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European Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 1.016
Citation Impact (citeScore): 4
Number of Followers: 170  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0928-0987
Published by Elsevier Homepage  [3184 journals]
  • The effects of scopolamine on the survival time and microcirculation of
           septic shock rats
    • Abstract: Publication date: Available online 13 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Linlin Song, Rai Chu, Zhongping CaoIntroductionShock has been established as a disorder of the microcirculation. Despite various treatments, the mortality rate of infectious shocks remains 30–50%. The study was designed to explore the effects of scopolamine on the survival time, microcirculation and inflammatory cytokine secretion in rats with septic shock.MethodsSD rats were randomly divided into seven groups: a sham group, a control group, a saline group and four scopolamine group. The rat septic shock model was induced by cecal ligation, perforation and drainage, while the operation in the sham group involved opening and closing the abdominal cavity. The survival time was recorded to determine a suitable dose for the subsequent experiments. The microcirculation of the terminal ileum was observed. The concentrations of IL-10, IL-6 and TNF-α in the plasma and lungs were detected by ELISA, and the wet-dry ratio of the lung was calculated.ResultsCompared to the control and saline group, the septic shock rats treated in the scopolamine group had a longer survival time, a lower reduction in arteriolar blood flow, and a decreased change in the average diameter of arterioles and venules. The rat wet–dry lung ratio was less in the sham, control and scopolamine groups compared to the saline group. The plasma and lung cytokine concentrations of the rats belonging to the scopolamine group were less than those of the control and saline groups; however, all of the cytokine concentrations were higher than those of the sham group.ConclusionsScopolamine reduced the plasma and lung concentrations of specific cytokines, improved the function of the microcirculation and prolonged the survival time of rats with septic shock.Graphical abstractUnlabelled Image
       
  • Investigation on vitamin E succinate based intelligent hyaluronic acid
           
    • Abstract: Publication date: Available online 13 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Lin Hou, Chunyu Tian, Dandan Chen, Yujie Yuan, Yingshan Yan, Qianxiao Huang, Huijuan Zhang, Zhenzhong ZhangMultidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.Graphical abstractHyaluronic acid modified vitamin E succinate micelles through redox-sensitive linkage are developed into intelligent vehicles to carry anticancer drug and overcome multidrug resistance.Unlabelled Image
       
  • PEGylated lipid bilayer coated mesoporous silica nanoparticles co-delivery
           of paclitaxel and curcumin leads to increased tumor site drug accumulation
           and reduced tumor burden
    • Abstract: Publication date: Available online 10 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Jiafeng Gao, Kai Fan, Yipeng Jin, Linna Zhao, Qian Wang, Yinian Tang, Huihao Xu, Zhongjie Liu, Shuaiyu Wang, Jiahao Lin, Degui LinHomogeneous PEGylated lipid bilayer coated highly ordered MSNs (PLMSNs) which were systematically optimized and characterized to co-encapsulate paclitaxel (Tax) and curcumin (Cur) were verified to manifest prolonged and enhanced cytotoxic effect against canine breast cancer cells in our previous study. In this article, we took further study of the pharmacokinetic property, cellular uptake, subcellular localization, in vivo distribution and tumor accumulation ability, and treatment efficacy of the drug delivery system. The results revealed that the delivery system could significantly increase the AUC of two drugs, and the anti-tumor effect showed that both intravenous and intratumoral administration group better controlled the tumor weight than that of other groups (P 
       
  • I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in
           vitro and in vivo
    • Abstract: Publication date: Available online 10 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Panli Jia, Yao Wu, Hongzhi Du, Lijun Yang, Zhibo Zhang, Tianfang Ma, Li Sun, Shengtao Yuan, Ligong Lu, Xiaoming ZhaIsocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clinical potential in tumor therapies as a effective mutant IDH1 inhibitor, and provided scientific guidance for the development of mutant IDH1 inhibitor in the future.Graphical abstractUnlabelled Image
       
