to the proton transfer from benzoic acid to the desloratadine molecule. By forming the salt multicomponent crystal, we demonstrated that the tabletability and plasticity of the multicomponent crystal was improved from the parent drug. In addition, neither capping nor lamination tendency was observed in the desloratadine-benzoic acid multicomponent crystal. The existence of a layered structure and slip planes are proposed to be associated with this improvement. The desloratadine-benzoate in this case shows an improved solubility in water and HCl 0.1N media and a better dissolution profile in water. However, the dissolution rate in HCl 0.1N media was found to be essentially indifference.
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      PubDate: 2017-09-29T23:36:09Z
       
  • Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for
           enhancement of rosuvastatin oral bioavailability
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Mai Mahmoud Gabr, Sana Mohamed Mortada, Marwa Ahmed Sallam
      Cyclodextrins play an important role in supramolecular chemistry acting as building blocks than can be cross-linked by various linker molecules forming nano-porous structures called nanosponges (NS). NS have the ability to enhance the stability, solubility and bioavailability of various actives. This work aimed at elaborating rosuvastatin (ROS) loaded NS to improve its oral bioavailability. Carboxylate-linked NS were synthesized by reacting β-CD with pyromellitic dianhydride (PDA) at different molar ratios under specific conditions. ROS-loaded NS were prepared by lyophilisation technique and characterized for particle size, zeta potential, entrapment efficiency and drug release. Occurrence of cross-linking and ROS incorporation within the NS were assessed by DSC, FT-IR and SEM micrographs. NS prepared at a molar ratio of 1:6 of β-CD: PDA demonstrated the highest entrapment efficiency (88.76%), an optimum particle size of 275nm, a narrow size distribution (PDI of 0.392), and zeta potential of −61.9 indicating good colloidal stability. In vivo oral pharmacokinetics study in male Sprague Dawley rats showed that ROS-NS provided an outstanding enhancement in oral bioavailability compared to drug suspension and marketed tablets besides their physicochemical stability for 3month. Accordingly, ROS-NS represent a superior alternative to the conventional marketed formulation for effective ROS delivery.
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      PubDate: 2017-09-23T23:08:02Z
       
  • Effect of dronedarone on the pharmacokinetics of carvedilol following oral
           administration to rats
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Min-Soo Kim, In-hwan Baek
      Dronedarone is a CYP2D6 inhibitor; therefore, it is prudent to exercise caution when concurrently administering CYP2D6-metabolized β-blockers because of a lack of published data on potential drug interactions. The aim of this study was to investigate the effect of dronedarone on the pharmacokinetics of orally administered carvedilol in rats. Twenty male Sprague-Dawley rats were randomly divided into two groups and 10mg/kg carvedilol was administered to the rat with or without dronedarone pretreatment in a parallel design. Blood samples were collected before and after 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24h of drug administration. The plasma concentration of carvedilol was determined using LC-MS/MS. The systemic exposure to carvedilol was significantly increased and elimination of carvedilol was significantly decreased in the dronedarone-pretreated rats than in the vehicle-pretreated rats. The one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characters after single oral administration of carvedilol to both vehicle-pretreated and dronedarone-pretreated rats. This study suggests that dronedarone inhibits CYP2D6-mediated carvedilol metabolism, and dose adjustment is needed in carvedilol and dronedarone combination therapy. Further studies are needed to clarify the effect of dronedarone on carvedilol and CYP2D6 substrates in clinical use.
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      PubDate: 2017-09-23T23:08:02Z
       
  • A physiologically-based model to predict individual pharmacokinetics and
           pharmacodynamics of remifentanil
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Sara Cascone, Gaetano Lamberti, Ornella Piazza, Roberto Andrea Abbiati, Davide Manca
      Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.
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      PubDate: 2017-09-23T23:08:02Z
       
  • Amino acid or peptide conjugates of acridine/acridone and
           quinoline/quinolone-containing drugs. A critical examination of their
           clinical effectiveness within a twenty-year timeframe in antitumor
           chemotherapy and treatment of infectious diseases
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Monika Kukowska
      Acridines/acridones, quinolines/quinolones (chromophores) and their derivatives constitute extremely important family of compounds in current medicine. Great significance of the compounds is connected with antimicrobial and antitumor activities. Combining these features together in one drug seems to be long-term benefit, especially in oncology therapy. The attractiveness of the chromophore drugs is still enhanced by elimination their toxicity and improvement not only selectivity, specificity but also bioavailability. The best results are reached by conjugation to natural peptides. This paper highlights significant advance in the study of amino acid or peptide chromophore conjugates that provide highly encouraging data for novel drug development. The structures and clinical significance of amino acid or peptide chromophore conjugates are widely discussed.
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      PubDate: 2017-09-23T23:08:02Z
       
