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Journal Cover European Journal of Pharmaceutical Sciences
  [SJR: 1.176]   [H-I: 98]   [115 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0928-0987
   Published by Elsevier Homepage  [3089 journals]
  • Synthesis and characterization of IUdR loaded PEG/PCL/PEG polymersome in
           mixed DCM/DMF solvent: Experimental and molecular dynamics insights into
           the role of solvent composition and star architecture in drug dispersion
           and diffusion
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Sepideh Khoee, Ali Hashemi, Sajjad Molavipordanjani
      Combined experimental and simulation investigations have provided molecular level insights into 5-iodo-2′-deoxyuridine (IUdR) loading behavior for the novel PEG/PCL/PEG polymersome-like carriers in mixed dichloromethane/N,N-dimethylformamide (DCM/DMF) solvent. As with the experiments, a novel approach was applied for layer by layer tailoring of polyethylene glycol (PEG) and polycaprolactone (PCL) as PEG/PCL/PEG copolymer on the surface of magnetite nanoparticles (MNPs) by click chemistry. Experimental results indicated that IUdR, as an anti-cancer drug, could be encapsulated up to 80% EE in this nanocarrier and could be in-vitro released up to 90% during 120h. Computational studies, on the other hand, provide molecular level insights into the optimal performance of the carrier in terms of drug “Dispersion” and “Diffusion” patterns in equimolar DCM/DMF solvent. Molecular dynamics simulations of the system in four distinct solvation scenarios including pure DCM, mixed DCM/DMF, pure DMF and water, have proven that while hydrophobic solvents give rise to better “dispersion” of drugs, hydrophilic solvents lead for drug molecules to penetrate into the carrier and improve “diffusion” properties. Optimal conditions for drug encapsulation, as also confirmed through experiments, was observed for mixed DCM/DMF solvent in terms of proper diffusion and well dispersion. While drug “aggregates” were observed in DCM, poorly stable drug molecules with lowered penetrations were observed in pure DMF. Proper release properties with IUdR molecules staying on the surface of the carrier was also observed in water. The interesting role of the star-linear architecture was further scrutinized through distinctions made through analysis of interactions between IUdR molecules with “inner” and “outer” PEG sections.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Identification and characterization of potential druggable targets among
           hypothetical proteins of extensively drug resistant Mycobacterium
           tuberculosis (XDR KZN 605) through subtractive genomics approach
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Reaz Uddin, Quratulain Nehal Siddiqui, Syed Sikander Azam, Bibi Saima, Abdul Wadood
      Among the resistant isolates of tuberculosis (TB), the multidrug resistance tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are the areas of growing concern for which the front-line antibiotics are no more effective. As a result, the search of new therapeutic targets against TB is an imperative need of time. On the other hand, the target identification is an a priori step in drug discovery based research. Furthermore, the availability of the complete proteomic data of extensively drug resistant Mycobacterium tuberculosis (XDR-MTB) made it possible to carry out in silico analysis for the discovery of new drug targets. In the current study, we aimed to prioritize the potential drug targets among the hypothetical proteins of XDR-TB via subtractive genomics approach. In the subtractive genomics, we stepwise reduced the complete proteome of XDR-MTB to only two hypothetical proteins and evidently proposed them as new therapeutic targets. The 3D structure of one of the two target proteins was predicted via homology modeling and later on, validated by various analysis tools. Our study suggested that the domains identified and the motif hits found in the sequences of the shortlisted drug targets are crucial for the survival of the XDR-MTB. To the best of our knowledge, the current study is the first attempt in which the complete proteomic data of XDR-MTB was subjected to the computational subtractive genomics approach and therefore, would provide an opportunity to identify the unique therapeutic targets against deadly XDR-MTB.
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      PubDate: 2017-12-12T08:07:25Z
       