  • Using mechanistic physiologically-based pharmacokinetic models to assess
           prenatal drug exposure: Thalidomide versus efavirenz as case studies
    • Abstract: Publication date: Available online 10 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Shakir Adeyinka Atoyebi, Rajith K.R. Rajoli, Ebunoluwa Adejuyigbe, Andrew Owen, Oluseye Bolaji, Marco Siccardi, Adeniyi OlagunjuMaternofoetal physiologically-based pharmacokinetic models integrating multi-compartmental maternal and foetal units were developed using Simbiology® to estimate prenatal drug exposure. Processes governing drug disposition were described using differential equations with key system and drug-specific parameters. Transplacental drug transfer was modelled as bidirectional passive diffusion and benchmarked against those for thalidomide as a control. Model-predictions for pharmacokinetic parameters during pregnancy were within acceptable ranges for qualification (two-fold difference of clinically-observed values). Predicted foetal exposure to thalidomide was higher than efavirenz, with median (range) foetal-to-maternal plasma ratios of 4.55 (3.06–9.57) for 400 mg thalidomide versus 0.89 (0.73–1.05) for 400 mg efavirenz at third trimester. Model-predictions indicated foetal exposure consistently above 300% of maternal plasma concentration for thalidomide throughout pregnancy, while exposure to efavirenz increased from under 20% at second trimester to above 100% at third trimester. Further qualification of this approach as a tool in evaluating drug exposure and safety during pregnancy is warranted.Graphical abstractUnlabelled Image
       
  • End-point modification of recombinant thrombomodulin with enhanced
           stability and anticoagulant activity
    • Abstract: Publication date: Available online 9 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Xia Liu, Mallorie Boron, Yu Zhao, Xue-Long SunThrombomodulin (TM) is an endothelial cell membrane protein that plays essential roles in controlling vascular haemostatic balance. The 4, 5, 6 EGF-like domain of TM (TM456) has cofactor activity for thrombin binding and subsequently protein C activation. Therefore, recombinant TM456 is a promising anticoagulant candidate but has a very short half-life. Ligation of poly (ethylene glycol) to a bioactive protein (PEGylation) is a practical choice to improve stability, extend circulating life, and reduce immunogenicity of the protein. Site-specific PEGylation is preferred as it could avoid the loss of protein activity resulting from nonspecific modification. We report herein two site-specific PEGylation strategies, enzymatic ligation and copper-free click chemistry (CFCC), for rTM456 modification. Recombinant TM456 with a C-terminal LPETG tag (rTM456-LPETG) was expressed in Escherichia coli for its end-point modification with NH2-diglycine-PEG5000-OMe via Sortase A-mediated ligation (SML). Similarly, an azide functionality was easily introduced at the C-terminus of rTM456-LPETG via SML with NH2-diglycine-PEG3-azide, which facilitates a site-specific PEGylation of rTM456 via CFCC. Both PEGylated rTM456 conjugates retained protein C activation activity as that of rTM456. Also, they were more stable than rTM456 in Trypsin digestion assay. Further, both PEGylated rTM456 conjugates showed a concentration-dependent prolongation of thrombin clotting time (TCT) compared to non-modified protein, which confirms the effectiveness of these two site-specific PEGylation schemes.Graphical abstractUnlabelled Image
       