  • Cytochrome P450 inhibition by three licorice species and fourteen licorice
           constituents
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Guannan Li, Charlotte Simmler, Luying Chen, Dejan Nikolic, Shao-Nong Chen, Guido F. Pauli, Richard B. van Breemen
      The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.
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      PubDate: 2017-08-27T13:24:48Z
       
  • Direct comparison of UDP-glucuronosyltransferase and cytochrome P450
           activities in human liver microsomes, plated and suspended primary human
           hepatocytes from five liver donors
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Shalenie P. den Braver-Sewradj, Michiel W. den Braver, Audrey Baze, Joachim Decorde, Massimiliano Fonsi, Philippe Bachellier, Nico P.E. Vermeulen, Jan N.M. Commandeur, Lysiane Richert, J. Chris Vos
      UDP-glucuronosyltransferases (UGTs) and cytochrome P450s (CYPs) are the major enzymes involved in hepatic metabolism of drugs. Hepatic drug metabolism is commonly investigated using human liver microsomes (HLM) or primary human hepatocytes (PHH). We describe the development of a sensitive assay to phenotype activities of six major hepatic UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7) in intact PHH by analysis of glucuronidation of selective probe substrates. The non-selective, general substrate 7-hydroxycoumarin was included for comparison. For each liver donor preparation (five donors) UGT activities in cryopreserved suspended and plated PHH were compared to HLM prepared from the same donors. Standard CYP reaction phenotyping of seven major isoforms was performed in parallel. For all donors, CYP- and UGT-isoforms activity profiles were comparable in PHH and HLM, indicating that reaction phenotyping with selective probe substrates in intact cells primarily reflects respective CYP or UGT activity. System-dependent effects on UGT and CYP isoform activity were still found. While UGT activity of UGT1A1 was equivalent in plated and suspended PHH, UGT1A3, UGT1A6 and UGT2B7 activity was higher in suspended PHH and UGT1A9 and UGT1A4 activity was higher in plated PHH. The well-known decrease in activity of most CYP isoforms in plated compared to suspended PHH was confirmed. Importantly, we found a significant loss in CYP2C19 and CYP2B6 in HLM, activity being lower than in intact cells. Taken together, these findings implicate that, dependent on the UGT or CYP isoforms involved in the metabolism of a given compound, the outcome of metabolic assays is strongly dependent on the choice of the in vitro system. The currently described UGT- and CYP- activity profiling method can be used as a standard assay in intact cells and can especially aid in reaction phenotyping of in vitro systems for which a limited number of cells are available.
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      PubDate: 2017-08-16T11:34:56Z
       
  • Virtual bioequivalence for achlorhydric subjects: The use of PBPK
           modelling to assess the formulation-dependent effect of achlorhydria
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Kosuke Doki, Adam S. Darwich, Nikunjkumar Patel, Amin Rostami-Hodjegan
      Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations.
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      PubDate: 2017-08-16T11:34:56Z
       
  • Solubility, volumetric and compressibility properties of acetaminophen in
           some aqueous solutions of choline based deep eutectic solvents at
           T=(288.15 to 318.15) K
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Hemayat Shekaari, Mohammed Taghi Zafarani-Moattar, Masumeh Mokhtarpour
      Deep eutectic solvents (DESs) as a new class of green solvents have been used to overcome the low solubility of drugs during the recent years. In this work, the effect of some DESs containing choline chloride as hydrogen bond acceptor and urea, oxalic acid and malonic acid as hydrogen bond donors have been studied on acetaminophen (ACP) solubility at temperature ranges (298.15 to 313.15) K. The results indicate that the solubility of ACP increase with increasing concentration of DES and at higher temperatures and the DES containing malonic acid have a greater impact on the solubility of acetaminophen. The solubility data were correlated by the modified Apelblat, λh (Buchowski) and Yalkowsky models which Apelblat model is more consistent with experimental data. In addition, to elucidate the interactions between the components, the thermodynamic properties including volumetric, compressibility properties have been investigated using density and speed of sound measurements at T =(288.15 to 318.15K). The calculated thermodynamic parameters values confirm the strong solute – solvent interactions between ACP – DESs that is in agreement with solubility data.
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      PubDate: 2017-08-16T11:34:56Z
       