  • The possibility of obtaining marketing authorization of orphan
           pharmaceutical compounding preparations: 3,4-DAP for Lambert-Eaton
           Myasthenic Syndrome
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Sofieke de Wilde, Maria G.H. de Jong, Alexander F. Lipka, Henk-Jan Guchelaar, Kirsten J.M. Schimmel
      Background Pharmaceutical compounding preparations, produced by (hospital) pharmacies, usually do not have marketing authorization. As a consequence, some of these pharmaceutical compounding preparations can be picked-up by a pharmaceutical company to obtain marketing authorization, often leading to price increases. An example is the 3,4-diaminopyridine slow release (3,4-DAP SR) tablets for Lambert-Eaton Myasthenic Syndrome (LEMS). In 2009 marketing authorization was given for the commercial immediate release phosphate salt of the drug, including a fifty-fold price increase compared to the pharmaceutical compounding preparation. Obtaining marketing authorization for 3,4-DAP SR by academia might have been a solution to prevent this price increase. To determine whether the available data of a pharmaceutical compounding preparation with long-term experience in regular care are adequate to obtain marketing authorization, 3,4-DAP SR is used as a case study. Methods A retrospective qualitative case-study was performed. Initially, document analysis was executed by collecting the required data for marketing authorization in general and whether data of Firdapse® and 3,4-DAP SR met these requirements. Secondly, the (non-) available data of the two formulations were compared with each other to determine the differences in availability. Results At the time of approval, almost all data were available for both Firdapse® and 3,4-DAP SR. Conversely, much of the data used for the approval of Firdapse® originated from the 3,4-DAP immediate release (3,4-DAP IR) formulation. Only two bioequivalence studies and one pharmacology safety study was performed with Firdapse® before marketing authorization application. Conclusions In conclusion, at time Firdapse® obtained approval, the data available did not differ substantially from 3,4-DAP SR, indicating that approval with 3,4-DAP SR would have been possible. We make a plea for approval of orphan medicinal products developed and manufactured by academic institutions as to keep utilization of these products affordable.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Cyclodextrin-siRNA conjugates as versatile gene silencing agents
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Meenakshi Malhotra, Matt Gooding, James C. Evans, Daniel O'Driscoll, Raphael Darcy, Caitriona M. O'Driscoll
      Functional siRNAs (luciferase and PLK1) have been conjugated to β-cyclodextrin and the ability of the conjugates to retain gene knockdown activity has been assessed by delivery to cancer cell lines using various formulations. Initially two formulations used complexation with polycations, namely Lipofectamine 2000 and an amphiphilic polycationic cyclodextrin. Gene knockdown results for human glioblastoma cells (U87) and prostate cancer cells (PC3, DU145) showed that conjugation to the cyclodextrin did not reduce gene silencing by the RNA. A third mode of delivery involved formation of targeted nanoparticles in which the conjugate was first complexed with adamantyl-PEG-ligands (targeting ligand RVG peptide or dianisamide) by adamantyl inclusion in the cyclodextrin cavities of the conjugates, followed by charge neutralisation with the cationic polymer chitosan. Enhanced knockdown was achieved by these ligand-targeted formulations. In summary, while this study illustrated the gene silencing efficacy of a simple cyclodextrin-siRNA conjugate it is envisaged that future studies will explore the use of conjugates with a modified cyclodextrin which would be self-delivering. Detailed data such as stability, lysosomal escape etc. will then be reported for each conjugate, since this will be appropriate for conjugates which are intended to exploit, rather than merely demonstrate, the concept. The present paper was intended to demonstrate the viability and generality of this novel concept.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Population pharmacokinetics of articaine with 1:200,000 epinephrine during
           third molar surgery and simulation of high-dose regimens
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Yoann Cazaubon, Cédric Mauprivez, Catherine Feliu, Laurent Binet, Olivier Oget, Claire Gozalo, Zoubir Djerada
      Background and objectives Articaine is more and more used in third molar surgery under local anesthesia (LA). The objectives of this analysis were to characterize the pharmacokinetics of articaine for this type of surgery and to simulate dosing regimens. Methods Non-linear mixed-effects modeling conducted in Monolix 4.4.0 was used to describe articaine plasma concentration-time data from 20 patients. Monte Carlo simulations were then performed to evaluate the probability of cardiotoxic target attainment (PCTA) of various dosage regimens. Results Articaine concentration data were best described by a linear one-compartment model, with an additional depot compartment for submucosal route with a zero-order transfer to central compartment. Age and gender were found to influence duration transfer (Tk0) and elimination rate constant (Ke), respectively. Simulated maximum recommended dose regimen (7mg/kg) had a PCTA of 0%. Simulated higher doses of 10mg/kg and 15mg/kg had a PCTA of 0% and about 1–4%, respectively. Conclusions The model adequately described the articaine pharmacokinetics. This is the first PK model qualified for articaine administered by submucosal route. The simulations suggest that maximum recommended dose regimen is safe concerning the cardiotoxicity in healthy patients.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Population pharmacokinetic evaluation of ADV6209, an innovative oral
           solution of midazolam containing cyclodextrin
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Frédéric Marçon, Catherine Guittet, Maria A. Manso, Ingrid Burton, Luc-André Granier, Philippe Jacqmin, Hervé Dupont
      Introduction In the absence of a licensed formulation in many countries worldwide, ADV6209, an innovative 2mg/ml oral solution of midazolam containing cyclodextrin, has been developed for moderate sedation in paediatric patients. Population pharmacokinetics for ADV6209 is reported. Methods Plasma concentration data were collected from 37 paediatric patients and 12 healthy adults recruited in a single dose, open-label phase II pharmacokinetic study and in a single dose, randomised, open-label two-period crossover bioavailability study, respectively. Data were analysed using non-linear mixed effect modelling. Plasma concentrations of midazolam were described by a two-compartment model. An additional one-compartment model was added for α- hydroxymidazolam. Results The body weight covariate was found to have a significant impact on midazolam and α-hydroxymidazolam clearance, and on midazolam volume of distribution. The population pharmacokinetic model indicated that 77% of the midazolam dose was absorbed within 30min after oral administration. Parameter estimations for a subject of 34kg indicated values of midazolam clearance of 34.7l·h−1, a central volume of distribution of 27.9l and a peripheral volume of distribution of 413l. A higher metabolic ratio and a higher midazolam clearance per body weight were observed in the youngest group of subjects, in accordance with literature data. The clearance per body weight of α-hydroxymidazolam remained constant over the different age groups. Conclusion Pharmacokinetic parameters were close to those reported in the literature with midazolam extemporaneous oral solutions or syrups, demonstrating that cyclodextrin had no significant effect on measured parameters.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Differential effects of hepatic cirrhosis on the intrinsic clearances of
           sorafenib and imatinib by CYPs in human liver
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Michael Murray, Tina B. Gillani, Sussan Ghassabian, Robert J. Edwards, Tristan Rawling
      The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40–44% of control (P <0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Tannic acid (TA): A molecular tool for chelating and imaging labile iron
    • Abstract: Publication date: 1 March 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 114
      Author(s): Isara Phiwchai, Wiphawee Yuensook, Natsaree Sawaengsiriphon, Saowalak Krungchanuchat, Chalermchai Pilapong
      This report presents the potential utilization of tannic acid (TA) as a natural iron chelator. TA is capable of binding with small ferric complexes without competitive binding with endogenous iron-containing molecules such as ferritin and transferrin. It was observed that the extracellular iron binding of TA resulted in the formation of self-assembled Fe3+-TA complexes, which were then taken up by HepG2 cells via phagocytosis pathway with autophagy-inducing properties. Obviously, TA was found to inhibit iron-induced HepG2 cell growth. However, cellular interactions and biological responses to the treatment were found to depend on availability of iron. Based on the results of the iron efflux experiment, it can be stated that TA has the capability to mobilize iron from cells in the form of assembled Fe3+-TA complexes. Interestingly, TA-mediated cellular iron influx and efflux were successfully monitored via MRI. The results of this study suggest that TA can be used as a molecular tool for chelating and imaging labile iron. This might be a promising approach for prevention and treatment of iron-associated cancer or other iron overload disorders.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Liposomes assembled from dimeric retinoic acid phospholipid with improved
           pharmacokinetic properties
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Lu Lu, Yawei Du, Muhammad Ismail, Longbing Ling, Chen Yao, Zhenglin Fu, Xinsong Li
      All-trans-retinoic acid (ATRA) exhibits potent cytotoxicities against different cancer cells by binding to retinoic acid receptors (RARs), which is regarded as the first example of targeted therapy in acute promyelocytic leukemia (APL). However, its extensive clinical applications have been limited because of poor aqueous solubility, short half-life time and side effects. In this report, dimeric ATRA phosphorylcholine prodrug (Di-ATRA-PC) was designed and assembled into nanoliposomes to improve its pharmacokinetic properties. Di-ATRA-PC prodrug was synthesized by a facile esterification and characterized by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). The Di-ATRA-PC assembled liposomes were prepared by thin film hydration method with ATRA loading efficiency up to 73wt%. The liposomes have a uniform particle size (73.1±3.6nm) with negatively charged surface (−20.5±2.5mV) and typical lipid bilayer structure as measured by dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscope (cryo-TEM). In vitro drug release study confirmed that Di-ATRA-PC liposomes could sustainedly release free ATRA in a weakly acidic condition. Furthermore, cellular uptake, MTT and cell apoptosis analysis demonstrated that the liposomes could be successfully internalized into tumor cells to induce apoptosis of MCF-7 and HL-60 cells. More importantly, in vivo pharmacokinetic assay indicated that Di-ATRA-PC liposomes had much longer retention time in comparison with ATRA. In conclusion, Di-ATRA-PC liposomal formulation could be a potential drug delivery system of ATRA with enhanced pharmacokinetic properties.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility,
           oral bioavailability and anti-osteoporotic effects of raloxifene
           hydrochloride
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Jaleh Varshosaz, Mohsen Minaiyan, Ladan Dayyani
      Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.
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      PubDate: 2017-12-12T08:07:25Z
       