  • Design and characterization of a novel 3D printed pressure-controlled drug
           delivery system
    • Abstract: Publication date: Available online 6 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Julius Krause, Malte Bogdahn, Felix Schneider, Mirko Koziolek, Werner WeitschiesThe aim of the present work was to explore the feasibility of 3D printing via fused deposition modeling (FDM) in the manufacturing of a pressure-controlled drug delivery system. Eudragit® RS, a brittle polymer with pH-independent solubility, was chosen to be a suitable excipient for the 3D printing of a pressure-sensitive, capsule-like dosage form. A self-constructed piston extruder was used for hot melt extrusion (HME) of filaments made from Eudragit® RS that could be used for 3D printing. Subsequently, the printing parameters were experimentally optimized with the aid of a self-programmed software. This G-code generator allowed the simple adjustment of printing speed, temperature, extrusion multiplier and layer height. By this, capsule-shaped dosage forms with the desired mechanical properties could be obtained. The effect of physiological pressure events on the drug release behaviour from the novel dosage form was finally tested by using a biorelevant stress test device. These in vitro experiments demonstrated the rapid and quantitative release of the probe drug after applying realistic pressure events. This work illustrated that 3D printing can be an interesting technique for the production of pressure-controlled dosage forms as a new concept of oral drug delivery.Graphical abstractUnlabelled Image
       
  • Efficacy of instillation treatment with hyaluronic acid in relieving
           symptoms in patients with BPS/IC and uncomplicated recurrent urinary tract
           infections - Long-term results of a multicenter study
    • Abstract: Publication date: Available online 6 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ioan Scarneciu, Simona Bungau, Aura-Mihaela Lupu, Camelia C. Scarneciu, Ovidiu Gabriel Bratu, Orsolya Martha, Delia Mirela Tit, Lotfi Aleya, Sorin LupuAbstractThe purpose of this study is to evaluate the efficacy of intra-vesical instillations with hyaluronic acid (HA) in relieving lower urinary tract irritation symptoms in patients with urinary tract infections (UTIs) and bladder pain syndrome/interstitial cystitis (BPS/IC). This research, conducted in Romania, includes 30 patients with UTIs (Group I) and 24 with BPS/IC (Group II) as defined by European Association of Urology (EAU) Diagnostic Criteria. Data were collected prospectively, using pre- and post-treatment questionnaires for pelvic pain with a symptom scale for urination and frequency as well as visual analog scale (VAS) pain quizzes. At follow-up visits, at an average of 20 months, a significant improvement in urinary bladder pain, day-time urinary frequency and quality of life was observed in Group I patients. Group II patients experienced significant improvement in urinary bladder pain, urgency, nocturia and quality of life at the 15-month follow-up visit. Eighteen patients (75%) showed a complete response to intravesical HA instillations and required no further treatment. Our study demonstrates that intravesical HA instillations may be considered as an important treatment component, with long term positive effects in therapeutic strategy for optimal results in uncomplicated recurrent UTIs and BPS/IC, with good compliance and minimal side effects.
       
  • Impact of drug particle shape on permeability and cellular uptake in the
           lung
    • Abstract: Publication date: Available online 4 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): S. Zellnitz, L. Zellnitz, M.T. Müller, Meindl Claudia, H. Schröttner, E. FröhlichThe generation of inhalable sized particles (1–5 μm) usually involves a particle-processing step; most commonly milling but spray drying has shown to be a suitable alternative. Besides particle size, processing may affect other particle properties, like shape and solid-state. For example, spray drying of salbutamol sulphate leads to spherical shaped predominantly amorphous particles whereas jet milling frequently maintains the irregular shape and the crystallinity of the raw material. The aim of the present study was to investigate whether particle properties, especially shape, change the biological action of the inhaled particles as well. Therefore, high water soluble salbutamol sulphate and low water soluble budesonide were compared regarding dissolution, permeation and preferential uptake by epithelial cells compared to macrophages after jet milling and spray drying.For both drugs the spray dried, predominantly amorphous, particles resulted in lower respirable fractions, but higher permeability and cell uptake rates compared to the needle shaped, predominantly crystalline particles. The distinct particle properties did not affect the dissolution behaviour of salbutamol sulphate. In turn for drugs with lower solubility (budesonide), spray dried particles dissolved slower compared to jet milled particles. Preferential uptake by macrophages was higher for spray dried particles, suggesting that processing may improve targeted delivery. The comparison between murine cell lines and human monocyte derived macrophages primary cells showed similar trends in rate and preference of particle uptake.Graphical abstractUnlabelled Image
       