  • Co-encapsulation of paclitaxel and C6 ceramide in tributyrin-containing
           nanocarriers improve co-localization in the skin and potentiate cytotoxic
           effects in 2D and 3D models
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Vanessa F.M. Carvalho, Amanda Migotto, Daniela V. Giacone, Débora P. de Lemos, Thalita B. Zanoni, Silvya S. Maria-Engler, Leticia V. Costa-Lotufo, Luciana B. Lopes
      Considering that tumor development is generally multifactorial, therapy with a combination of agents capable of potentiating cytotoxic effects is promising. In this study, we co-encapsulated C6 ceramide (0.35%) and paclitaxel (0.50%) in micro and nanoemulsions containing tributyrin (a butyric acid pro-drug included for potentiation of cytotoxicity), and compared their ability to co-localize the drugs in viable skin layers. The nanoemulsion delivered 2- and 2.4-fold more paclitaxel into viable skin layers of porcine skin in vitro at 4 and 8h post-application than the microemulsion, and 1.9-fold more C6 ceramide at 8h. The drugs were co-localized mainly in the epidermis, suggesting the nanoemulsion ability for a targeted delivery. Based on this result, the nanoemulsion was selected for evaluation of the nanocarrier-mediated cytotoxicity against cells in culture (2D model) and histological changes in a 3D melanoma model. Encapsulation of the drugs individually decreased the concentration necessary to reduce melanoma cells viability to 50% (EC50) by approximately 4- (paclitaxel) and 13-fold (ceramide), demonstrating an improved nanoemulsion-mediated drug delivery. Co-encapsulation of paclitaxel and ceramide further decreased EC50 by 2.5–4.5-fold, and calculation of the combination index indicated a synergistic effect. Nanoemulsion topical administration on 3D bioengineered melanoma models for 48h promoted marked epidermis destruction, with only few cells remaining in this layer. This result demonstrates the efficacy of the nanoemulsion, but also suggests non-selective cytotoxic effects, which highlights the importance of localizing the drugs within cutaneous layers where the lesions develop to avoid adverse effects.
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      PubDate: 2017-08-16T11:34:56Z
       
  • Melanin binding study of clinical drugs with cassette dosing and rapid
           equilibrium dialysis inserts
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Laura Pelkonen, Unni Tengvall-Unadike, Marika Ruponen, Heidi Kidron, Eva M. del Amo, Mika Reinisalo, Arto Urtti
      Melanin pigment is a negatively charged polymer found in pigmented human tissues. In the eye, iris, ciliary body, choroid and retinal pigment epithelium (RPE) are heavily pigmented. Several drug molecules are known to bind to melanin, but larger sets of drugs have not been compared often in similar test conditions. In this study, we introduce a powerful tool for screening of melanin binding. The binding of a set of 34 compounds to isolated porcine RPE melanin was determined by cassette (n-in-one) dosing in rapid equilibrium dialysis inserts and the binding was quantitated with LC-MS/MS analytics. The compounds represented large variety in melanin binding (from 8.6%, ganciclovir) to over 95% bound (ampicillin and ciprofloxacin). The data provides information on melanin binding of small molecular weight compounds that are used for ocular (e.g. brinzolamide, ganciclovir) and systemic (e.g. tizanidine, indomethacin) therapy. Interestingly, competition among compounds was seen for melanin binding and the binding did not show any correlation with plasma protein binding. These results increase the understanding of melanin binding of ocular drugs and can be further exploited to predict pharmacokinetics in the eye. Pigment binding provides an interesting option for improved drug distribution to retina and choroid that are difficult target tissues in drug delivery.
      Graphical abstract image