  • Formulations based on solid lipid nanoparticles (SLN) and nanostructured
           lipid carriers (NLC) for cutaneous use: A review
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): A. Garcês, M.H. Amaral, J.M. Sousa Lobo, A.C. Silva
      Cutaneous use of lipid nanoparticles (solid lipid nanoparticles, SLN and nanostructured lipid carriers, NLC) has been showing promising results. These systems consist of low viscosity aqueous dispersions, being usually employed by means of semi-solid formulations with adequate consistency for skin application. This review addresses the cutaneous use of lipid nanoparticles for therapeutic and cosmetic applications. Initially, general information related to pharmaceutical semi-solid formulations is presented. Afterwards, the effects of SLN and NLC on the skin, and technological aspects related to semi-solid systems based on SLN or NLC are described. Finally, the most relevant studies related to the formulations based on SLN and NLC, for cosmetic and therapeutic applications, are reported. Notwithstanding the cutaneous use of SLN and NLC has been proposed for both local and transdermal delivery, the reported studies show promising results only for local application. In this sense, more research is required to better understanding the interaction mechanisms of lipid nanoparticles with skin lipids. Furthermore, the development of standard methods for skin experiments with nanoparticles is necessary.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Revisiting in vitro release test for topical gel formulations: The effect
           of osmotic pressure explored for better bio-relevance
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Soorin Jeong, Seonghee Jeong, Sungyoon Chung, Aeri Kim
      Release test methods for topical dosage forms including pharmacopeial tests require a large volume of release media, with limited application for high throughput screening. In the present study, we evaluated Transwell assay to miniaturize the release test method for optimization of thermoreversible topical gel formulations. We also explored the osmotic effect on the in vitro release rates from gel formulations to understand the bio-relevance of release media. An extreme vertices type of mixture design in Minitab®16 generated eleven formulations composed of poloxamer 407, poloxamer 188, and phosphate buffered saline (PBS). A quadratic equation adequately described the composition dependence of gelation temperature. Epidermal growth factor (EGF) and trypan blue were used as model drugs for proteins and small molecules, respectively. Cumulative release in PBS containing 30% sucrose exhibited linear correlation with respect to the gel compositions, while PBS without sucrose did not differentiate various compositions. Higher release rates in PBS than in sucrose media are attributable to the osmotic water flow from PBS into the donor phase, and subsequent increase in diffusivity. The time course of in vivo near-infrared fluorescence imaging of topical EGF gels on the wound sites were consistent with the in vitro release profiles measured with PBS as the release media. To the best of our knowledge, this is the first study to propose a release test method suitable for high throughput screening of topical formulations with emphasis on the osmotic pressure effect. Bio-relevant release media composition for a topical formulation would vary depending on its clinical application because the osmotic water flow through the normal skin would be negligible compared to compromised skin.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for
           identification of P-gp substrates
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Burak Ozgür, Lasse Saaby, Kristine Langthaler, Birger Brodin
      Recently, we transfected the porcine intestinal cell line IPEC-J2, with human P-glycoprotein (P-gp, ABCB1). The resulting cell line, iP-gp, has a high expression of functional human P-gp in the apical membrane, and a low expression of nonhuman ATP-binding cassette (ABC) transporters. The aim of the present work was to investigate the usability of iP-gp cell line for determining transepithelial transport kinetics of the prototypical P-gp substrates digoxin and rhodamine 123. The cell line generated tight monolayers after 16days of culture, reflected by high transepithelial electrical resistance values (TEER>15,000Ω·cm2), immunocytochemistry and low fluxes of the paracellular flux marker [14C]-mannitol. Monolayer integrity was not affected the common solvents dimethyl sulfoxide (DMSO), methanol and ethanol in concentrations up to 2% (v/v). Transepithelial fluxes of [3H]-labeled digoxin and rhodamine 123 were measured at varying donor concentrations, and kinetic parameters were estimated. Km and Vmax of P-gp mediated basolateral-to-apical (B-A) flux of rhodamine 123 were estimated to 332±124μM and 111±16pmol·cm−2·min−1 (n =3, total N =6), respectively. Vmax and Km of digoxin B-A flux could not be estimated due to the low aqueous solubility of digoxin. The half maximal inhibitory concentrations (IC50) of the selective P-gp inhibitor, zosuquidar (LY-335979), were estimated to 0.05±0.01μM (n =3, total N =6) and 0.04±0.01μM (n =3, total N =6) in transport experiments with digoxin and rhodamine 123 as substrates, respectively. Bidirectional fluxes of digoxin and rhodamine 123 were measured in transfected Madin Darby canine kidney cells (MDCK II MDR1) and compared with the fluxes obtained with the iP-gp cell monolayers. Efflux ratios were highest in the iP-gp cells, due to a tighter paracellular pathway. In conclusion, both digoxin and rhodamine 123 could be used to obtain IC50 values of inhibition, Ki values were only possible to obtain using rhodamine 123. The observed tightness, robustness towards solvents and the high efflux ratios confirmed that the iP-gp cell line may serve as a useful screening tool for investigations of substrate-P-gp interactions and modulation of P-gp function.