  • Enhanced dissolution and oral bioavailability of praziquantel by
           emulsification with human serum albumin followed by spray drying
    • Abstract: Publication date: Available online 3 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Keishi Yamasaki, Kazuaki Taguchi, Koji Nishi, Masaki Otagiri, Hakaru SeoThe goal of this study was to enhance the oral bioavailability of praziquantel through its conjugation with human serum albumin (HSA). Praziquantel-HSA particles were produced by spray drying an emulsion of an aqueous solution of HSA and a solution of praziquantel in oil. The particles were agglomerates of multiple smooth corrugated particles containing amorphous praziquantel nearly equivalent to the theoretical doses. The solubility of praziquantel in an aqueous medium was enhanced in both the produced particles and the physical mixture. In addition, the dissolution rate in an aqueous medium was enhanced in the case of particles, but not in a physical mixture. Thus, the inclusion of HSA by emulsification followed by spray drying appeared to contribute to the enhanced dissolution rate. In a pharmacokinetic study, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) for the produced particles (HSA/praziquantel = 1/1 w/w) were approximately two times higher than the corresponding values for raw praziquantel. This increased oral bioavailability of the particles was considered to be due to the enhanced dissolution rate. This process for producing praziquantel-HSA particles could be useful in terms of improving the oral bioavailability of the other hydrophobic drugs.Graphical abstractUnlabelled Image
       
  • Comparison of PEGylated and non-PEGylated proticles: An in vitro
           and in vivo study
    • Abstract: Publication date: Available online 2 September 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Katja Fresacher, Anna Helbok, Martin Reiser, Sandra Blass, Christine Rangger, Christian Mair, Elisabeth von Guggenberg, Clemens Decristoforo, Fritz Andreae, Andreas ZimmerThe development of so-called Proticles opens attractive possibilities for new drug delivery systems. Proticles are nanoparticles (NPs), which are formed by self-assembly of negatively charged oligonucleotides in combination with the positively charged peptide protamine. Polyethylene glycol (PEG) is a widely known pharmaceutical agent to stop particle growth and prolong circulation half-life of drug delivery systems. Therefore, two different NP formulations – one PEGylated and one non-PEGylated – were used in this work to gain information about the biological stability and half-life in circulation of Proticles. Thus, this study presents data of in vitro stability and in vivo pharmacokinetics of both, non-PEGylated and PEGylated Proticles radiolabeled with 111InCl3. The study demonstrated that successful radiolabeling of both Proticle-formulations was performed resulting in high radiochemical yields (> 85%). Furthermore, the influence of PEGylation on the in vitro stability of 111In-radiolabeled NPs was investigated. No significant difference due to PEGylation was found. Unlike in vitro results, non-PEGylated 111In-Proticles seemed to degrade faster in vivo than PEGylated 111In-proticles, resulting in significantly higher blood values (111In-PEG-proticles: 0.23 ± 0.01% ID/g 1 h p.i.; 111In-proticles: 0.06 ± 0.01% ID/g 1 h p.i.; p 
       
  • Assessing pharmacokinetic differences in Caucasian and East Asian
           (Japanese, Chinese and Korean) populations driven by CYP2C19 polymorphism
           using physiologically-based pharmacokinetic modelling
    • Abstract: Publication date: Available online 31 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Li Zhou, Pradeep Sharma, Karen Rowland Yeo, Mitsuo Higashimori, Hongmei Xu, Nidal Al-Huniti, Diansong ZhouUnderstanding the influence of ethnicity on drug exposure is key to patient safety and could minimize repetitive clinical studies. This analysis aimed to evaluate the ability of physiologically-based pharmacokinetic modelling to predict exposure of CYP2C19 substrates (lansoprazole, (es)citalopram, voriconazole) across Caucasian and East Asian populations. CYP2C19 abundance levels in Japanese and Chinese populations have been re-assessed based on clinical evidence. Model performance in each population was evaluated by predicted-over-observed AUC ratios and comparison of observed data with simulated plasma concentration profiles. Exposures in 84.4% (76 out of 90) of the clinical studies were predicted within 1.5-fold of observed values. The reported concentration-time profiles were well-captured within the 90% prediction intervals. With specified CYP2C19 phenotype, PBPK modelling is capable to predict systemic exposure of drugs largely metabolized by CYP2C19 in different ethnic populations. This study demonstrated PBPK modelling can be applied to assess genotype-dependent exposure difference across ethnicities.Graphical abstractUnlabelled Image
       