      PubDate: 2017-08-16T11:34:56Z
       
  • ERE-dependent transcription and cell proliferation: Independency of these
           two processes mediated by the introduction of a sulfone function into the
           weak estrogen estrothiazine
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Yves Jacquot, Dany Spaggiari, Julie Schappler, Eric Lesniewska, Serge Rudaz, Guy Leclercq
      The synthetic coumestrol derivative 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (estrothiazine, ESTZ) has been identified as a weak estrogen receptor α (ERα) ligand unable to compete with tritiated estradiol. The biological activity of this compound, supported by a methoxy group in position 3, seems mainly to result from its capacity to activate ERα dimerization without any participation of coactivators. In support of this view and referring to conventional estrogens, an ESTZ metabolism study conducted with hepatic human microsomes failed to provide any argument in favour of an estrogenic activity dependent on a metabolic conversion of the compound into hydroxylated metabolites with strong receptor activation ability. Interestingly, we failed to detect any oxidation of the sulfur atom of the compound. In the light of pharmacological literature data concerning sulfonylation, we assessed ERα-mediated activities generated by two sulfonylated ESTZ derivatives in which the methoxy group that plays a key role in its mechanism of action was maintained or removed. Sulfonylated ESTZ, even in its demethoxylated form, induced ERE-mediated transcriptions in MCF-7 breast cancer cells, without affecting the ERα turnover rate. In contrast to ESTZ, this compound failed to enhance the proliferation of ERα-positive breast cancer cells, suggesting that its sulfone function confers upon the receptor a capacity to elicit some of the known characteristics associated with estrogenic responses. Moreover, we demonstrated that this sulfone may contribute to ERα dimerization without any requirement of the methoxy group. Nevertheless, it seems to cooperate with this group, as reflected by a weak ability of the sulfonylated form of ESTZ to compete with tritiated estradiol for ERα-binding. Assessment of the docking of this compound within the ligand-binding domain of the receptor by molecular dynamics provided an explanation for this observation since the sulfone is engulfed in a small hydrophobic pocket involving the residues Leu-346, Leu-349, Ala-350 and Leu-384, also known to recruit coactivators. This work not only reports the sulfone functional group as a pharmacophore for estrogenic activity, but also opens new perspectives for the development of estrogenic molecules with therapeutic purpose and devoid of proliferative side effects.
      Graphical abstract image

      PubDate: 2017-08-16T11:34:56Z
       
  • Self-assembled polypeptide nanoparticles for intracellular irinotecan
           delivery
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): N.N. Zashikhina, M.V. Volokitina, V.A. Korzhikov-Vlakh, I.I. Tarasenko, A. Lavrentieva, T. Scheper, E. Rühl, R.V. Orlova, T.B. Tennikova, E.G. Korzhikova-Vlakh
      In this research poly(l-lysine)-b-poly(l-leucine) (PLys-b-PLeu) polymersomes were developed. It was shown that the size of nanoparticles depended on pH of self-assembly process and varied from 180 to 650nm. The biodegradation of PLys-b-PLeu nanoparticles was evaluated using in vitro polypeptide hydrolysis in two model enzymatic systems, as well as in human blood plasma. The experiments on the visualization of cellular uptake of rhodamine 6g-loaded and fluorescein-labeled nanoparticles were carried out and the possibility of their penetration into the cells was approved. The cytotoxicity of polymersomes obtained was tested using three cell lines, namely, HEK, NIH-3T3 and A549. It was shown that tested nanoparticles did not demonstrate any cytotoxicity in the concentrations up to 2mg/mL. The encapsulation of specific to colorectal cancer anti-tumor drug irinotecan into developed nanocontainers was performed by means of pH gradient method. The dispersion of drug-loaded polymersomes in PBS was stable at 4°C for a long time (at least 1month) without considerable drug leakage. The kinetics of drug release was thoroughly studied using two model enzymatic systems, human blood serum and PBS solution. The approximation of irinotecan release profiles with different mathematical drug release models was carried out and allowed identification of the release mechanism, as well as the morphological peculiarities of developed particles. The dependence of encapsulation efficiency, as well as maximal loading capacity, on initial drug concentration was studied. The maximal drug loading was found as 320±55μg/mg of polymersomes. In vitro anti-tumoral activity of irinotecan-loaded polymersomes on a colon cancer cell line (Caco-2) was measured and compared to that for free drug.
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      PubDate: 2017-08-05T11:21:59Z
       