      PubDate: 2017-12-01T07:51:04Z
       
  • Stereoselective and domain-specific effects of ibuprofen on the thermal
           stability of human serum albumin
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Alexa Guglielmelli, Bruno Rizzuti, Rita Guzzi
      Ibuprofen is one of the most used anti-inflammatory drugs, and it is transported in the blood by human serum albumin, a major plasmatic protein with a peculiar adaptability in the binding of several different ligands. We have characterized the interaction between albumin and ibuprofen, either in racemic mixture, or in the S(+) and R(−) enantiomeric forms, by using differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, and molecular dynamics simulation. The results show that increasing concentrations of ibuprofen (up to sixfold drug/protein molar ratio) improve the protein resistance to thermal unfolding without altering the secondary structure. Deconvolution of the calorimetric thermal profiles at different albumin/ibuprofen molar ratios demonstrates a selective stability of the protein domains where the binding sites of the drug are localized. At the highest ibuprofen concentration, the melting temperature increased by about 10°C with respect to the drug-free protein, whereas the unfolding enthalpy maintains an almost constant value. Furthermore, the degree of protein stabilization depends upon the chirality of the drug, and the R(−) enantiomer is more effective compared to the S(+) form. The stability is supported by molecular dynamics simulations, showing that ibuprofen maintains a stable coordination in the most favorable binding sites, leading to a more compact protein structure at high temperature. The overall results attest that the binding of ibuprofen determines on albumin a stereoselective and domain-specific stabilization with a predominantly entropic character, contributing to clarify significant aspects of the molecular mechanism of protein/drug interaction.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Correlation between glucuronidation and covalent adducts formation with
           proteins of nonsteroidal anti-inflammatory drugs
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Hiroaki Shimada, Yuri Kobayashi, Sakiko Tanahashi, Atsushi Kawase, Taro Ogiso, Masahiro Iwaki
      Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause idiosyncratic liver injury. Mechanisms involved in NSAID-induced liver injury are complex. Previous studies have suggested that acyl glucuronide of NSAIDs (NSAIDs-Glu) plays an important role in the development of liver injury via covalently binds to proteins and the resultant adduct induces immunological toxicity. As only some NSAIDs-Glu are commercially available, the evaluation of covalent protein adduct formation using ready-made NSAIDs-Glu is difficult and inconvenient. Moreover, glucuronidation potency varies with the NSAID, including stereoisomers. Therefore, in this study, we simultaneously examined the glucuronidation and covalent adduct formation using enantiomers of parent NSAIDs (ibuprofen, naproxen, pranoprofen, ketoprofen, and flurbiprofen) in rat liver microsomes. Glucuronides and covalent adducts were quantified by HPLC. The amount of covalent adduct increased with NSAIDs-Glu formation in the rat liver microsomes in a time-dependent manner. A significant positive correlation was observed between the AUC of NSAIDs-Glu and that of covalent adduct, except ketoprofen. Although ketoprofen exhibited the highest glucuronidation rate among the NSAIDs investigated, the amount of covalent adduct was similar to that for pranoprofen, which had the lowest glucuronidation rate. Thus, it may be difficult for ketoprofen glucuronide to covalently bind with proteins in the rat liver microsomes. Our results suggested that the amount of glucuronide formed is a key factor in predicting covalent bond formation with protein in NSAIDs, in addition to degradability and bindability with proteins of NSAIDs-Glu. Further studies are required to confirm the relationship between the tendency of glucuronidation and the formation of covalent adducts of NSAIDs.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Impact of processing methods on the dissolution of artemether from two
           non-ordered mesoporous silicas
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Hira Tahir, Yasser Shahzad, Laura J. Waters, Talib Hussain, Abid Mehmood Yousaf, Tariq Mahmood, Rizwan Sheikh
      Poor aqueous solubility is often linked with a poor dissolution rate and ultimately, limited bioavailability of pharmaceutical compounds. This study describes the application of mesoporous materials (Syloid 244 and Syloid AL1) in improving the dissolution rate of a drug with poor aqueous solubility, namely artemether, utilising different processing methods including physical mixing, co-grinding and solid dispersions prepared by solvent evaporation and the lyophilisation technique. The prepared formulations were extensively characterised for their solid-state properties and the drug release attributes were studied. Differential scanning calorimetry and X-ray diffraction confirmed conversion of crystalline artemether into a disordered and amorphous form, whilst no intermolecular interactions were detected between artemether and silica. Both silica grades enhanced the dissolution rate of artemether in comparison with drug alone, for example from 17.43% (±0.87%) to 71.55% (±3.57%) after 120mins with lyophilisation and Syloid 244 at a 1:3 ratio. This enhancement was also dependant on the choice of processing method, for example, co-ground and lyophilised formulations prepared with Syloid 244 at 1:3 ratio produced the most extensive dissolution, thus endorsing the importance of materials as well as choice of formulation method.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Drug-excipient compatibility assessment of solid formulations containing
           meloxicam
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Lucas Melo da Silveira, Ariadne Botto Fiorot, Thiago Padovani Xavier, Maria Irene Yoshida, Marcelo Antonio de Oliveira
      Meloxicam (MLX) is a non-steroidal anti-inflammatory cyclooxygenase (COX) inhibitor that is used to relieve inflammation and pain. MLX has a preferential affinity for COX-2, which is associated with a lower incidence of gastrointestinal side effects. The drug belongs to Class II of the Biopharmaceutical Classification System (BCS) in which dissolution is the limiting step of its bioavailability. In view of this classification, carrying out further studies regarding the compatibility of MLX with excipients and the mechanisms and kinetics of its degradation reactions is fundamental because any changes would directly influence the quality of the product. The aim of the present work is to evaluate solid pharmaceutical formulations containing MLX found on the market to define the more suitable excipients to improve the stability of the pharmaceutical formulations. Thermal analysis techniques were used to characterize and evaluate the compatibility between the drug and the excipients present in the market formulations. In the evaluation of its solid-state kinetics, MLX raw material under inert conditions had a shelf life of approximately 6years. In the study of compatibility between the drug and excipients, MLX was found to be incompatible with magnesium stearate after DSC analysis under binary mixtures, which was confirmed by stress studies and chromatographic analyzes.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Circadian variations in the pharmacokinetics of capecitabine and its
           metabolites in rats
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Shinji Kobuchi, Yukiko Yazaki, Yukako Ito, Toshiyuki Sakaeda
      Capecitabine, an orally available prodrug of 5-fluorouracil, is widely used to treat patients with colorectal cancer. Although various studies have shown circadian variations in plasma 5-fluorouracil concentrations during long-term infusion, it is still unknown whether circadian variations also exist following administration of capecitabine. The present study aimed to investigate whether the pharmacokinetics of capecitabine and its metabolites, including 5-fluorouracil, vary according to administration time in rats. Rats were orally administered capecitabine (180mg/kg) at 07:00 (23h after light onset, HALO), 13:00 (5 HALO), or 19:00h (11 HALO). Plasma concentrations of capecitabine and its metabolites, such as 5′-deoxy-5-fluorocytidine (5′-DFCR), 5′-deoxy-5-fluorouridine (5′-DFUR), and 5-fluorouracil, were determined after capecitabine administration. The results showed that the t 1/2 and AUC 0–∞ values of 5-fluorouracil differed as a function of the dosing time of capecitabine. The maximum and minimum mean t 1/2 values of 5-fluorouracil were obtained when the drug was administered at 07:00h (23 HALO: 3.1±1.2h) and 13:00h (5 HALO: 1.5±0.6h), respectively. The AUC 0–∞ value of 5-fluorouracil at 07:00h (23 HALO: 533.9±195.7μmol∙h/L) was 1.8-fold higher than the value at 13:00h (5 HALO: 302.5±157.1μmol∙h/L). The clearance of 5-fluorouracil followed a cosine circadian curve, and the simulated population mean clearance was highest at rest times and lowest during active times in rats. The results for the plasma 5′-DFCR and 5′-DFUR levels indicated that circadian variations in the sequential metabolism of capecitabine to 5-fluorouracil would also affect plasma 5-fluorouracil levels following capecitabine administration. In conclusion, the pharmacokinetics of capecitabine and its metabolites, including 5-fluorouracil, varied according to time of dosing, suggesting that the capecitabine administration time is an important factor in achieving sufficient efficacy and reducing toxicity in patients.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Prediction of human CNS pharmacokinetics using a physiologically-based
           pharmacokinetic modeling approach
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Yumi Yamamoto, Pyry A. Välitalo, Yin Cheong Wong, Dymphy R. Huntjens, Johannes H. Proost, An Vermeulen, Walter Krauwinkel, Margot W. Beukers, Hannu Kokki, Merja Kokki, Meindert Danhof, Johan G.C. van Hasselt, Elizabeth C.M. de Lange
      Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Novel controlled ionic gelation strategy for chitosan nanoparticles
           preparation using TPP-β-CD inclusion complex
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Anjali Pant, Jeetendra Singh Negi
      The aim of this study was to develop a novel controlled ionic gelation strategy for chitosan nanoparticle preparation to avoid particle aggregation tendency associated with conventional ionic gelation process. In this study inclusion complexation behaviour of sodium tripolyphosphate (TPP) with beta cyclodextrin (β-CD) has been investigated. The TPP-β-CD inclusion complex was characterized by FT-IR, XRD and DSC techniques. The complexation behaviour was also investigated by molecular docking study. The results showed that the TPP molecule formed inclusion complex with β-CD. Further, TPP-β-CD inclusion complex was used to prepare chitosan nanoparticles. The chitosan nanoparticles based on TPP-β-CD inclusion complex had smaller size of 104.2nm±0.608, good PDI value of 0.346±0.016 and acceptable zeta potential of +27.33mV±0.416. The surface characteristics of chitosan nanoparticles were also observed with transmission electron microscopy. Results indicates that TPP-β-CD inclusion complex can be used for the formation of chitosan nanoparticles with smaller and more uniform particle size in comparison to conventional TPP based chitosan nanoparticles.
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      PubDate: 2017-12-01T07:51:04Z
       