  • Design, synthesis and evaluation of halogenated furanone derivatives as
           quorum sensing inhibitors in Pseudomonas aeruginosa
    • Abstract: Publication date: Available online 28 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Yiqun Chang, Peng-Cheng Wang, Hong-Ming Ma, Si-Yu Chen, Yu-Hang Fu, Yuan-Yuan Liu, Xuan Wang, Guang-Chao Yu, Tao Huang, David E. Hibbs, Hai-Bo Zhou, Wei-Min Chen, Jing Lin, Chao Wang, Jun-Xia Zheng, Ping-Hua SunThe biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) is regulated by a phenomenon of quorum sensing (QS). With 5-hydroxyl-3,4-halogenated-5H-furan-2-ones as beginning, analogs bearing alkyl chains, vinyl bromide, or aromatic rings were designed and synthesized. The minimum inhibitory concentration (MIC) of the compounds against P. aeruginosa was assayed and the biofilm inhibition ratio was determined at different concentrations lower than the MIC. C-5 aromatic substituted furanones showed remarkable biofilm formation as well as inhibition of virulence factor production in P. aeruginosa. Fluorescence report analysis identified the QS regulatory mechanism of the most active compound 29. This study provides us a novel candidate for combating drug resistant bacteria strains by merely inhibiting biofilm formation. Without suppressing the regular life cycle of the bacteria, bacterial resistance mechanisms may not be activated.Graphical abstractUnlabelled Image
       
  • Real-life budesonide and formoterol dose emission from the medium and high
           strength fixed dosed combinations in a Spiromax┬« dry powder inhaler using
           inhalation profiles from patients with chronic obstructive pulmonary
           disease
    • Abstract: Publication date: Available online 28 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Golshan Bagherisadeghi, Henry Chrystyn, Mohamad Abadelah, El Hassane LarhribDry powder inhalers (DPIs) are passive devices used to administer inhaled medication for the management of asthma and chronic obstructive pulmonary disease (COPD). DPIs require patients to generate a sufficient internal turbulent airflow force during each inhalation to deaggregate the powdered drug formulation into an emitted dose containing particles with the greatest likelihood of lung deposition. This internal force is generated by the interaction between the user's inhalation flow and the resistance of the DPI. Traditional compendial in vitro methods of measuring dose emission use a vacuum pump to simulate inhalation. We have adapted this in vitro method by replacing the square wave inhalation profile generated by a vacuum pump with the inhalation profiles of patients using an empty DPI. This method enables accurate assessment of the actual dose they would have inhaled. In the present study, real-life inhalation profiles were selected from 15 patients with COPD who inhaled through an empty placebo Spiromax® DPI. Ex vivo dose emissions were measured for the medium (emitted dose of 160 μg/4.5 μg) and high-strength (320 μg/9 μg) budesonide/formoterol formulations from the Spiromax DPI. These profiles were used to investigate the effect of the primary inhalation parameter—peak inhalation flow (PIF). Some profiles were modified to isolate other inhalation parameters (namely, inhaled volume [Vin] and acceleration rate of the inhalation maneuver [ACIM]). Both the medium-strength and high-strength DuoResp Spiromax displayed flow-dependent dose emission. When the PIF of a patient's inhalation maneuver increased from 26.8 L/min to 69.7 L/min, there was a significant (p 
       