  • Pemetrexed conjugated with gold nanoparticles – Synthesis,
           characterization and a study of noncovalent interactions
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Elżbieta U. Stolarczyk, Krzysztof Stolarczyk, Marta Łaszcz, Marek Kubiszewski, Andrzej Leś, Olga Michalak
      Gold nanoparticles (AuNPs) have been widely used as nanocarriers in drug delivery application. However, the binding mechanism between AuNPs and drug bases still remains a puzzle. Our study included: (i) optimization of three synthesis of the AuNPs-pemetrexed (PE) nanocomposites formation which was monitored by UV–Vis spectroscopy, (ii) identification of PE in gold nanocomposites and mechanism of PE interaction with gold nanoparticles by electrochemistry, NMR and Raman measurements, (iii) characterization of the three nanocomposites by TEM, DSL, ESL, zeta potential, XRPD and TGA analysis. The obtained nanocomposites are homogeneously shaped and have a maximum diameter of around 14nm and 88nm, as measured by the TEM and DSL techniques, respectively. The zeta potential of the nanocomposites is −43mV and suggests a high stability of the nanoparticles and lower toxicity for the normal cells. Quantum chemical calculations were also performed on model systems to estimate the strength of the AuNPs-PE interaction. Taking into account the experimental and theoretical data a mechanism of the nanocomposites' formation has been proposed in which PE interacts with the gold surface by the COOH/COO– group.
      Graphical abstract image

      PubDate: 2017-08-05T11:21:59Z
       
  • The effect of Pro NanoLipospheres (PNL) formulation containing natural
           absorption enhancers on the oral bioavailability of
           delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Irina Cherniakov, Dvora Izgelov, Abraham J. Domb, Amnon Hoffman
      The lipophilic phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.
      Graphical abstract image

      PubDate: 2017-08-05T11:21:59Z
       
  • Cocrystal formation, crystal structure, solubility and permeability
           
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Artem O. Surov, Tatyana V. Volkova, Andrei V. Churakov, Alexey N. Proshin, Irina V. Terekhova, German L. Perlovich
      The cocrystallization approach has been applied to modify the poor solubility profile of the biologically active 1,2,4-thiadiazole derivative (TDZ). Extensive cocrystal screening with a library of coformers resulted in formation of a new solid form of TDZ with vanillic acid in a 1:1 molar ratio. The cocrystalline phase was identified and characterized by thermal and diffraction analyses including single-crystal X-ray diffraction. The energies of intermolecular interactions in the crystal were calculated by solid-state DFT and PIXEL methods. Both calculation schemes show good consistency in terms of total energy of the intermolecular interactions and suggest that the cocrystal is mainly stabilized via hydrogen bonds, which provide ca. 44% of the lattice energy. Since the cocrystal contained the hydroxybenzoic acid derivative as a coformer, the solubility profile of the cocrystal was investigated at different pHs using eutectic concentrations of the components. Furthermore, the influence of the cocrystallization on the permeability performance of the 1,2,4-thiadiazole through an artificial regenerated cellulose membrane was also evaluated. In addition, the thermodynamic functions of the cocrystal formation were estimated from the solubility of the cocrystal and the corresponding solubility of the pure compounds at various temperatures. The cocrystal formation process was found to have a relatively small value of the driving force (−5.3kJ·mol−1). The most significant contribution to the Gibbs energy was provided by the exothermic enthalpy of formation.
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      PubDate: 2017-08-05T11:21:59Z
       
  • S-oxiracetam protect against ischemic stroke via alleviating blood brain
           barrier dysfunction in rats
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Liangliang Huang, Erxin Shang, Wenxiang Fan, Xiang Li, Binbin Li, Shucheng He, Yuxin Fu, Yizhi Zhang, Yunman Li, Weirong Fang
      The blood brain barrier (BBB) maintains the basic stability of the brain tissue under physiological conditions, while destroys and exaggerates brain edema and inflammatory response after ischemic stroke. In this study, we researched S-oxiracetam (S-ORC), a nootropic drug, alleviates BBB dysfunction and protects against ischemic stroke in rats. Middle cerebral artery occlusion(MCAO)/reperfusion in rats is applied to mimic ischemic stroke. One hour after reperfusion, rats are administered intravenously with different dose (0.12, 0.24, or 0.48g/kg) of S-ORC for continuative three days. Seventy-two hours after MCAO, TTC staining, hematoxylin and eosin (H&E) staining, brain water content, immunohistochemical staining, EB extravasation, western blot are provided to evaluate the protective effect and possible mechanism of S-ORC on BBB dysfunction. Furthermore, brain concentration of verapamil (P-glycoprotein substrate) and atenolol (paracellular transport marker) were assayed by UPLC-MS/MS co administration with or without S-ORC. The results show that post-treatment of S-ORC decreases cerebral infarct size, lessens brain edema, inhibits neutrophil infiltration and cytokines releasing. Furthermore, S-ORC treatment decreases EB leakage, downregulates MMP-9, upregulates occludin and claudin-5, and decreases brain concentration of verapamil and atenolol after MCAO surgery. In conclusion, the present study demonstrates that post-treatment of S-ORC alleviates BBB dysfunction by regulating tight junction proteins (TJPs), upregulating P-glycoprotein function, and protects against ischemic stroke as result.
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      PubDate: 2017-08-05T11:21:59Z
       