  • Experimentally designed lyophilized dry emulsion tablets for enhancing the
           antihyperlipidemic activity of atorvastatin calcium: Preparation, in-vitro
           evaluation and in-vivo assessment
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Alaa H. Salama, Mona Basha, Sally El Awdan
      This article presents the development of lyophilized orally disintegrating tablets prepared with the dry emulsion technique to enhance the in-vitro dissolution and in-vivo performance of the poorly bioavailable drug atorvastatin calcium (ATV). Tablets were fabricated by freeze-drying o/w emulsions of ATV. The Emulsions were prepared using a matrix former solution (alginate or gelatin, 2 or 4%) containing a sugar alcohol (mannitol) and a collapse protectant (glycine) as the water phase and Labrafac® as the oil phase in the presence of surfactant (synperonic® PE/P 84 or synperonic® F108) under proper homogenization. The influence of formulation parameters on friability of the prepared tablets, disintegration time and in-vitro dissolution of the drug from these tablets were investigated. Results showed the significant influence of the matrix former and emulsifier type on the disintegration time. In-vitro dissolution study revealed the enhanced dissolution rate of ATV from the lyophilized dry emulsion tablets (LDET) compared to the plain drug. DSC and XRD studies of the optimized ATV-loaded LDET proved the presence of the drug in the amorphous form. SEM images showed the intact, porous and non-collapsible structure of the prepared LDET with complete loss of ATV crystallinity. Administration of ATV-loaded LDET to high fat diet-induced hyperlipidemic rats demonstrated a significant decrease (p <0.05) in the serum and tissue levels of the tested parameters compared to the market product used. The obtained results suggest a promising, easy-to-manufacture and effective dosage form for the treatment of hyperlipidemia.
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      PubDate: 2017-11-18T15:32:16Z
       