  • The physical stability of drugs linked to quality-by-design (QbD) and
           in-process technology (PAT) perspectives
    • Abstract: Publication date: Available online 27 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Marique Aucamp, Marnus MilneThe physical stability of solid-state forms in which drugs may exist is in some sense an overlooked aspect. In an era where strategies such as amorphous solid dispersions or co-amorphous preparations might provide answers to stumbling blocks such as poor drug solubility and bioavailability, the physical stability of such solid-state preparations should be a priority. Furthermore, the pharmaceutical industry is moving towards adapting a real time release of pharmaceutical products strategy, through the utilization of process analytical technology. It is thus becoming imperative to investigate the various types phase transformations specific solid-state of a drug may undergo. Also to critically assess the applicability of process analytical tools that may be sensitive enough to monitor not only chemical but also physical drug stability. These combined efforts allow quality to be built into the product, rather than dealing with costly post batch release recalls. Given that drug stability is an essential quality attribute for a drug product and the quality by design approach (QbD) is a best solution to build quality in all pharmaceutical products we focussed on the critical material attributes (CMAs), specifically relating to the physical stability of any given drug. This review highlights physical drug stability in relation to CMAs and how this ultimately link to the finished pharmaceutical product. Investigated challenges associated current PAT strategies were also discussed.Graphical abstractUnlabelled Image
       
  • Combination of cyclodextrin complexation and iontophoresis as a promising
           strategy for the cutaneous delivery of aluminum-chloride phthalocyanine in
           photodynamic therapy
    • Abstract: Publication date: Available online 22 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Thaiene A. Reis, Ana Elise Jaculi, Khellida L.V. Ramos, Paulo Eduardo N. Souza, Fabiane H. Veiga-Souza, Graziela A. Joanitti, Ricardo B. Azevedo, Taís Gratieri, Marcílio Cunha-Filho, Guilherme M. GelfusoTopical application of aluminum-chloride phthalocyanine (AlClPc) is a challenge because of the drug's extremely low solubility, which prevents its absorption into deeper skin layers and causes molecule aggregation, reducing the photophysical effect. The goal of this study was to obtain a formulation applied in a certain condition that would allow homogeneous accumulation of AlClPc in cutaneous tissues, meaning a safer and non-invasive topical treatment for skin tumors based on photodynamic therapy. We first prepared and characterized AlClPc complexes with cyclodextrin to increase the photosensitizing agent solubility. The inclusion complex of AlClPc with hydroxypropyl-β-cyclodextrin (HP-βCD) amplified its loading dose in aqueous medium and maintained its photosensitizing properties in terms of reactive oxygen species production. Assays to determine the complex's in vitro cytotoxicity against murine melanoma skin cancer cells showed that when irradiated, the complex significantly reduced cell viability, whereas the absence of irradiation did not affect cell viability. Three physical techniques for permeation enhancement (i.e., tape-stripping abrasion, microneedle pretreatment and iontophoresis) were then evaluated. When applied in impaired skin, the complex could not increase drug penetration. The skin penetration of AlClPc, however, increased 2.3-fold following iontophoresis application in a shorter period compared to passive permeation. Therefore, these results suggest the administration of complexed AlClPc mediated by iontophoresis, followed by application of photodynamic therapy, might be an effective and non-invasive alternative for topical treatment of cutaneous tumors.Graphical abstractUnlabelled Image
       
  • Co amorphous valsartan nifedipine system: Preparation, characterization,
           in vitro and in vivo evaluation
    • Abstract: Publication date: Available online 22 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Anurag Lodagekar, Rahul B. Chavan, M.K. Chaitanya Mannava, Balvant Yadav, Naveen Chella, Ashwini K. Nangia, Nalini R. ShastriCo amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan–nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier transform infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ± 2 °C and 75 ± 5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed due to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.Graphical abstractUnlabelled Image
       
  • Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for
           enhanced liver-cancer targeting therapy
    • Abstract: Publication date: Available online 22 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ying Qu, Feifei Sun, Feng He, Chenggong Yu, Jiahui Lv, Qiuqiong Zhang, Dong Liang, Chen Yu, Jun Wang, Xiangna Zhang, Ana Xu, Jingde WuGraphene oxide (GO) has attracted huge attention in biomedical field in recent years. However, limited attempts have been invested in utilizing GO on active targeted delivery for gene therapy in liver cancer treatments. Glycyrrhetinic acid (GA) has been reported to be widely used as a targeting ligand to functionalize nanomaterials to treat hepatocellular carcinoma. In this article, GA is employed as a liver targeting ligand to construct GA, polyethylene glycol (PEG), polyamidoamine dendrimer (Dendrimer) and nano-graphene oxide (NGO) conjugate (GA-PEG-NGO-Dendrimer, GPND) for siRNA delivery for the first time. As we expected, GPND exhibited excellent stability, low toxicity, negligible hemolytic activity and remarkably high transfection efficiency in vitro. We also found effective VEGFa gene silencing in both mRNA and protein level in HepG2 cells. Notably, siRNA efficiently gathered in liver tumor tissues by the delivery of GPND, and eventually the growth of tumor tissues were inhibited with enhanced targeting capability and no obvious pathological changes. Moreover, histopathological results preliminarily support the high in vivo safety of GPND/anti-VEGFa siRNA nanocomplex. Collectively, GPND/siRNA nanocomplex, with high safety, targeting and transfection as well as prolonged half-life, is a promising nanomedicine and may provide a new direction for highly-specific targeted gene therapy.Graphical abstractUnlabelled Image
       
  • TSPO-targeted NIR-fluorescent ultra-small iron oxide nanoparticles for
           glioblastoma imaging
    • Abstract: Publication date: Available online 15 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Nunzio Denora, Chaedong Lee, Rosa Maria Iacobazzi, Ji Young Choi, In Ho Song, Jung Sun Yoo, Yuanzhe Piao, Antonio Lopalco, Francesco Leonetti, Byung Chul Lee, Sang Eun KimThe translocator protein 18 kDa (TSPO) is mainly located in outer membrane of mitochondria and results highly expressed in a variety of tumor including breast, colon, prostate, ovarian and brain (such as glioblastoma). Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. Although GBM patients had currently available therapies, the median survival is
       
  • Design, synthesis and anticancer evaluation of novel 1,3-benzodioxoles and
           1,4-benzodioxines
    • Abstract: Publication date: Available online 14 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Rasha Mohamed Hassan, Walaa Hamada Abd-Allah, Asmaa Mohamed Salman, Aida Abdel-Sattar El-Azzouny, Mohamed Nabil Aboul-EneinA new set of 1,3-benzodioxoles and 1,4-benzodioxines was designed and synthesized starting from gallic acid as anticancer agents. The antiproliferative effect of the target compounds was evaluated against a panel of cancer cell lines (HepG2, PC-3, MCF-7 and A549) using MTT assay. The 1,4-benzodioxine derivative 11a manifested broad spectrum effect towards the four tested cancer cell lines (IC50 
       
  • Exploration of supersaturable lacidipine ternary amorphous solid
           dispersion for enhanced dissolution and in vivo absorption
    • Abstract: Publication date: Available online 12 August 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Jian Guan, Liwei Jin, Qiaoyu Liu, Huan Xu, Haiyang Wu, Xin Zhang, Shirui MaoAmorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6–7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0–∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.Graphical abstractUnlabelled Image
       
  • Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in
           preclinical and human in vitro models: Implication for the choice of
           toxicology species
    • Abstract: Publication date: Available online 3 April 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Francesca Wood, Sam Shepherd, Angela Hayes, Manjuan Liu, Katia Grira, Yi Mok, Spiros Linardopoulos, Vassilios Bavetsias, Butrus Atrash, Amir Faisal, Julian Blagg, Florence I. RaynaudCCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CLint) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies.Graphical abstractUnlabelled Image
       
 
 
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