  • Production of human recombinant phenylalanine hydroxylase in Lactobacillus
           plantarum for gastrointestinal delivery
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Aura María Ramírez, Alexander Rodriguez-López, Andrea Ardila, Laura Beltran, Camilo Andres Patarroyo, Adelina Del Pilar Melendez, Oscar Fernando Sánchez, Carlos Javier Alméciga-Díaz
      Phenylketonuria (PKU) is an autosomal recessive disorder caused by a defective phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of l-phenylalanine (l-Phe) to l-tyrosine (l-Tyr) in presence of the cofactor tetrahydrobiopterin (BH4). Defective PAH causes accumulation of phenylalanine, which has neurotoxic effects and leads to dermatological, behavioral, and neurocognitive problems. Treatments for this disease consist in life-long diets that are hard for patients to keep, or supplementation with BH4. In this study, we propose a system where a probiotic lactic acid bacteria (LAB) can be used as vehicle to express in situ an engineered human PAH. Engineered PAHs contain a secretion peptide, a gastrointestinal signal (GI), the human PAH, and a flexible glycine linker followed by the fluorescence protein mEGFP. Engineered constructs were successfully transformed, expressed, and secreted in Lactobacillus plantarum CM_PUJ411. PAH construct containing either the signal peptide GI1 or GI2 were transported through a Caco-2 cell monolayer. Nevertheless, the one containing GI1 allowed the highest transport through the cell monolayer. Co-culture of L. plantarum and Caco-2 cells showed that engineered PAH is produced in-situ and transported through the cell monolayer. Finally, the activity test showed that the engineered PAH secreted by L. plantarum CM_PUJ411 is active, leading to a reduction in l-Phe and an increase in l-Tyr levels, respectively. These results show the potential of this system as a new therapeutic alternative for the treatment of PKU patients.
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      PubDate: 2017-08-05T11:21:59Z
       
  • Development of an XBP1 agonist, HLJ2, as a potential therapeutic agent for
           ulcerative colitis
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): HaiJing Zhang, ZhiHui Zhang, GuangMing Song, XiaoNan Tang, HuaChen Song, AnJun Deng, WenJie Wang, LianQiu Wu, Hailin Qin
      There is a severe lack of effective treatments for ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. The identification of valid targets and new drugs is an urgent need. In this study, we identified the XBP-1 agonist HLJ2 as a promising treatment candidate. In an in vivo mouse model of DSS-induced colitis, HLJ2 decreased weight loss, colon contracture, disease activity index (DAI), colon mucosa damage index (CMDI) and histopathological index (HI). HLJ2 also decreased myeloperoxidase (MPO) activity and reduced production of the inflammatory cytokines TNF-α, IL-1β, and IL-6. HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate (DSS) and increased the expression of ZO-1 and claudin-1. Fecal 16s rRNA high-throughput sequencing demonstrated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2, including increased abundance of probiotics such as Lachnospiraceae, Prevotellaceae, and Lactobacillaceae. At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microorganisms such as Bacteroidaceae, Porphyromonadaceae, Deferribacteraceae, and Pseudomonadaceae in HLJ2-treated mice compared with untreated mice. Our results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation, regulates the intestinal flora, and protects the intestinal mucosa. It is thus a potential therapeutic agent for ulcerative colitis.
      Graphical abstract image