  • A novel double-layer mucoadhesive tablet containing probiotic strain for
           vaginal administration: Design, development and technological evaluation
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): María Teresa Sánchez, María Adolfina Ruiz, Herminia Castán, María Encarnación Morales
      Vulvovaginal candidosis caused by Candida spp. is the most prevalent vaginal infection in Europe and the second one in EE.UU, so it has become a major female concern. Probiotics bacteria have been proposed as an alternative treatment with the aim of avoiding the adverse effects associated with conventional therapies including antibiotics and other aggressive drugs for the vaginal mucosa and microbiota. The purpose of this work was to design and develop a novel vaginal tablet that contained Lactobacillus spp. bacteria as a treatment against vulvovaginal infections. A total of 21 two-layers vaginal tablets, which contained different polymeric ratios, were proposed. However, formulation F4 (20mg Na-CMC; 50mg Carbopol® 934; 20mg chitosan) was selected as optimal according to its swelling index and dissolution/erosion capability. F4 tablets showed suitable technological properties for vaginal administration as well as mucoadhesion time (24.36±0.88h) and force (0.0941N). Disintegration assay in simulated vaginal fluid (SVF, pH5.5) showed that effervescent layer disappeared in 27.48±0.05s whilst matrix layer was totally gelled in 1h. Two different release profiles were achieved; on the one hand, a promptly release due to the dissolution of both effervescent layer and matrix layer's surface (1.10×108 CFU/g), on the second hand, a prolonged released of the remaining bacteria until 24h (5.48×107 CFU/g). For stability and storage study, it was found that bacteria viability was constant until 90days in both ways of storage, in a desiccator and at room temperature, with a final dosage of 108 CFU/g which was considered appropriate for vaginal therapy (108–1010 CFU/g).
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      PubDate: 2017-11-18T15:32:16Z
       
  • Intracellular trafficking of a dynein-based nanoparticle designed for gene
           delivery
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Marianna Teixeira de Pinho Favaro, Ugutz Unzueta, Martí de Cabo, Antonio Villaverde, Neus Ferrer-Miralles, Adriano Rodrigues Azzoni
      The success of viruses in the delivery of the viral genome to target cells relies on the evolutionary selection of protein-based domains able to hijack the intermolecular interactions through which cells respond to intra- and extracellular stimuli. In an effort to mimic viral infection capabilities during non-viral gene delivery, a modular recombinant protein named T-Rp3 was recently developed, containing a DNA binding domain, a dynein molecular motor interacting domain, and a TAT-derived transduction domain. Here, we analyzed at the microscopic level the mechanisms behind the cell internalization and intracellular trafficking of this highly efficient modular protein vector. We found that the protein has the ability to self-assemble in discrete protein nanoparticles resembling viral capsids, to bind and condense plasmid DNA (pDNA), and to interact with eukaryotic cell membranes. Confocal and single particle tracking assays performed on living HeLa cells revealed that the T-Rp3 nanoparticles promoted an impressive speed of cellular uptake and perinuclear accumulation. Finally, the protein demonstrated to be a versatile vector, delivering siRNA at efficiencies comparable to Lipofectamine™. These results demonstrate the high potential of recombinant modular proteins with merging biological functions to fulfill several requirements needed to obtain cost-effective non-viral vectors for gene-based therapies.
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      PubDate: 2017-11-18T15:32:16Z
       
  • Milk from transgenic goat expressing human lysozyme for recovery and
           treatment of gastrointestinal pathogens
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Igor de Sá Carneiro, José Nilson Rodrigues de Menezes, Julyana Almeida Maia, André Marrocos Miranda, Victor Bruno Soares de Oliveira, James D. Murray, Elizabeth A. Maga, Marcelo Bertolini, Luciana Relly Bertolini
      Lysozyme is an important non-specific immune protein in human milk, modulating the immune response against bacterial infections. The aim of this study was to characterize the milk of a transgenic goat expressing a recombinant human lysozyme (rhLZ) in the milk, also testing the in vitro antibacterial activity of the rhLZ milk against pathogens of the gastrointestinal tract. Milk samples collected from Tg and non-transgenic goats (nTg) from the 3rd to the 11th week of lactation were submitted to physicochemical analyses, rhLZ semi-quantification, and to rhLZ antimicrobial activity against Micrococcus luteus, Shiguella sonnei and Enterococcus faecalis. Viability and cell migration were studied in ileum epithelial cells (IEC-18) in absence or presence of E. faecalis, Staphylococcus aureus, Escherichia coli (EPEC) and S. sonnei. The expression of ZO-1 and IL-6 genes was evaluated in IEC-18 to evaluate the effect of rhLZ milk on intestinal barrier function and intestinal inflammation. Physicochemical parameters between goat Tg and nTg milk were similar and within normal values for human consumption, with hLZ concentrations being similar between Tg (224μg/mL) and human (226μg/mL) milk. The Tg milk had bactericidal activity against M. luteus, no bactericidal effect on S. sonnei, and relative to discrete sensitivity against E. feacalis than controls. Better migrating parameters were observed in cells in culture with nTg and Tg than controls. In the presence of pathogens, the Tg milk promoted improved migrating parameters than controls, except for S. sonnei, with lower cell numbers in the presence of nTg samples and E. faecalis and S. sonnei. No differences in ZO-1 relative expression patterns were observed in cultured cells, with increased expression in IL-6 in cells exposed to nTg milk than controls, with the Tg group being similar to all groups. In conclusion, goat milk containing rhLZ demonstrated valid evidence for its potential use as a nutraceutical for improvement of health and nutrition quality in humans.
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      PubDate: 2017-11-18T15:32:16Z
       
  • Novel mixed vesicles containing lactobacilli biosurfactant for vaginal
           delivery of an anti-Candida agent
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Angela Abruzzo, Barbara Giordani, Carola Parolin, Beatrice Vitali, Michele Protti, Laura Mercolini, Martina Cappelletti, Stefano Fedi, Federica Bigucci, Teresa Cerchiara, Barbara Luppi
      The purpose of this work was to prepare and characterize an innovative formulation for vaginal delivery of econazole nitrate, commonly used for the treatment of Candida infections. A novel biosurfactant isolated from a vaginal Lactobacillus strain was used to prepare phosphatidylcholine based mixed vesicles. Biosurfactant was produced by Lactobacillus gasseri BC9, isolated from the vagina of a healthy premenopausal woman, and was chemically characterized by FT-IR and ESI-MS. Mixed vesicles, obtained through film rehydration and extrusion method, were characterized in terms of size, zeta potential, encapsulation efficiency, mucoadhesion properties and econazole release. Moreover, the antimicrobial activity of the mixed vesicles was tested towards both planktonic cultures and biofilms of Candida albicans. Biosurfactant produced by L. gasseri BC9 was composed by peptide-like molecules containing hydrocarbon chains and possessed a high surface activity together with a low critical micelle concentration. All the mixed vesicles presented optimal diameter range (226–337nm) for topical vaginal administration. Econazole-loaded mixed vesicles containing biosurfactant showed higher encapsulation efficiency and mucoadhesion ability with respect to vesicles containing Tween 80. Further, they allowed a sustained release of econazole nitrate, maintaining the antifungal activity against C. albicans planktonic culture. Notably, biosurfactant-based vesicles were significantly more active than free econazole in the eradication of Candida biofilm. In conclusion, mixed vesicles are promising new vaginal delivery systems for the potential employment in the treatment of chronic infections.
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      PubDate: 2017-11-18T15:32:16Z
       
  • Editorial board members
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111


      PubDate: 2017-11-18T15:32:16Z
       
  • Renal organic anion transporters in drug–drug interactions and
           diseases
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Xiaokui Huo, Kexin Liu
      The kidney plays a vital role in maintaining systemic homeostasis. Active tubular secretion and reabsorption, which are mainly mediated by transporters, is an efficient mechanism for retaining glucose, amino acids, and other nutrients and for the clearance of endogenous waste products and xenobiotics. These substances are recognized by uptake transporters located in the basolateral and apical membranes of renal proximal tubule cells and are extracted from plasma and urine. Organic anion transporters (OATs) belong to the solute carrier (SLC) 22 superfamily and facilitate organic anions across the plasma membranes of renal proximal tubule cells. OATs are responsible for the transmembrane transport of anionic and zwitterionic organic molecules, including endogenous substances and many drugs. The alteration in OAT expression and function caused by diseases, drug–drug interactions (DDIs) or other issues can thus change the renal disposition of substrates, induce the accumulation of toxic metabolites, and lead to unexpected clinically outcome. This review summarizes the recent information regarding the expression, regulation, and substrate spectrum of OATs and discusses the roles of OATs in diseases and DDIs. These findings will enables us to have a better understanding of the related disease therapy and the potential risk of DDIs mediated by OATs.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Chlorhexidine sustained-release varnishes for catheter coating –
           Dissolution kinetics and antibiofilm properties
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Julia Gefter (Shenderovich), Batya Zaks, David Kirmayer, Eran Lavy, Doron Steinberg, Michael Friedman
      Catheter-associated urinary tract infections are difficult to eradicate or prevent, due to their biofilm-related nature. Chlorhexidine, a widely used antiseptic, was previously found to be effective against catheter-related biofilms. For the present study, we developed sustained-release chlorhexidine varnishes for catheter coating and evaluated their antibiofilm properties and chlorhexidine-dissolution kinetics under various conditions. The varnishes were based on ethylcellulose or ammonio methacrylate copolymer type A (Eudragit® RL). Chlorhexidine was released by diffusion from a heterogeneous matrix in the case of the ethylcellulose-based formulation, and from a homogeneous matrix in the case of Eudragit® RL. This dictated the release pattern of chlorhexidine under testing conditions: from film specimens, and from coated catheters in a static or flow-through system. Momentary saturation was observed with the flow-through system in Eudragit® RL-based coatings, an effect that might be present in vivo with other formulations as well. The coatings were retained on the catheters for at least 2weeks, and showed prolonged activity in a biological medium, including an antibiofilm effect against Pseudomonas aeruginosa. The current study demonstrates the potential of catheter coatings with sustained release of chlorhexidine in the prevention of catheter-associated urinary tract infections.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Electrically controlled release of ibuprofen from conductive
           poly(3-methoxydiphenylamine)/crosslinked pectin hydrogel
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Sirivipa Mongkolkitikul, Nophawan Paradee, Anuvat Sirivat
      The pristine pectin hydrogels and conductive polymer/hydrogel blends were prepared by the solution casting using ferrous chloride (FeCl2) and citric acid as the crosslinking agents, and ibuprofen as the model drug and the doping agent. A conductive polymer, poly(3-methoxydiphenylamine), was successfully synthesized and embedded into the pristine pectin hydrogels as the drug encapsulation host. The in-vitro release of ibuprofen from the hydrogels was investigated by a modified Franz diffusion cell filled with a MES buffer solution, with pH of 5.5, at 37°C, for a period of 48h to investigate the effects of the crosslinking agent type, crosslinking mole ratio, mesh size, electric potential, and conductive polymer. The release behavior of ibuprofen from the pectin hydrogels was found to involve 4 modes of release: Fickian diffusion; Anomalous transport; Case-II transport; and Super case II transport. The diffusion coefficient was shown to be significantly improved by two factors: using a FeCl2 as the crosslinking agent and applied electric potential. For both crosslinking agents, the drug diffusion coefficient increased with decreasing crosslinking ratio. Under electric field of 5V, the drug diffusion coefficients of the FeCl2 and citric acid hydrogels were enhanced by more than a factor of two due to the electro-repulsive interaction between ibuprofen and the negatively charged electrode. Moreover, the synthesized poly(3-methoxydiphenylamine) embedded in the pectin hydrogels as the drug encapsulation host was shown to enhance the diffusion coefficients and to reduce the overall release times.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Development of PLGA nanoparticles loaded with clofazimine for oral
           