      PubDate: 2017-08-05T11:21:59Z
       
  • Improved selectivity and cytotoxic effects of irinotecan via liposomal
           delivery: A comparative study on Hs68 and HeLa cells
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Ana Casadó, Margarita Mora, Maria Lluïsa Sagristá, Santi Rello-Varona, Pilar Acedo, Juan Carlos Stockert, Magdalena Cañete, Angeles Villanueva
      Irinotecan (CPT-11) is an effective chemotherapeutic agent widely used to treat different cancers. Otherwise, the liposomal delivery of anti-tumor agents has been shown to be a promising strategy. The aim of this study has been to analyze the effect of liposomal CPT-11 (CPT-11lip) on two human cell lines (Hs68 and HeLa) to establish the suitability of this CPT-11 nanocarrier. We have demonstrated the highest uptake of CPT-11lip in comparison with that of CPT-11sol, in lactate buffer, and that CPT-11lip was internalized in the cells through an endocytic process whereas CPT-11sol does so by passive diffusion. CPT-11lip was not cytotoxic to normal fibroblast Hs68 cells, but induced a massive apoptosis accompanied by cell senescence in HeLa cells. CPT-11lip treatment modified the morphology of HeLa cells, induced different cell cycle alterations and accumulated into lysosomes in both cell lines. In particular, CPT-11lip treatment showed that surviving HeLa cells remained in a state of senescence whereas only a temporal growth arrest was induced in Hs68 cells. Results of RT-PCR indicated that the different responses in Hs68 (survival) and HeLa cells (apoptotic death), seemed to be induced by a p53- and p53- independent mechanism, respectively. An analysis of DNA damage also determined that released CPT-11 from liposomes was able to reach the nucleus and exert a genotoxic effect in both cell lines, which was repaired in Hs68 but not in HeLa cells. All results indicate that phospholipid-cholesterol liposomes possess optimum properties for CPT-11 delivery, being biocompatible and selectively cytotoxic against HeLa tumorigenic cells.
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      PubDate: 2017-08-05T11:21:59Z
       
  • A Phase I randomized clinical trial testing the safety, tolerability and
           preliminary pharmacokinetics of the mGluR5 negative allosteric modulator
           GET 73 following single and repeated doses in healthy volunteers
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Carolina L. Haass-Koffler, Kimberly Goodyear, Victoria M. Long, Harrison H. Tran, Antonella Loche, Roberto Cacciaglia, Robert M. Swift, Lorenzo Leggio
      Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N =48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses (N =32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers.
      Graphical abstract image

      PubDate: 2017-08-05T11:21:59Z
       
  • The interaction of dendrimer-doxorubicin conjugates with a model pulmonary
           epithelium and their cosolvent-free, pseudo-solution formulations in
           pressurized metered-dose inhalers
    • Abstract: Publication date: 15 November 2017
      Source:European Journal of Pharmaceutical Sciences, Volume 109
      Author(s): Qian Zhong, Bruno V. Humia, Alisha R. Punjabi, Francine F. Padilha, Sandro R.P. da Rocha
      Oral inhalation (OI) of nano-chemotherapeutics holds great potentials in the treatment of lung cancers as it enables direct targeting of drugs to lung tissues, spatial and temporal control of drug release, and decrease in drug-associated systemic and local lung toxicity. Therefore, the design of chemistry of the nanocarriers and their OI formulations for chemotherapeutics delivery to the peripheral lungs and extrapulmonary tissues of relevance such as lymph nodes, may thus afford new opportunities for treating such relevant diseases. In this work we investigated the effect of polyethylene glycol 1000Da (PEG1000) density and doxorubicin (DOX) payload on the interaction of poly(amidoamine) dendrimer (PAMAM) with an in vitro pulmonary epithelium model (Calu-3). DOX, which was conjugated to the PAMAM through a pH-labile bond, showed a strong time-dependent cell kill against Calu-3 cells due to sustained DOX release. The conjugation of DOX to PEGylated PAMAM dendrimers significantly enhances DOX transport across pulmonary epithelium compared to free drug, with the rate of transport increasing as PEGylation degree increases. Transient interaction of PEGylated dendrimers with cellular junctions of the polarized epithelium as probed by a reduction in transepithelial electrical resistance, faster mucus diffusion, along with reduced cellular internalization compared to the non-PEGylated counterpart promotes transport across the epithelial barrier. A cosolvent free method was developed to formulate PEGylated PAMAM-DOX conjugates in pressurized metered-dose inhalers. The resulting aerosol formulations show a very high final particle fractions (>82%). We further demonstrate that aerodynamic particle size distribution of the nanoconjugates can be tweaked with the addition of a biodegradable lactide-based copolymer, which may help tune lung deposition of PAMAM-DOX conjugates to a specific pulmonary area. The combined results suggest that conjugation to PAMAM dendrimers and their surface modification with PEG1000 can be utilized to modulate the transport of DOX across pulmonary epithelium, and also to easily formulate the conjugates in propellant-based inhalers for pulmonary administration of anticancer therapeutics.
      Graphical abstract image

      PubDate: 2017-08-05T11:21:59Z
       
 
 
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