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Luíse L. Chaves, Sofia A. Costa Lima, Alexandre C.C. Vieira, Luísa Barreiros, Marcela A. Segundo, Domingos Ferreira, Bruno Sarmento, Salette Reis
      The use of polymeric nanoparticles as delivery systems is a promising tool to overcome drawbacks related to low aqueous solubility of drugs, which limit their in vivo bioavailability. The aim of this study was to decrease clofazimine (CLZ) toxicity using experimental design to formulate CLZ loaded in PLGA nanoparticles (NPs-CLZ) through a Plackett–Burman design (PBD). A screening PBD was constructed with twelve formulations involving six variables among process and formulation parameters and the selected responses were particle size, polydispersity index (PDI), association efficiency (AE) and drug loading (DL). The formulation was achieved based on the desirability tool, and the obtained NPs-CLZ formulation was characterized regarding morphology, physicochemical properties, in vitro release and cellular studies. Particle size, PDI, AE and DL were found to be 211±3nm, 0.211±0.009, 70±5% and 12±1%, respectively. Physicochemical studies confirmed the absence of chemical interactions between CLZ and other nanoparticles constituents and the amorphous state of CLZ, while morphological analysis revealed the spherical shape of the particles. In vitro release profile of CLZ from NPs-PLGA showed a slow pattern of drug release. Cell viability studies towards intestinal cells revealed that NPs-CLZ did not show CLZ toxicity on Caco-2 and HT29-MTX cells compared to free CLZ solutions. Moreover, CLZ could permeate Caco-2 monolayers substantially at the end of 8h. It can be concluded that the proposed NPs-CLZ represent a promising platform to the oral delivery of CLZ as they were able to decrease its intrinsic toxicity, with improved absorption.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Experimental optimization of Lornoxicam liposomes for sustained topical
           delivery
    • Abstract: Publication date: 15 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 112
      Author(s): Joshny Joseph, Vedha Hari B.N., Ramya Devi D.
      The purpose of the present investigation is to formulate liposomes of Lornoxicam for topical delivery using Central Composite Design, to provide a sustained release of the drug and thereby extend its elimination half-life. Liposomes were prepared by thin film hydration method with pH induced vesiculation. The liposomes were assessed for their particle size, charge, morphology and drug entrapment and characterized using TGA-DSC and FTIR analysis, to assess the interaction between the drug and excipients. The in vitro release study was performed using modified USP dissolution apparatus-I using three different dissolution media and the ex vivo release study was performed using goat skin. The cytotoxicity of Lornoxicam liposomes were studied on NIH 3T3 cells by MTT assay. The optimized formulation with particle size ranging from 100–200nm provided sustained release for 8h. The characterization studies proved very less interactions between the drug and the excipients. The ex vivo studies showed flux value of 23.29μg/cm2/h and Kp 0.011645cm/h. The cytotoxicity study showed increase in toxicity with increase in concentration more than 0.5μg/mL. The in vivo skin toxicity studies and histopathology analysis showed absence of toxic lesions, which confirmed the suitability of the formulation for topical application. Lornoxicam liposomes with good skin permeation and sustained release of drug were finally optimized by the experimental design.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Current strategies to streamline pharmacotherapy for older adults
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): Jan-F. Schlender, Valvanera Vozmediano, Adam G. Golden, Monica Rodriguez, Tanay S. Samant, Chakradhar V. Lagishetty, Thomas Eissing, Stephan Schmidt
      Although the term “personalized medicine” has been associated in many cases with pharmacogenomics, its definition embraces the use of specific biomarkers and covariates to help in the selection of medical treatments and procedures which are best for each patient. While several efforts have been performed for the tailored selection of therapies and dosing regimens in the general population, developing personalized medicine initiatives for elderly patients remains understudied. The personalized drug therapy for older patients requires the consideration of anatomical, physiological and functional alterations in a multimorbid setting requiring multiple medications. The present review focuses on currently employed qualitative and quantitative precision medicine approaches for elderly patients and discusses some of the associated challenges and limitations. Furthermore, the use of and confidence in physiologically-based approaches for optimal dose selection in this understudied yet clinically important patient population will be highlighted and discussed.
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      PubDate: 2017-11-11T19:52:20Z
       
  • Implementing the additional strength biowaiver for generics: EMA
           recommended approaches and challenges for a US-FDA submission
    • Abstract: Publication date: 1 January 2018
      Source:European Journal of Pharmaceutical Sciences, Volume 111
      Author(s): J.-M. Cardot, A. Garcia-Arieta, P. Paixao, I. Tasevska, B. Davit
      This review describes the EMA requirements on biowaivers for additional strengths of immediate release and modified release oral solid dosage forms focused on generic applications and highlights the challenges for a simultaneous EMA and FDA submission. Some specificities of the current EMA guidelines are compared with the current FDA Guidance for Industry, with a special focus on the strength to be investigated in vivo, formulation suitability for biowaiver, and optimizing dissolution studies for additional strength biowaivers. In Europe, the same principles applied for generics may be considered for deriving the biowaivers for innovator products. Several case studies are presented to illustrate the challenges of applying for additional strength biowaivers in EMA and FDA simultaneously.
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      PubDate: 2017-10-28T15:38:04Z
       
  • 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
       
  • 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
       
  • 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.
      Graphical abstract image

      PubDate: 2017-09-23T23:08:02Z
       
 
 
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